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Mitchell NDP, Pierre TGS, Ramm LE, Ramm GA, Olynyk JK. Risk profiling for cirrhosis and hepatocellular carcinoma in HFE hemochromatosis using mobilizable iron stores and alcohol consumption. Sci Rep 2025; 15:16011. [PMID: 40341892 PMCID: PMC12062215 DOI: 10.1038/s41598-025-99672-8] [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] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 04/22/2025] [Indexed: 05/11/2025] Open
Abstract
HFE hemochromatosis (HH) may cause cirrhosis and hepatocellular carcinoma (HCC). Progression to these endpoints depends on the severity of iron overload and cofactors, such as alcohol. We evaluated alcohol and iron-related risk factors in relation to cirrhosis at diagnosis and future development of HCC in a retrospective analysis of 197 HH subjects. The proportion of subjects either with cirrhosis or who developed HCC during follow-up were 29/197 (14.7%) or 10/197 (5.1%), respectively. The median (IQR) follow-up time after diagnosis was 15.2 (4.6 to 22.1) years. The median mobilizable iron stores and daily alcohol consumption (IQR) were 6.0 (3.8-11.0) g and 20 (0-40) g, respectively. An optimal logistic regression model for the odds of cirrhosis was developed by adding candidate liver insult variables (mobilizable iron, alcohol consumption, and age as a surrogate for duration of exposure) in a forward stepwise strategy using area under the receiver operating characteristic curve (AUROC) analysis and the corrected Akaike information criterion. This model demonstrated an AUROC (95% CI) of 0.966 (0.935-0.996), with sensitivity 76 (58-88)% and specificity 97 (93-99) % for prediction of cirrhosis and had a negative predictive value of 99.4 (95% CI 96.7-99.97) % for development of HCC. Thus, future risk of HCC can be assessed from mobilizable iron stores and alcohol consumption of HH subjects.
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Affiliation(s)
| | - Timothy G St Pierre
- School of Physics, Mathematics, and Computing, The University of Western Australia, Perth, WA, Australia
| | - Louise E Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Grant A Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - John K Olynyk
- Department of Gastroenterology, Fiona Stanley Hospital, Murdoch, WA, Australia.
- Curtin Medical School, Curtin University, Kent St., Bentley, WA, 6102, Australia.
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Tang D, Kroemer G, Kang R. Ferroptosis in hepatocellular carcinoma: from bench to bedside. Hepatology 2024; 80:721-739. [PMID: 37013919 PMCID: PMC10551055 DOI: 10.1097/hep.0000000000000390] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 03/21/2023] [Indexed: 04/05/2023]
Abstract
The most widespread type of liver cancer, HCC, is associated with disabled cellular death pathways. Despite therapeutic advancements, resistance to current systemic treatments (including sorafenib) compromises the prognosis of patients with HCC, driving the search for agents that might target novel cell death pathways. Ferroptosis, a form of iron-mediated nonapoptotic cell death, has gained considerable attention as a potential target for cancer therapy, especially in HCC. The role of ferroptosis in HCC is complex and diverse. On one hand, ferroptosis can contribute to the progression of HCC through its involvement in both acute and chronic liver conditions. In contrast, having ferroptosis affect HCC cells might be desirable. This review examines the role of ferroptosis in HCC from cellular, animal, and human perspectives while examining its mechanisms, regulation, biomarkers, and clinical implications.
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Affiliation(s)
- Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus; 94800 Villejuif, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP; 75015 Paris, France
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas 75390, USA
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Olynyk JK, St. Pierre TG, Chen J, Frazer DM, Ramm LE, Ramm GA. Extrahepatic Iron Loading Associates With the Propensity to Develop Advanced Hepatic Fibrosis in Hemochromatosis. GASTRO HEP ADVANCES 2024; 3:454-460. [PMID: 39131712 PMCID: PMC11307999 DOI: 10.1016/j.gastha.2024.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 01/22/2024] [Indexed: 08/13/2024]
Abstract
Background and Aims Hemostatic iron regulator-hemochromatosis can result in progressive iron-loading and advanced hepatic fibrosis in some individuals. We studied total body and hepatic iron loading to determine whether the distribution of iron-loading influences the risk of advanced fibrosis. Methods One hundred thirty-eight men and 66 women with hemochromatosis who underwent liver biopsy for staging of hepatic fibrosis had evaluation of hepatic iron concentration (HIC), hepatic iron index (HIC/age), total body iron stores (mobilizable iron), and mobilizable iron/HIC ratio (a marker of total body iron relative to hepatic iron). The potential impact of liver volume on mobilizable iron stores was assessed using magnetic resonance imaging in a separate cohort of 19 newly diagnosed individuals with hemochromatosis. Results Of 204 biopsied subjects, 41 had advanced fibrosis and exhibited 60% greater accumulation of mobilizable iron relative to HIC (mean 0.070 ± 0.008 g Fe/[μmol Fe/g]) compared with 163 subjects with low-grade fibrosis (mean 0.044 ± 0.002 g Fe/[μmol Fe/g], P < .0001). Linear regression modeling confirmed a discrete advanced hepatic fibrosis phenotype associated with greater mobilizable iron stores relative to HIC. The ratios of the upper to lower 95% limits of the distributions of liver volumes and the mobilizable iron/HIC ratios were 2.7 (95% confidence interval 2.3-3.0) and 9.7 (95% confidence interval 8.0-11.7), respectively, indicating that the distribution of liver volumes is not sufficiently wide to explain the variability in mobilizable iron/HIC ratios, suggesting that significant extrahepatic iron loading is present in those with advanced hepatic fibrosis. Conclusion Advanced hepatic fibrosis develops in hemostatic iron regulator-hemochromatosis individuals who also have excessive extrahepatic mobilizable iron stores.
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Affiliation(s)
- John K. Olynyk
- Curtin Medical School, Curtin University, Bentley, Western Australia, Australia
- Department of Gastroenterology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
| | - Timothy G. St. Pierre
- School of Physics, Mathematics, and Computing, University of Western Australia, Crawley, Western Australia, Australia
| | - James Chen
- Department of Gastroenterology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
| | - David M. Frazer
- Molecular Nutrition Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- School of Biomedical Sciences, Queensland University of Technology, Gardens Point, Queensland, Australia
- School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia
| | - Louise E. Ramm
- Molecular Nutrition Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Grant A. Ramm
- Molecular Nutrition Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia
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Abo-Elghiet F, Mohamed SA, Yasin NAE, Temraz A, El-Tantawy WH, Ahmed SF. The effect of Alnus incana (L.) Moench extracts in ameliorating iron overload-induced hepatotoxicity in male albino rats. Sci Rep 2023; 13:7635. [PMID: 37169909 PMCID: PMC10175300 DOI: 10.1038/s41598-023-34480-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 05/02/2023] [Indexed: 05/13/2023] Open
Abstract
Iron overload causes multiorgan dysfunction and serious damage. Alnus incana from the family Betulaceae, widely distributed in North America, is used for treating diseases. In this study, we investigated the iron chelating, antioxidant, anti-inflammatory, and antiapoptotic activities of the total and butanol extract from Alnus incana in iron-overloaded rats and identified the bioactive components in both extracts using liquid chromatography-mass spectrometry. We induced iron overload in the rats via six intramuscular injections of 12.5 mg iron dextran/100 g body weight for 30 days. The rats were then administered 60 mg ferrous sulfate /kg body weight once daily using a gastric tube. The total and butanol extracts were given orally, and the reference drug (deferoxamine) was administered subcutaneously for another month. After two months, we evaluated the biochemical, histopathological, histochemical, and immunohistochemical parameters. Iron overload significantly increased the serum iron level, liver biomarker activities, hepatic iron content, malondialdehyde, tumor necrosis factor-alpha, and caspase-3 levels. It also substantially (P < 0.05) reduced serum albumin, total protein, and total bilirubin content, and hepatic reduced glutathione levels. It caused severe histopathological alterations compared to the control rats, which were markedly (P < 0.05) ameliorated after treatment. The total extract exhibited significantly higher anti-inflammatory and antiapoptotic activities but lower antioxidant and iron-chelating activities than the butanol extract. Several polyphenolic compounds, including flavonoids and phenolic acids, were detected by ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) analysis. Our findings suggest that both extracts might alleviate iron overload-induced hepatoxicity and other pathological conditions characterized by hepatic iron overload, including thalassemia and sickle-cell anemia.
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Affiliation(s)
- Fatma Abo-Elghiet
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy for Girls, Al Azhar University, Cairo, Egypt
| | - Shaza A Mohamed
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy for Girls, Al Azhar University, Cairo, Egypt
| | - Noha A E Yasin
- Cytology and Histology Department, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
| | - Abeer Temraz
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy for Girls, Al Azhar University, Cairo, Egypt
| | | | - Samah Fathy Ahmed
- National Organization for Drug Control and Research, Dokki, Cairo, Egypt
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Crawford DHG, Ramm GA, Bridle KR, Nicoll AJ, Delatycki MB, Olynyk JK. Clinical practice guidelines on hemochromatosis: Asian Pacific Association for the Study of the Liver. Hepatol Int 2023; 17:522-541. [PMID: 37067673 DOI: 10.1007/s12072-023-10510-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 02/28/2023] [Indexed: 04/18/2023]
Affiliation(s)
- Darrell H G Crawford
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Gallipoli Medical Research Foundation, Brisbane, Australia
| | - Grant A Ramm
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Kim R Bridle
- Faculty of Medicine, The University of Queensland, Brisbane, Australia.
- Gallipoli Medical Research Foundation, Brisbane, Australia.
| | - Amanda J Nicoll
- Department of Gastroenterology, Eastern Health, Box Hill, VIC, Australia
- Monash University, Melbourne, VIC, Australia
| | - Martin B Delatycki
- Bruce Lefroy Centre, Murdoch Children's Research Institute, Melbourne, VIC, Australia
- The University of Melbourne, Melbourne, VIC, Australia
- Victorian Clinical Genetics Services, Parkville, VIC, Australia
| | - John K Olynyk
- Department of Gastroenterology, Fiona Stanley Hospital, Murdoch, WA, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
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Affiliation(s)
- John K Olynyk
- From the Department of Gastroenterology and Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, and the School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA (J.K.O.); and the Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, QLD (G.A.R.) - all in Australia
| | - Grant A Ramm
- From the Department of Gastroenterology and Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, and the School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA (J.K.O.); and the Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, QLD (G.A.R.) - all in Australia
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Ma Y, Jang H, Jerban S, Chang EY, Chung CB, Bydder GM, Du J. Making the invisible visible-ultrashort echo time magnetic resonance imaging: Technical developments and applications. APPLIED PHYSICS REVIEWS 2022; 9:041303. [PMID: 36467869 PMCID: PMC9677812 DOI: 10.1063/5.0086459] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 09/12/2022] [Indexed: 05/25/2023]
Abstract
Magnetic resonance imaging (MRI) uses a large magnetic field and radio waves to generate images of tissues in the body. Conventional MRI techniques have been developed to image and quantify tissues and fluids with long transverse relaxation times (T2s), such as muscle, cartilage, liver, white matter, gray matter, spinal cord, and cerebrospinal fluid. However, the body also contains many tissues and tissue components such as the osteochondral junction, menisci, ligaments, tendons, bone, lung parenchyma, and myelin, which have short or ultrashort T2s. After radio frequency excitation, their transverse magnetizations typically decay to zero or near zero before the receiving mode is enabled for spatial encoding with conventional MR imaging. As a result, these tissues appear dark, and their MR properties are inaccessible. However, when ultrashort echo times (UTEs) are used, signals can be detected from these tissues before they decay to zero. This review summarizes recent technical developments in UTE MRI of tissues with short and ultrashort T2 relaxation times. A series of UTE MRI techniques for high-resolution morphological and quantitative imaging of these short-T2 tissues are discussed. Applications of UTE imaging in the musculoskeletal, nervous, respiratory, gastrointestinal, and cardiovascular systems of the body are included.
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Affiliation(s)
- Yajun Ma
- Department of Radiology, University of California, San Diego, California 92037, USA
| | - Hyungseok Jang
- Department of Radiology, University of California, San Diego, California 92037, USA
| | - Saeed Jerban
- Department of Radiology, University of California, San Diego, California 92037, USA
| | | | | | - Graeme M Bydder
- Department of Radiology, University of California, San Diego, California 92037, USA
| | - Jiang Du
- Author to whom correspondence should be addressed:. Tel.: (858) 246-2248, Fax: (858) 246-2221
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Andersson L, Powell LW, Ramm LE, Ramm GA, Olynyk JK. Arthritis Prediction of Advanced Hepatic Fibrosis in HFE Hemochromatosis. Mayo Clin Proc 2022; 97:1649-1655. [PMID: 35422339 DOI: 10.1016/j.mayocp.2022.02.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 01/23/2022] [Accepted: 02/14/2022] [Indexed: 11/21/2022]
Abstract
OBJECTIVE To evaluate whether arthritis predicts the likelihood of advanced hepatic fibrosis in HFE hemochromatosis. PATIENTS AND METHODS We conducted a retrospective, cross-sectional analysis of 112 well-characterized patients with HFE hemochromatosis and liver biopsy-validated fibrosis staging recruited between January 1, 1983, and December 31, 2013. Complete clinical, biochemical, hematologic, and noninvasive serum biochemical indices (aspartate aminotransferase to platelet ratio index [APRI] and fibrosis 4 index [FIB4]) were available. Scheuer fibrosis stages 3 and 4, APRI greater than 0.44, or FIB4 greater than 1.1 were used to define advanced hepatic fibrosis. Comparisons between groups were performed using categorical analysis, unpaired or paired t test. RESULTS Male (n=76) and female (n=36) patients were similar in age. Nineteen patients had advanced hepatic fibrosis, and 47 had hemochromatosis arthritis. Arthritis was significantly associated with the presence of advanced hepatic fibrosis as determined by liver biopsy (sensitivity, 84%, [95% CI, 62% to 95%]; negative predictive value, 95% [95% CI, 87% to 99%]; relative risk, 7.4 [95% CI, 2.5 to 23]; P<.001), APRI (sensitivity, 75% [95% CI, 55% to 88%]; negative predictive value, 91% [95% CI, 81% to 96%]; relative risk, 4.5 [95% CI, 2.0 to 10.2]; P<.001), or FIB4 (sensitivity, 61% [95% CI, 41% to 78%]; negative predictive value, 67% [95% CI, 68% to 90%]; relative risk, 2.2 [95% CI, 1.1 to 4.6]; P=.03). Mean cell volume values were significantly higher pretreatment in patients with F3-4 fibrosis (96.7±1.1 fL) compared with F0-2 fibrosis (93.4±0.5 fL; P=.004) and declined following treatment (F3-4, 93.2±0.9 fL, P=.01; F0-2, 91.7±0.6 fL, P=.01). CONCLUSION Advanced hepatic fibrosis is strongly associated with arthritis in HFE hemochromatosis. The absence of arthritis predicts a low likelihood of advanced hepatic fibrosis, supporting its use as a clinical marker for advanced hepatic fibrosis in HFE hemochromatosis.
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Affiliation(s)
- Lauren Andersson
- Department of Gastroenterology and Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, Western Australia, Australia
| | - Lawrie W Powell
- Faculty of Medicine, The University of Queensland, Herston, Brisbane, Queensland, Australia
| | - Louise E Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Grant A Ramm
- Faculty of Medicine, The University of Queensland, Herston, Brisbane, Queensland, Australia; Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - John K Olynyk
- Department of Gastroenterology and Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, Western Australia, Australia; School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.
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Role of Iron in Aging Related Diseases. Antioxidants (Basel) 2022; 11:antiox11050865. [PMID: 35624729 PMCID: PMC9137504 DOI: 10.3390/antiox11050865] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/17/2022] [Accepted: 04/25/2022] [Indexed: 02/05/2023] Open
Abstract
Iron progressively accumulates with age and can be further exacerbated by dietary iron intake, genetic factors, and repeated blood transfusions. While iron plays a vital role in various physiological processes within the human body, its accumulation contributes to cellular aging in several species. In its free form, iron can initiate the formation of free radicals at a cellular level and contribute to systemic disorders. This is most evident in high iron conditions such as hereditary hemochromatosis, when accumulation of iron contributes to the development of arthritis, cirrhosis, or cardiomyopathy. A growing body of research has further identified iron’s contributory effects in neurodegenerative diseases, ocular disorders, cancer, diabetes, endocrine dysfunction, and cardiovascular diseases. Reducing iron levels by repeated phlebotomy, iron chelation, and dietary restriction are the common therapeutic considerations to prevent iron toxicity. Chelators such as deferoxamine, deferiprone, and deferasirox have become the standard of care in managing iron overload conditions with other potential applications in cancer and cardiotoxicity. In certain animal models, drugs with iron chelating ability have been found to promote health and even extend lifespan. As we further explore the role of iron in the aging process, iron chelators will likely play an increasingly important role in our health.
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Chin J, Powell LW, Ramm LE, Hartel GF, Olynyk JK, Ramm GA. Utility of Serum Biomarker Indices for Staging of Hepatic Fibrosis Before and After Venesection in Patients With Hemochromatosis Caused by Variants in HFE. Clin Gastroenterol Hepatol 2021; 19:1459-1468.e5. [PMID: 32745684 DOI: 10.1016/j.cgh.2020.07.052] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/26/2020] [Accepted: 07/27/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Hemochromatosis that is associated with variants in the homeostatic iron regulator gene (HFE) is characterized by intestinal absorption of iron and excessive body and hepatic iron stores; it can lead to hepatic fibrosis and cirrhosis. Fibrosis has been staged by analysis of liver biopsies, but non-invasive staging methods are available. We evaluated the ability of aspartate aminotransferase:platelet ratio index (APRI), the fibrosis-4 (FIB-4) index, and gamma-glutamyl transferase:platelet ratio (GPR) to assess hepatic fibrosis staging in subjects with HFE-associated hemochromatosis, using liver biopsy-staged fibrosis as the reference standard. METHODS We performed a retrospective, cross-sectional analysis of 181 subjects with HFE-associated hemochromatosis and hepatic fibrosis staged by biopsy analysis and available serum samples. We calculated APRI, FIB-4, and GPR at diagnosis for all 181 subjects and following venesection therapy in 64 of these subjects (7 subjects had follow-up biopsy analysis). We used area under the receiver operating characteristic curve (AUROC) analysis to assess the relationships between APRI score, FIB-4 score, and GPR and advanced (F3-F4) fibrosis and to select cut-off values. RESULTS Hepatic fibrosis stage correlated with APRI score (r = 0.54; P < .0001), FIB-4 score (r = 0.35; P < .0001), and GPR (r = 0.36, P < .0001). An APRI score above 0.44 identified patients with advanced fibrosis with an AUROC of 0.88, 79.4% sensitivity, 79.4% specificity, and 81% accuracy. A FIB-4 score above 1.1 identified patients with advanced fibrosis with an AUROC of 0.86, 80% sensitivity, 80.3% specificity, and 81% accuracy. A GPR above 0.27 identified patients with advanced fibrosis with an AUROC of 0.76, 67.7% sensitivity, 70.3% specificity, and 69% accuracy. APRI score was significantly more accurate than GPR (P = .05) in detecting advanced fibrosis; there was no difference between APRI and FIB-4. Venesection treatment was associated with significant reductions in APRI (P < .0001) and GPR (P < .001), paralleling fibrosis regression observed in available liver biopsies. Post-venesection APRI identified 87% of subjects with advanced fibrosis that decreased to levels that indicate stage F1-F2 fibrosis. CONCLUSIONS In a retrospective study of 181 subjects with HFE-associated hemochromatosis, we found that APRI and FIB-4 scores identified patients with advanced hepatic fibrosis with 81% accuracy. APRI scores might also be used to monitor fibrosis regression following venesection.
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Affiliation(s)
- Justin Chin
- Department of Gastroenterology & Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, Western Australia, Australia
| | - Lawrie W Powell
- Faculty of Medicine, University of Queensland, Herston, Brisbane, Queensland, Australia
| | - Louise E Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Gunter F Hartel
- Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - John K Olynyk
- Department of Gastroenterology & Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, Western Australia, Australia; School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia
| | - Grant A Ramm
- Faculty of Medicine, University of Queensland, Herston, Brisbane, Queensland, Australia; Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
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Anderson GJ, Bardou-Jacquet E. Revisiting hemochromatosis: genetic vs. phenotypic manifestations. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:731. [PMID: 33987429 PMCID: PMC8106074 DOI: 10.21037/atm-20-5512] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Iron overload disorders represent an important class of human diseases. Of the primary iron overload conditions, by far the most common and best studied is HFE-related hemochromatosis, which results from homozygosity for a mutation leading to the C282Y substitution in the HFE protein. This disease is characterized by reduced expression of the iron-regulatory hormone hepcidin, leading to increased dietary iron absorption and iron deposition in multiple tissues including the liver, pancreas, joints, heart and pituitary. The phenotype of HFE-related hemochromatosis is quite variable, with some individuals showing little or no evidence of increased body iron, yet others showing severe iron loading, tissue damage and clinical sequelae. The majority of genetically predisposed individuals show at least some evidence of iron loading (increased transferrin saturation and serum ferritin), but a minority show clinical symptoms and severe consequences are rare. Thus, the disorder has a high biochemical penetrance, but a low clinical prevalence. Nevertheless, it is such a common condition in Caucasian populations (1:100–200) that it remains an important clinical entity. The phenotypic variability can largely be explained by a range of environmental, genetic and physiological factors. Men are far more likely to manifest significant disease than women, with the latter losing iron through menstrual blood loss and childbirth. Other forms of blood loss, immune system influences, the amount of bioavailable iron in the diet and lifestyle factors such as high alcohol intake can also contribute to iron loading and disease expression. Polymorphisms in a range of genes have been linked to variations in body iron levels, both in the general population and in hemochromatosis. Some of the genes identified play well known roles in iron homeostasis, yet others are novel. Other factors, including both co-morbidities and genetic polymorphisms, do not affect iron levels per se, but determine the propensity for tissue pathology.
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Affiliation(s)
- Gregory J Anderson
- Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute and School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
| | - Edouard Bardou-Jacquet
- Liver Disease Department, University of Rennes and French Reference Center for Hemochromatosis and Iron Metabolism Disease, Rennes, France
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Mansi K, Tabaza Y, Aburjai T. The iron chelating activity of Gundelia tournefortii in iron overloaded experimental rats. JOURNAL OF ETHNOPHARMACOLOGY 2020; 263:113114. [PMID: 32736049 DOI: 10.1016/j.jep.2020.113114] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 06/08/2020] [Accepted: 06/16/2020] [Indexed: 05/26/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Gundelia tournefortii is a member of the Asteraceae (Compositae) family which is widely consumed as edible plant in the Eastern Mediterranean. In folkloric medicine, it is used for the treatment of various diseases and conditions, including pain, liver diseases, kidney stones and inflammations. AIM OF THE STUDY Recently, many commoners use this plant as adjuvant therapy for treating symptoms associated with liver diseases and thalassemia. Thus, the present study was conducted to evaluate, biochemically, the iron chelating activity of G. tournefortii methanolic extract in iron overloaded rats. MATERIALS AND METHODS Fifty Wister male rats were divided into five groups: one group was a healthy control, while iron overload was induced in the other four groups by 100 mg/kg iron-dextran. Of these, one group was left untreated as a control, while the other three groups were treated with 50 mg/kg deferoxamine, 100 mg/kg and 200 mg/kg of G. tournefortii methanolic extract, respectively. The total flavonoid and phenolic contents of the methanolic extract were estimated. The biochemical assessment was performed by measuring blood levels of iron, ferritin, liver biomarkers (ALT, ALP and AST), cardiac biomarkers (CPK and LDH) and lipid profile. RESULTS Not only the blood levels of iron, ferritin, liver biomarkers and cardiac biomarkers were reduced significantly by G. tournefortii methanolic extract, but also the lipid profile was improved. This clearly supports the chelating activity of G. tournefortii and its hepatoprotective and cardioprotective effects in iron overloaded rats. CONCLUSIONS This highlights the value of medicinal plants as alternative therapies for iron overload conditions such as thalassemia.
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Affiliation(s)
- Kamal Mansi
- Department of Medical Laboratory Science, Faculty of Science, Al Al-Bayt University, P.O. Box 130040, Mafraq, 25113, Jordan.
| | - Yahia Tabaza
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, 11942, Jordan.
| | - Talal Aburjai
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, 11942, Jordan.
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Pinto VM, Forni GL. Management of Iron Overload in Beta-Thalassemia Patients: Clinical Practice Update Based on Case Series. Int J Mol Sci 2020; 21:E8771. [PMID: 33233561 PMCID: PMC7699680 DOI: 10.3390/ijms21228771] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/14/2020] [Accepted: 11/18/2020] [Indexed: 12/29/2022] Open
Abstract
Thalassemia syndromes are characterized by the inability to produce normal hemoglobin. Ineffective erythropoiesis and red cell transfusions are sources of excess iron that the human organism is unable to remove. Iron that is not saturated by transferrin is a toxic agent that, in transfusion-dependent patients, leads to death from iron-induced cardiomyopathy in the second decade of life. The availability of effective iron chelators, advances in the understanding of the mechanism of iron toxicity and overloading, and the availability of noninvasive methods to monitor iron loading and unloading in the liver, heart, and pancreas have all significantly increased the survival of patients with thalassemia. Prolonged exposure to iron toxicity is involved in the development of endocrinopathy, osteoporosis, cirrhosis, renal failure, and malignant transformation. Now that survival has been dramatically improved, the challenge of iron chelation therapy is to prevent complications. The time has come to consider that the primary goal of chelation therapy is to avoid 24-h exposure to toxic iron and maintain body iron levels within the normal range, avoiding possible chelation-related damage. It is very important to minimize irreversible organ damage to prevent malignant transformation before complications set in and make patients ineligible for current and future curative therapies. In this clinical case-based review, we highlight particular aspects of the management of iron overload in patients with beta-thalassemia syndromes, focusing on our own experience in treating such patients. We review the pathophysiology of iron overload and the different ways to assess, quantify, and monitor it. We also discuss chelation strategies that can be used with currently available chelators, balancing the need to keep non-transferrin-bound iron levels to a minimum (zero) 24 h a day, 7 days a week and the risk of over-chelation.
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Affiliation(s)
- Valeria Maria Pinto
- Centro della Microcitemia e delle Anemie Congenite Ente Ospedaliero Ospedali Galliera, Via Volta 6, 16128 Genoa, Italy;
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Chan LKL, Mak VWM, Chan SCH, Yu ELM, Chan NCN, Leung KFS, Ng CKM, Ng MHL, Chan JCW, Lee HKK. Liver complications of haemoglobin H disease in adults. Br J Haematol 2020; 192:171-178. [PMID: 33095929 DOI: 10.1111/bjh.17115] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/27/2020] [Indexed: 12/15/2022]
Abstract
Haemoglobin H (HbH) disease is a type of non-transfusion-dependent thalassaemia. This cross-sectional study aimed at determining the prevalence and severity of liver iron overload and liver fibrosis in patients with HbH disease. Risk factors for advanced liver fibrosis were also identified. A total of 80 patients were evaluated [median (range) age 53 (24-79) years, male 34%, non-deletional HbH disease 24%]. Patients underwent 'observed' T2-weighted magnetic resonance imaging examination for liver iron concentration (LIC) quantification, and transient elastography for liver stiffness measurement (LSM) and fibrosis staging. In all, 25 patients (31%) had moderate-to-severe liver iron overload (LIC ≥7 mg/g dry weight). The median LIC was higher in non-deletional than in deletional HbH disease (7·8 vs. 2.9 mg/g dry weight, P = 0·002). In all, 16 patients (20%) had advanced liver fibrosis (LSM >7.9 kPa) and seven (9%) out of them had probable cirrhosis (LSM >11.9 kPa). LSM positively correlated with age (R = 0·24, P = 0·03), serum ferritin (R = 0·36, P = 0·001) and LIC (R = 0·28, P = 0·01). In multivariable regression, age ≥65 years [odds ratio (OR) 4·97, 95% confidence interval (CI) 1·52-17·50; P = 0·047] and moderate-to-severe liver iron overload (OR 3·47, 95% CI 1·01-12·14; P = 0·01) were independently associated with advanced liver fibrosis. The findings suggest that regular screening for liver complications should be considered in the management of HbH disease.
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Affiliation(s)
- Luke K L Chan
- Division of Haematology, Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong, China
| | - Vivien W M Mak
- Division of Haematology, Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong, China
| | - Stanley C H Chan
- Department of Radiology, Princess Margaret Hospital, Hong Kong, China
| | - Ellen L M Yu
- Clinical Research Centre, Princess Margaret Hospital, Hong Kong, China
| | - Nelson C N Chan
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Kate F S Leung
- Division of Haematology, Department of Pathology, Princess Margaret Hospital, Hong Kong, China
| | - Carmen K M Ng
- Division of Gastroenterology and Hepatology, Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong, China
| | - Margaret H L Ng
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Joyce C W Chan
- Division of Haematology, Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong, China
| | - Harold K K Lee
- Division of Haematology, Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong, China
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15
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Kim HY, Kwon WY, Park JB, Lee MH, Oh YJ, Suh S, Baek YH, Jeong JS, Yoo YH. Hepatic STAMP2 mediates recombinant FGF21-induced improvement of hepatic iron overload in nonalcoholic fatty liver disease. FASEB J 2020; 34:12354-12366. [PMID: 32721044 DOI: 10.1096/fj.202000790r] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/23/2020] [Accepted: 07/01/2020] [Indexed: 12/14/2022]
Abstract
Although previous studies have shown that the administration of fibroblast growth factor 21 (FGF21) reverses hepatic steatosis, the mechanism by which FGF21 exerts a therapeutic effect on nonalcoholic fatty liver disease (NAFLD) is not yet entirely understood. We previously demonstrated that hepatic six transmembrane protein of prostate 2 (STAMP2) may represent a suitable target for NAFLD. We investigated the mechanism underlying the therapeutic effect of recombinant FGF21 on NAFLD, focusing on the involvement of hepatic STAMP2. In this study, we used human nonalcoholic steatosis patient pathology samples, C57BL/6 mice for a high-fat diet (HFD)-induced in vivo NAFLD model, and used human primary hepatocytes and HepG2 cells for oleic acid (OA)-induced in vitro NAFLD model. We observed that recombinant FGF21 treatment ameliorated hepatic steatosis and insulin resistance through the upregulation of STAMP2 expression. We further observed hepatic iron overload (HIO) and reduced iron exporter, ferroportin expression in the liver samples obtained from human NAFLD patients, and HFD-induced NAFLD mice and in OA-treated HepG2 cells. Importantly, recombinant FGF21 improved HIO through the hepatic STAMP2-mediated upregulation of ferroportin expression. Our data suggest that hepatic STAMP2 may represent a suitable therapeutic intervention target for FGF21-induced improvement of NAFLD accompanying HIO.
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Affiliation(s)
- Hye Young Kim
- Department of Anatomy and Cell Biology, Dong-A University College of Medicine, Busan, South Korea
| | - Woo Young Kwon
- Department of Anatomy and Cell Biology, Dong-A University College of Medicine, Busan, South Korea
| | - Joon Beom Park
- Department of Anatomy and Cell Biology, Dong-A University College of Medicine, Busan, South Korea
| | - Mi Hwa Lee
- Department of Anatomy and Cell Biology, Dong-A University College of Medicine, Busan, South Korea
| | - Yoo Jin Oh
- Department of Anatomy and Cell Biology, Dong-A University College of Medicine, Busan, South Korea
| | - SungHwan Suh
- Department of Endocrinology, Dong-A University College of Medicine, Busan, South Korea
| | - Yang Hyun Baek
- Department of Gastroenterology, Dong-A University College of Medicine, Busan, South Korea
| | - Jin Sook Jeong
- Department of Pathology, Dong-A University College of Medicine, Busan, South Korea
| | - Young Hyun Yoo
- Department of Anatomy and Cell Biology, Dong-A University College of Medicine, Busan, South Korea
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Chin J, Powell LW, Ramm LE, Ayonrinde OT, Ramm GA, Olynyk JK. Utility of hepatic or total body iron burden in the assessment of advanced hepatic fibrosis in HFE hemochromatosis. Sci Rep 2019; 9:20234. [PMID: 31882912 PMCID: PMC6934689 DOI: 10.1038/s41598-019-56732-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 12/03/2019] [Indexed: 01/02/2023] Open
Abstract
Development of advanced hepatic fibrosis in HFE Hemochromatosis (HH) is influenced by hepatic iron concentration (HIC) and age. In patients with HH, it is important to assess the likelihood of cirrhosis and thus the need for confirmatory liver biopsy. Therapeutic phlebotomy also provides an estimate of mobilisable iron stores. We determined whether mobilisable iron stores may predict the presence of advanced fibrosis. Retrospective analysis of 137 male and 65 female HH subjects was undertaken. Biochemical, histological and phlebotomy data were available on all subjects. The mean values of HIC, HIC × [age], mobilisable iron, mobilisable iron × [age] and serum ferritin in the cohort were higher in the group with advanced fibrosis. HIC had an optimum sensitivity and specificity of 73% for the diagnosis of advanced liver fibrosis, with a cut-off HIC level of 200 µmol/g (AUROC 0.83, p < 0.0001). AUROC for HIC was greater in females (0.93) than males (0.79). Mobilisable iron had an optimum sensitivity and specificity both of 83% at a cut-off of 9.6 g for the prediction of advanced fibrosis in all subjects (AUROC 0.92, p < 0.0001). Mobilisable iron stores provide a simple, clinically useful indication of the risk of advanced fibrosis and should routinely be considered.
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Affiliation(s)
- Justin Chin
- Department of Gastroenterology & Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, Western Australia, Australia.
| | - Lawrie W Powell
- Faculty of Medicine, The University of Queensland, Herston, Brisbane, Queensland, Australia
| | - Louise E Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Oyekoya T Ayonrinde
- Department of Gastroenterology & Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, Western Australia, Australia
| | - Grant A Ramm
- Faculty of Medicine, The University of Queensland, Herston, Brisbane, Queensland, Australia
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - John K Olynyk
- Department of Gastroenterology & Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, Western Australia, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia
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17
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Abe N, Tsuchida T, Yasuda SI, Oka K. Dietary iron restriction leads to a reduction in hepatic fibrosis in a rat model of non-alcoholic steatohepatitis. Biol Open 2019; 8:bio.040519. [PMID: 31097447 PMCID: PMC6550076 DOI: 10.1242/bio.040519] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Iron overload in the liver causes oxidative stress and inflammation, which result in organ dysfunction, making it a risk factor for non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. We aimed to evaluate the effect of dietary iron restriction on disease progression in rats fed a choline-deficient L-amino acid-defined (CDAA) diet. Male F344 rats were fed a choline-sufficient amino acid-defined (control) diet, a CDAA diet or an iron-restricted CDAA diet for 4, 8 and 12 weeks. At each time point, hepatic iron levels, oxidative stress, inflammation and fibrosis were evaluated by immunohistochemistry. The iron-restricted CDAA diet significantly decreased serum iron levels for 12 weeks compared with the CDAA diet. Histological analysis confirmed that feeding with the CDAA diet induced hepatic iron overload and that this was associated with oxidative stress (number of 8-hydroxydeoxyguanosine-positive cells), inflammation (CD68 positive area) and fibrosis (Sirius Red positive area). Iron restriction with the CDAA diet significantly led to a reduction in the hepatic iron levels, oxidative stress, inflammation and fibrosis. Therefore, dietary iron restriction could be a useful therapeutic approach for NASH patients with hepatic iron overload. Summary: We reveal that dietary iron restriction leads to a reduction in hepatic inflammation, oxidative stress and fibrosis in rats fed a choline-deficient L-amino acid-defined (CDAA) diet.
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Affiliation(s)
- Naomichi Abe
- Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan
| | - Takuma Tsuchida
- Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan
| | - Shin-Ichiro Yasuda
- Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan
| | - Kozo Oka
- Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan
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18
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Gabr SA, Gabr NS, Elsaed WM. Protective Activity of Taurine and Molecular Fibrogenesis in Iron Overloaded Hepatic Tissues. INT J PHARMACOL 2019. [DOI: 10.3923/ijp.2019.418.427] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Abstract
Thalassemia syndromes are among the most serious and common genetic conditions. They are indigenous in a wide but specific geographical area. However, through migration they are spreading across regions not previously affected. Thalassemias are caused by mutations in the α (HBA1/HBA2) and β globin (HBB) genes and are usually inherited in an autosomal recessive manner. The corresponding proteins form the adult hemoglobin molecule (HbA) which is a heterotetramer of two α and two β globin chains. Thalassemia-causing mutations lead to an imbalanced globin chain production and consecutively to impaired erythropoiesis. The severity of the disease is largely determined by the degree of chain imbalance. In the worst case, survival is dependent on regular blood transfusions, which in turn cause transfusional iron overload and secondary multi-organ damage due to iron toxicity. A vigorous monitoring and treatment regime is required, even for the milder syndromes. Thalassemias are a major public health issue in many populations which many health authorities fail to address. Even though comprehensive care has resulted in long-term survival and good quality of life, poor access to essential components of management results in complications which increase the cost of treatment and lead to poor outcomes. These requirements are not recognized by measures such as the Global Burden of Disease project, which ranks thalassemia very low in terms of disability-adjusted life years (DALYs), and fails to consider that it ranks highly in the one to four-year-old age group, making it an important contributor to under-5 mortality. Thalassemia does not fulfil the criteria to be accepted as a target disease for neonatal screening. Nevertheless, depending on the screening methodology, severe cases of thalassemia will be detected in most neonatal screening programs for sickle cell disease. This is very valuable because: (1) it helps to prepare the affected families for having a sick child and (2) it is an important measure of secondary prevention.
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Affiliation(s)
| | - Stephan Lobitz
- Department of Pediatric Oncology/Hematology, Kinderkrankenhaus Amsterdamer Straße, 50735 Cologne, Germany
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20
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Simchick G, Liu Z, Nagy T, Xiong M, Zhao Q. Assessment of MR-based R2* and quantitative susceptibility mapping for the quantification of liver iron concentration in a mouse model at 7T. Magn Reson Med 2018; 80:2081-2093. [PMID: 29575047 PMCID: PMC6107404 DOI: 10.1002/mrm.27173] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 02/15/2018] [Accepted: 02/15/2018] [Indexed: 01/19/2023]
Abstract
PURPOSE To assess the feasibility of quantifying liver iron concentration (LIC) using R2* and quantitative susceptibility mapping (QSM) at a high field strength of 7 Tesla (T). METHODS Five different concentrations of Fe-dextran were injected into 12 mice to produce various degrees of liver iron overload. After mice were sacrificed, blood and liver samples were harvested. Ferritin enzyme-linked immunosorbent assay (ELISA) and inductively coupled plasma mass spectrometry were performed to quantify serum ferritin concentration and LIC. Multiecho gradient echo MRI was conducted to estimate R2* and the magnetic susceptibility of each liver sample through complex nonlinear least squares fitting and a morphology enabled dipole inversion method, respectively. RESULTS Average estimates of serum ferritin concentration, LIC, R2*, and susceptibility all show good linear correlations with injected Fe-dextran concentration; however, the standard deviations in the estimates of R2* and susceptibility increase with injected Fe-dextran concentration. Both R2* and susceptibility measurements also show good linear correlations with LIC (R2 = 0.78 and R2 = 0.91, respectively), and a susceptibility-to-LIC conversion factor of 0.829 ppm/(mg/g wet) is derived. CONCLUSION The feasibility of quantifying LIC using MR-based R2* and QSM at a high field strength of 7T is demonstrated. Susceptibility quantification, which is an intrinsic property of tissues and benefits from being field-strength independent, is more robust than R2* quantification in this ex vivo study. A susceptibility-to-LIC conversion factor is presented that agrees relatively well with previously published QSM derived results obtained at 1.5T and 3T.
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Affiliation(s)
- Gregory Simchick
- Physics and Astronomy, University of Georgia, Athens, GA, United States
- Bio-Imaging Research Center, University of Georgia, Athens, GA, United States
| | - Zhi Liu
- Pharmaceutical & Biomedical Sciences, University of Georgia, Athens, GA United States
| | - Tamas Nagy
- Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA United States
| | - May Xiong
- Pharmaceutical & Biomedical Sciences, University of Georgia, Athens, GA United States
| | - Qun Zhao
- Physics and Astronomy, University of Georgia, Athens, GA, United States
- Bio-Imaging Research Center, University of Georgia, Athens, GA, United States
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21
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Tipirneni-Sajja A, Loeffler RB, Krafft AJ, Sajewski AN, Ogg RJ, Hankins JS, Hillenbrand CM. Ultrashort echo time imaging for quantification of hepatic iron overload: Comparison of acquisition and fitting methods via simulations, phantoms, and in vivo data. J Magn Reson Imaging 2018; 49:1475-1488. [PMID: 30358001 DOI: 10.1002/jmri.26325] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 08/13/2018] [Accepted: 08/13/2018] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Current R2*-MRI techniques for measuring hepatic iron content (HIC) use various acquisition types and fitting models. PURPOSE To evaluate the accuracy and precision of R2*-HIC acquisition and fitting methods. STUDY TYPE Signal simulations, phantom study, and prospective in vivo cohort. POPULATION In all, 132 patients (58/74 male/female, mean age 17.7 years). FIELD STRENGTH/SEQUENCE 2D-multiecho gradient-echo (GRE) and ultrashort echo time (UTE) acquisitions at 1.5T. ASSESSMENT Synthetic MR signals were created to mimic published GRE and UTE methods, using different R2* values (25-2000 s-1 ) and signal-to-noise ratios (SNR). Phantoms with varying iron concentrations were scanned at 1.5T. In vivo data were analyzed from 132 patients acquired at 1.5T. R2* was estimated by fitting using three signal models. Accuracy and precision of R2* measurements for UTE acquisition parameters (SNR, echo spacing [ΔTE], maximum echo time [TEmax ]) and fitting methods were compared for simulated, phantom, and in vivo datasets. STATISTICAL TESTS R2* accuracy was determined from the relative error and by linear regression analysis. Precision was evaluated using coefficient of variation (CoV) analysis. RESULTS In simulations, all models had high R2* accuracy (error <5%) and precision (CoV <10%) for all SNRs, shorter ΔTE (≤0.5 msec), and longer TEmax (≥10.1 msec); except the constant offset model overestimated R2* at the lowest SNR. In phantoms and in vivo, all models produced similar R2* values for different SNRs and shorter ΔTEs (slopes: 0.99-1.06, R2 > 0.99, P < 0.001). In all experiments, R2* results degraded for high R2* values with longer ΔTE (≥1 msec). In vivo, shorter and longer TEmax gave similar R2* results (slopes: 1.02-1.06, R2 > 0.99, P < 0.001) for the noise subtraction model for 25≤R2*≤2000 s-1 . However, both quadratic and constant offset models, using shorter TEmax (≤4.7 msec) overestimated R2* and yielded high CoVs up to ∼170% for low R2* (<250 s-1 ). DATA CONCLUSION UTE with TEmax ≥ 10.1 msec and ΔTE ≤ 0.5 msec yields accurate R2* estimates over the entire clinical HIC range. Monoexponential fitting with noise subtraction is the most robust signal model to changes in UTE parameters and achieves the highest R2* accuracy and precision. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1475-1488.
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Affiliation(s)
- Aaryani Tipirneni-Sajja
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.,Department of Biomedical Engineering, The University of Memphis, Memphis, Tennessee, USA
| | - Ralf B Loeffler
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Axel J Krafft
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.,Department of Radiology, Medical Physics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Andrea N Sajewski
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Robert J Ogg
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Jane S Hankins
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Claudia M Hillenbrand
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
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Nowak A, Giger RS, Krayenbuehl PA. Higher age at diagnosis of hemochromatosis is the strongest predictor of the occurrence of hepatocellular carcinoma in the Swiss hemochromatosis cohort: A prospective longitudinal observational study. Medicine (Baltimore) 2018; 97:e12886. [PMID: 30335010 PMCID: PMC6211894 DOI: 10.1097/md.0000000000012886] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hereditary hemochromatosis (HH) is the most common genetic disease in Caucasians which is characterized by an increased intestinal iron absorption, resulting into a progressive accumulation of iron in organs including liver, heart, and pancreas, leading to their progressive dysfunction. Hepatocellular carcinoma (HCC) is a long-term complication of HH, which contributes to increased mortality.We evaluated the risk factors of HCC in a prospective cohort of Swiss hemochromatosis patients with a long-term follow-up.We included 147 patients with the mean age at diagnosis of 48 years, in whom 70% were men. Overall, 9% of the patients developed HCC during the mean follow-up time of 14 years (range 1-40 years). Patients with HCC had higher age at diagnosis (61 ± 11 vs 47 ± 13 years, P = .003), more frequently liver cirrhosis on biopsy (90% vs 37.5%, P = .004), and higher serum ferritin levels [3704 (Q1:2025, Q3:4463) vs 1338 (Q1:691, Q3:2468) μg/L, P < .001], they needed more iron removed by phlebotomy until its depletion [8.9 (Q1:7.2, Q3:10.1) vs 3.8 (Q1:1.6, Q3:8.9) g, P = .029], compared to non-HCC patients. After adjustment for possible confounders, only higher age at diagnosis remained significantly associated with HCC development (odds ratio 1.19, 95% CI 0.056-0.397, P = .001, per year).Higher age at diagnosis showed the strongest association with the occurrence of HCC in Swiss hemochromatosis patients. Patients who were diagnosed at a higher age and with a high iron overload (serum ferritin levels >1000 μg/L) require regular screening even if they have no liver cirrhosis.
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Affiliation(s)
- Albina Nowak
- Department of Endocrinology and Clinical Nutrition, University Hospital Zurich
- Department of Internal Medicine, Psychiatric University Hospital Zurich, University of Zurich
| | - Rebekka S. Giger
- Department of Internal Medicine, University Hospital Zurich, Zurich
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23
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How I manage medical complications of β-thalassemia in adults. Blood 2018; 132:1781-1791. [PMID: 30206117 DOI: 10.1182/blood-2018-06-818187] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 09/09/2018] [Indexed: 02/06/2023] Open
Abstract
The complex pathophysiology in β-thalassemia can translate to multiple morbidities that affect every organ system. Improved survival due to advances in management means that patients are exposed to the harmful effects of ineffective erythropoiesis, anemia, and iron overload for a longer duration, and we started seeing new or more frequent complications in adult compared with younger patients. In this article, we highlight particular aspects of managing adult patients with β-thalassemia, using our own experience in treating such patients. We cover both transfusion-dependent and nontransfusion-dependent forms of the disease and tackle specific morbidities of highest interest.
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24
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Labranche R, Gilbert G, Cerny M, Vu KN, Soulières D, Olivié D, Billiard JS, Yokoo T, Tang A. Liver Iron Quantification with MR Imaging: A Primer for Radiologists. Radiographics 2018. [PMID: 29528818 DOI: 10.1148/rg.2018170079] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Iron overload is a systemic disorder and is either primary (genetic) or secondary (exogenous iron administration). Primary iron overload is most commonly associated with hereditary hemochromatosis and secondary iron overload with ineffective erythropoiesis (predominantly caused by β-thalassemia major and sickle cell disease) that requires long-term transfusion therapy, leading to transfusional hemosiderosis. Iron overload may lead to liver cirrhosis and hepatocellular carcinoma, in addition to cardiac and endocrine complications. The liver is one of the main iron storage organs and the first to show iron overload. Therefore, detection and quantification of liver iron overload are critical to initiate treatment and prevent complications. Liver biopsy was the historical reference standard for detection and quantification of liver iron content. Magnetic resonance (MR) imaging is now commonly used for liver iron quantification, including assessment of distribution, detection, grading, and monitoring of treatment response in iron overload. Several MR imaging techniques have been developed for iron quantification, each with advantages and limitations. The liver-to-muscle signal intensity ratio technique is simple and widely available; however, it assumes that the reference tissue is normal. Transverse magnetization (also known as R2) relaxometry is validated but is prone to respiratory motion artifacts due to a long acquisition time, is presently available only for 1.5-T imaging, and requires additional cost and delay for off-line analysis. The R2* technique has fast acquisition time, demonstrates a wide range of liver iron content, and is available for 1.5-T and 3.0-T imaging but requires additional postprocessing software. Quantitative susceptibility mapping has the highest sensitivity for detecting iron deposition; however, it is still investigational, and the correlation with liver iron content is not yet established. ©RSNA, 2018.
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Affiliation(s)
- Roxanne Labranche
- From the Department of Radiology (R.L., G.G., M.C., K.N.V., D.O., J.S.B., A.T.) and Service of Hemato-oncology, Department of Medicine (D.S.), Centre Hospitalier de l'Université de Montréal, 1000 rue Saint-Denis, Montréal, QC, Canada H2X 0C2; MR Clinical Science, Philips Healthcare Canada, Markham, ON, Canada (G.G.); Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Tex (T.Y.); and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada (A.T.)
| | - Guillaume Gilbert
- From the Department of Radiology (R.L., G.G., M.C., K.N.V., D.O., J.S.B., A.T.) and Service of Hemato-oncology, Department of Medicine (D.S.), Centre Hospitalier de l'Université de Montréal, 1000 rue Saint-Denis, Montréal, QC, Canada H2X 0C2; MR Clinical Science, Philips Healthcare Canada, Markham, ON, Canada (G.G.); Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Tex (T.Y.); and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada (A.T.)
| | - Milena Cerny
- From the Department of Radiology (R.L., G.G., M.C., K.N.V., D.O., J.S.B., A.T.) and Service of Hemato-oncology, Department of Medicine (D.S.), Centre Hospitalier de l'Université de Montréal, 1000 rue Saint-Denis, Montréal, QC, Canada H2X 0C2; MR Clinical Science, Philips Healthcare Canada, Markham, ON, Canada (G.G.); Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Tex (T.Y.); and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada (A.T.)
| | - Kim-Nhien Vu
- From the Department of Radiology (R.L., G.G., M.C., K.N.V., D.O., J.S.B., A.T.) and Service of Hemato-oncology, Department of Medicine (D.S.), Centre Hospitalier de l'Université de Montréal, 1000 rue Saint-Denis, Montréal, QC, Canada H2X 0C2; MR Clinical Science, Philips Healthcare Canada, Markham, ON, Canada (G.G.); Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Tex (T.Y.); and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada (A.T.)
| | - Denis Soulières
- From the Department of Radiology (R.L., G.G., M.C., K.N.V., D.O., J.S.B., A.T.) and Service of Hemato-oncology, Department of Medicine (D.S.), Centre Hospitalier de l'Université de Montréal, 1000 rue Saint-Denis, Montréal, QC, Canada H2X 0C2; MR Clinical Science, Philips Healthcare Canada, Markham, ON, Canada (G.G.); Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Tex (T.Y.); and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada (A.T.)
| | - Damien Olivié
- From the Department of Radiology (R.L., G.G., M.C., K.N.V., D.O., J.S.B., A.T.) and Service of Hemato-oncology, Department of Medicine (D.S.), Centre Hospitalier de l'Université de Montréal, 1000 rue Saint-Denis, Montréal, QC, Canada H2X 0C2; MR Clinical Science, Philips Healthcare Canada, Markham, ON, Canada (G.G.); Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Tex (T.Y.); and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada (A.T.)
| | - Jean-Sébastien Billiard
- From the Department of Radiology (R.L., G.G., M.C., K.N.V., D.O., J.S.B., A.T.) and Service of Hemato-oncology, Department of Medicine (D.S.), Centre Hospitalier de l'Université de Montréal, 1000 rue Saint-Denis, Montréal, QC, Canada H2X 0C2; MR Clinical Science, Philips Healthcare Canada, Markham, ON, Canada (G.G.); Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Tex (T.Y.); and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada (A.T.)
| | - Takeshi Yokoo
- From the Department of Radiology (R.L., G.G., M.C., K.N.V., D.O., J.S.B., A.T.) and Service of Hemato-oncology, Department of Medicine (D.S.), Centre Hospitalier de l'Université de Montréal, 1000 rue Saint-Denis, Montréal, QC, Canada H2X 0C2; MR Clinical Science, Philips Healthcare Canada, Markham, ON, Canada (G.G.); Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Tex (T.Y.); and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada (A.T.)
| | - An Tang
- From the Department of Radiology (R.L., G.G., M.C., K.N.V., D.O., J.S.B., A.T.) and Service of Hemato-oncology, Department of Medicine (D.S.), Centre Hospitalier de l'Université de Montréal, 1000 rue Saint-Denis, Montréal, QC, Canada H2X 0C2; MR Clinical Science, Philips Healthcare Canada, Markham, ON, Canada (G.G.); Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Tex (T.Y.); and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada (A.T.)
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Barton JC, McLaren CE, Chen WP, Ramm GA, Anderson GJ, Powell LW, Subramaniam VN, Adams PC, Phatak PD, Gurrin LC, Phillips JD, Parker CJ, Emond MJ, McLaren GD. Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes. Ann Hepatol 2018; 17:871-879. [PMID: 30145563 PMCID: PMC6368858 DOI: 10.5604/01.3001.0012.3169] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cross-sectional study. MATERIAL AND METHODS We evaluated 368 p.C282Y homozygotes who underwent liver biopsy and compared characteristics of those with and without cirrhosis. We performed multivariable logistic regression on cirrhosis with: age; sex; race/ethnicity; diabetes; blood pints/units donated voluntarily; erythrocyte pints/units received; iron supplement use; alcohol intake, g/d; body mass index, kg/m2; swollen/tender 2nd/3rd metacarpophalangeal joints; elevated alanine aminotransferase; elevated aspartate aminotransferase; steatosis/fatty liver; iron removed by phlebotomy, g; and GNPAT p.D519G positivity. RESULTS Mean age of 368 participants (73.6% men) was 47 ± 13 (standard deviation) y. Cirrhosis was diagnosed in 86 participants (23.4%). Participants with cirrhosis had significantly greater mean age, proportion of men, diabetes prevalence, mean daily alcohol intake, prevalence of swollen/ tender 2nd/3rd metacarpophalangeal joints, mean serum ferritin, elevated alanine aminotransferase, elevated aspartate aminotransferase, and mean iron removed; and significantly fewer mean blood pints/units donated. GNPAT p.D519G positivity was detected in 82 of 188 participants (43.6%). In a multivariable model for cirrhosis, there were four significant positive associations: age (10-y intervals) (odds ratio 2.2 [95% confidence interval 1.5, 3.3]); diabetes (3.3; [1.1, 9.7]); alcohol intake (14 g alcohol drinks/d) (1.5 [1.2, 1.8]); and iron removed, g (1.3 [1.2, 1.4]). There was no statistical evidence of two-way interactions between these variables. CONCLUSION In conclusion, cirrhosis in HFE p.C282Y homozygotes is significantly associated with age, diabetes, daily alcohol intake, and iron removed by phlebotomy, taking into account the effect of other variables.
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Affiliation(s)
- James C. Barton
- Southern Iron Disorders Center, Birmingham, AL, USA
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Wen-pin Chen
- Chao Family Comprehensive Cancer Center, lrvine, CA, USA
| | - Grant A. Ramm
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Gregory J. Anderson
- Faculty of Medicine, The University of Queensland, Herston, QLD, Australia
- School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane St. Lucia, QLD, Australia
| | - Lawrie W Powell
- Faculty of Medicine, The University of Queensland, Herston, QLD, Australia
- School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane St. Lucia, QLD, Australia
- Royal Brisbane & Women’s Hospital, Herston, QLD, Australia
| | - V. Nathan Subramaniam
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Paul C. Adams
- Department of Medicine, London Health Sciences Centre, London, ONT, Canada
| | | | - Lyle C. Gurrin
- Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
| | - John D. Phillips
- Departments of Medicine and Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Charles J. Parker
- Division of Hematology and Hematologic Malignancies, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Mary J. Emond
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Gordon D. McLaren
- Department of Veterans Affairs Long Beach Healthcare System, Long Beach, CA, USA
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA
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26
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Brissot P, Cavey T, Ropert M, Gaboriau F, Loréal O. Hemochromatosis: a model of metal-related human toxicosis. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2018; 25:2007-2013. [PMID: 27628916 DOI: 10.1007/s11356-016-7576-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 09/01/2016] [Indexed: 06/06/2023]
Abstract
Many environmental agents, such as excessive alcohol intake, xenobiotics, and virus, are able to damage the human body, targeting especially the liver. Metal excess may also assault the liver. Thus, chronic iron overload may cause, especially when associated with cofactors, diffuse organ damage that is a source of significant morbidity and mortality. Iron excess can be either of acquired (mostly transfusional) or of genetic origin. Hemochromatosis is the archetype of genetic iron overload diseases and represents a serious health problem. A better understanding of iron metabolism has deeply modified the hemochromatosis field which today benefits from much more efficient diagnostic and therapeutic approaches.
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Affiliation(s)
- Pierre Brissot
- Hepatology, Faculty of Medicine, University of Rennes1, 2, avenue Pr. Léon BERNARD, 35043, Rennes, France.
- Department of Biochemistry, Pontchaillou University Hospital, Rennes, France.
- Inserm-UMR 991, University of Rennes1, Rennes, France.
| | - Thibault Cavey
- Department of Biochemistry, Pontchaillou University Hospital, Rennes, France
- Inserm-UMR 991, University of Rennes1, Rennes, France
| | - Martine Ropert
- Department of Biochemistry, Pontchaillou University Hospital, Rennes, France
- Inserm-UMR 991, University of Rennes1, Rennes, France
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Tipirneni-Sajja A, Song R, McCarville MB, Loeffler RB, Hankins JS, Hillenbrand CM. Automated vessel exclusion technique for quantitative assessment of hepatic iron overload by R2*-MRI. J Magn Reson Imaging 2017; 47:1542-1551. [PMID: 29083524 DOI: 10.1002/jmri.25880] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 10/07/2017] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Extraction of liver parenchyma is an important step in the evaluation of R2*-based hepatic iron content (HIC). Traditionally, this is performed by radiologists via whole-liver contouring and T2*-thresholding to exclude hepatic vessels. However, the vessel exclusion process is iterative, time-consuming, and susceptible to interreviewer variability. PURPOSE To implement and evaluate an automatic hepatic vessel exclusion and parenchyma extraction technique for accurate assessment of R2*-based HIC. STUDY TYPE Retrospective analysis of clinical data. SUBJECTS Data from 511 MRI exams performed on 257 patients were analyzed. FIELD STRENGTH/SEQUENCE All patients were scanned on a 1.5T scanner using a multiecho gradient echo sequence for clinical monitoring of HIC. ASSESSMENT An automated method based on a multiscale vessel enhancement filter was investigated for three input data types-contrast-optimized composite image, T2* map, and R2* map-to segment blood vessels and extract liver tissue for R2*-based HIC assessment. Segmentation and R2* results obtained using this automated technique were compared with those from a reference T2*-thresholding technique performed by a radiologist. STATISTICAL TESTS The Dice similarity coefficient was used to compare the segmentation results between the extracted parenchymas, and linear regression and Bland-Altman analyses were performed to compare the R2* results, obtained with the automated and reference techniques. RESULTS Mean liver R2* values estimated from all three filter-based methods showed excellent agreement with the reference method (slopes 1.04-1.05, R2 > 0.99, P < 0.001). Parenchyma areas extracted using the reference and automated methods had an average overlap area of 87-88%. The T2*-thresholding technique included small vessels and pixels at the vessel/tissue boundaries as parenchymal area, potentially causing a small bias (<5%) in R2* values compared to the automated method. DATA CONCLUSION The excellent agreement between reference and automated hepatic vessel segmentation methods confirms the accuracy and robustness of the proposed method. This automated approach might improve the radiologist's workflow by reducing the interpretation time and operator dependence for assessing HIC, an important clinical parameter that guides iron overload management. LEVEL OF EVIDENCE 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1542-1551.
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Affiliation(s)
- Aaryani Tipirneni-Sajja
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.,Department of Biomedical Engineering, University of Memphis, Memphis, Tennessee, USA
| | - Ruitian Song
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - M Beth McCarville
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Ralf B Loeffler
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Jane S Hankins
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Claudia M Hillenbrand
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
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Green tea activity and iron overload induced molecular fibrogenesis of rat liver. Saudi J Biol Sci 2017; 26:531-540. [PMID: 30899168 PMCID: PMC6408694 DOI: 10.1016/j.sjbs.2017.08.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 05/24/2017] [Accepted: 08/17/2017] [Indexed: 12/21/2022] Open
Abstract
Iron overload toxicity was shown to associate with chronic liver diseases which lead to hepatic fibrosis and subsequently the progression to cancer through oxidative stress and apoptotic pathways. Green tea potential activity as chelating, anti-oxidative, or anti-apoptotic mechanisms against metal toxicity was poorly clarified. Here, we are trying to evaluate the anti-oxidant and anti-apoptotic properties of green tea in the regulation of serum hepcidin levels, reduction in iron overloads, and improve of liver fibrosis in iron overloaded experimental rats. Three groups of male adult rats were randomly classified into three groups and treated as follows: control rats, iron treated rats for two months in drinking water followed by either vehicle or green tea extract (AGTE; 100 mg/kg) treatment for 2 more months. Thereafter, we studied the effects of AGTE on iron overload-induced lipid peroxidation, anti-oxidant depletion, liver cell injury and apoptosis. Treatment of iron-overloaded rats with AGTE resulted in marked decreases in iron accumulation within liver, depletion in serum ferritin, and hepcidin levels. Iron-overloaded rats had significant increase in malonyldialdehyde (MDA), a marker of lipid peroxidation and nitric oxide (NO) in liver when compared to control group. Also, significant change in cytochrome c and DNA content as apoptotic markers were reported in iron treated rats. The effects of iron overload on lipid peroxidation, NO levels, cytochrome c and DNA content were significantly reduced by the intervention treatment with AGTE (P < 0.001). Furthermore, the endogenous anti-oxidant capacities/levels (TAC) in liver were also significantly decreased in chronic iron overload and administration of AGTE restored the decrease in the hepatic antioxidant activities/levels. Also, hepatic hepcidin was shown to be significantly correlated with oxidative and apoptotic relating biomarkers as well as an improvement in liver fibrosis of iron treated rats following AGTE treatment. In-vitro analysis showed that, the improvement in iron toxicity of the liver depend mainly on antioxidant and protective ability of green tea polyphenolic compounds especiallyepigallocatechin-3-gallate (EGCG). Our study showed that green tea extract (GTE) ameliorates iron overload induced hepatotoxicity, apoptosis and oxidative stress in rat liver via inhibition of hepatic iron accumulation; improve of liver antioxidant capacity, and down regulation of serum hepcidin as well as reduction in the release of apoptotic relating proteins.
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Radial Ultrashort TE Imaging Removes the Need for Breath-Holding in Hepatic Iron Overload Quantification by R2* MRI. AJR Am J Roentgenol 2017; 209:187-194. [PMID: 28504544 DOI: 10.2214/ajr.16.17183] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE The objective of this study is to evaluate radial free-breathing (FB) multiecho ultrashort TE (UTE) imaging as an alternative to Cartesian FB multiecho gradient-recalled echo (GRE) imaging for quantitative assessment of hepatic iron content (HIC) in sedated patients and subjects unable to perform breath-hold (BH) maneuvers. MATERIALS AND METHODS FB multiecho GRE imaging and FB multiecho UTE imaging were conducted for 46 test group patients with iron overload who could not complete BH maneuvers (38 patients were sedated, and eight were not sedated) and 16 control patients who could complete BH maneuvers. Control patients also underwent standard BH multiecho GRE imaging. Quantitative R2* maps were calculated, and mean liver R2* values and coefficients of variation (CVs) for different acquisitions and patient groups were compared using statistical analysis. RESULTS FB multiecho GRE images displayed motion artifacts and significantly lower R2* values, compared with standard BH multiecho GRE images and FB multiecho UTE images in the control cohort and FB multiecho UTE images in the test cohort. In contrast, FB multiecho UTE images produced artifact-free R2* maps, and mean R2* values were not significantly different from those measured by BH multiecho GRE imaging. Motion artifacts on FB multiecho GRE images resulted in an R2* CV that was approximately twofold higher than the R2* CV from BH multiecho GRE imaging and FB multiecho UTE imaging. The R2* CV was relatively constant over the range of R2* values for FB multiecho UTE, but it increased with increases in R2* for FB multiecho GRE imaging, reflecting that motion artifacts had a stronger impact on R2* estimation with increasing iron burden. CONCLUSION FB multiecho UTE imaging was less motion sensitive because of radial sampling, produced excellent image quality, and yielded accurate R2* estimates within the same acquisition time used for multiaveraged FB multiecho GRE imaging. Thus, FB multiecho UTE imaging is a viable alternative for accurate HIC assessment in sedated children and patients who cannot complete BH maneuvers.
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Abstract
Absolute or functional iron (Fe) deficiency is an important determinant of anemia in hemodialysis patients and parenteral Fe is routinely used to treat this condition in conjunction with erythropoiesis stimulating agents. While restoration of hemoglobin toward the target range is a good outcome of Fe replacement, it is well known that Fe overload and toxicity may be adverse consequences of this therapy. Dialysis clinical practice guidelines recommend tailoring Fe therapy based on transferrin saturation and serum ferritin levels. Unfortunately, serum Fe markers may not accurately reflect the amount of Fe in the body, because factors such as infections, inflammation, or malignancy can alter serum ferritin levels. Some recent trials in dialysis patients receiving high intravenous Fe doses have shown increased cardiovascular morbidity and mortality and studies using magnetic resonance imaging (MRI) in this population have shown excessive tissue liver iron content (LIC) suggesting Fe overload. While LIC measured by MRI correlates well with LIC quantitated by liver biopsy, it only represents a surrogate marker for total body Fe and its clinical relevance in dialysis patients in terms of mortality and morbidity remains to be demonstrated. Nevertheless, these recent findings challenge the use of current serum Fe markers recommended by clinical guidelines to guide safe Fe therapy in dialysis patients. While not yet established for the routine screening of dialysis patients for Fe overload, MRI should be considered in patients who have received a high cumulative dose of intravenous Fe, or have long cumulative dialysis vintage. Further studies are needed to assess how MRI will alter management.
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Affiliation(s)
- Ganesh Ramanathan
- Department of Nephrology, Prince of Wales Hospital, Sydney, New South Wales, Australia
| | - John K Olynyk
- Department of Gastroenterology, Fiona Stanley and Fremantle Hospitals, Perth, Western Australia, Australia.,School of Veterinary Sciences, Murdoch University, Perth, Western Australia, Australia.,School of Biomedical Sciences and Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.,Faculty of Health Sciences, Edith Cowan University, Perth, Western Australia, Australia
| | - Paolo Ferrari
- Department of Nephrology, Prince of Wales Hospital, Sydney, New South Wales, Australia.,Clinical School, University of New South Wales, Sydney, New South Wales, Australia
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31
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Pipaliya N, Solanke D, Parikh P, Ingle M, Sharma R, Sharma S, Sawant P. Comparison of Tissue Elastography With Magnetic Resonance Imaging T2* and Serum Ferritin Quantification in Detecting Liver Iron Overload in Patients With Thalassemia Major. Clin Gastroenterol Hepatol 2017; 15:292-298.e1. [PMID: 27650324 DOI: 10.1016/j.cgh.2016.08.046] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 08/07/2016] [Accepted: 08/30/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We investigated whether tissue elastography (TE) can be used as an alternative to magnetic resonance imaging (MRI) T2* analysis to determine the degree of iron overload in patients with thalassemia major. METHODS We conducted a prospective study of 154 patients (99 male; mean age, 12 ± 3.6 years) with thalassemia major requiring chronic blood transfusion and on iron chelator therapy. The study was performed at a tertiary hospital in India from January 2015 through June 2015. We performed routine blood sample analyses, measurements of serum levels of ferritin, and TE within 1 month of MRI T2* analysis of the liver. The Spearman correlation test and linear regression analysis were used to evaluate the correlation between TE liver stiffness measurements and R2* MRI results or serum ferritin levels. RESULTS The subjects' mean total serum levels of bilirubin, alanine aminotransferase, aspartate aminotransferase, and albumin were 1.4 ± 0.6 mg/dL, 65.0 ± 51.8 IU/L, 62.9 ± 44 IU/L, and 4.2 ± 0.2 g/d, respectively. Mean liver stiffness measurement, MRI T2* (3 T), corresponding MRI R2* (3 T), and ferritin values were 8.2 ± 4.4 kPa, 3.18 ± 2.6 milliseconds, 617.3 ± 549 Hz, and 4712 ± 3301 ng/mL, respectively. On the basis of MRI analysis, 67 patients (43.5%) had mild iron overload, 49 patients (31.8%) had moderate iron overload, and 22 patients (14.3%) had severe iron overload. Fibroscan liver stiffness measurements correlated with MRI R2* values (r = 0.85; P < .001). TE results identified the patients with severe, moderate, and mild iron overload with area under the receiver operating characteristic curve values of 94.8%, 84.5%, and 84.7%, respectively. Liver stiffness measurements greater than 13.5, 7.8, and 5.5 kPa identified patients with severe, moderate, and mild iron overload, respectively; the sensitivity and specificity values were 92% and 93% for severe overload, 82% and 82% for moderate overload, and 73% and 75% for mild overload. No correlation was found between TE results and serum level of ferritin (r = 0.19; P = .11). CONCLUSIONS Results of TE correlate with those from MRI T2* analysis. TE is cheaper and more available than MRI and might be used to estimate hepatic iron overload, especially moderate to severe overload in patients with thalassemia major who require chronic transfusion.
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Affiliation(s)
- Nirav Pipaliya
- Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, India.
| | - Dattatray Solanke
- Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, India
| | - Pathik Parikh
- Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, India
| | - Meghraj Ingle
- Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, India
| | - Ratna Sharma
- Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, India
| | - Sujata Sharma
- Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, India
| | - Prabha Sawant
- Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, India
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Krafft AJ, Loeffler RB, Song R, Tipirneni-Sajja A, McCarville MB, Robson MD, Hankins JS, Hillenbrand CM. Quantitative ultrashort echo time imaging for assessment of massive iron overload at 1.5 and 3 Tesla. Magn Reson Med 2017; 78:1839-1851. [PMID: 28090666 DOI: 10.1002/mrm.26592] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 11/30/2016] [Accepted: 12/01/2016] [Indexed: 01/12/2023]
Abstract
PURPOSE Hepatic iron content (HIC) quantification via transverse relaxation rate (R2*)-MRI using multi-gradient echo (mGRE) imaging is compromised toward high HIC or at higher fields due to the rapid signal decay. Our study aims at presenting an optimized 2D ultrashort echo time (UTE) sequence for R2* quantification to overcome these limitations. METHODS Two-dimensional UTE imaging was realized via half-pulse excitation and radial center-out sampling. The sequence includes chemically selective saturation pulses to reduce streaking artifacts from subcutaneous fat, and spatial saturation (sSAT) bands to suppress out-of-slice signals. The sequence employs interleaved multi-echo readout trains to achieve dense temporal sampling of rapid signal decays. Evaluation was done at 1.5 Tesla (T) and 3T in phantoms, and clinical applicability was demonstrated in five patients with biopsy-confirmed massively high HIC levels (>25 mg Fe/g dry weight liver tissue). RESULTS In phantoms, the sSAT pulses were found to remove out-of-slice contamination, and R2* results were in excellent agreement to reference mGRE R2* results (slope of linear regression: 1.02/1.00 for 1.5/3T). UTE-based R2* quantification in patients with massive iron overload proved successful at both field strengths and was consistent with biopsy HIC values. CONCLUSION The UTE sequence provides a means to measure R2* in patients with massive iron overload, both at 1.5T and 3T. Magn Reson Med 78:1839-1851, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Axel J Krafft
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.,Department of Radiology, Medical Physics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Ralf B Loeffler
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Ruitian Song
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Aaryani Tipirneni-Sajja
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - M Beth McCarville
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Matthew D Robson
- OCMR, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Jane S Hankins
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Claudia M Hillenbrand
- Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
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Afonso MB, Rodrigues PM, Simão AL, Ofengeim D, Carvalho T, Amaral JD, Gaspar MM, Cortez-Pinto H, Castro RE, Yuan J, Rodrigues CMP. Activation of necroptosis in human and experimental cholestasis. Cell Death Dis 2016; 7:e2390. [PMID: 27685634 PMCID: PMC5059878 DOI: 10.1038/cddis.2016.280] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 07/28/2016] [Accepted: 08/05/2016] [Indexed: 12/15/2022]
Abstract
Cholestasis encompasses liver injury and inflammation. Necroptosis, a necrotic cell death pathway regulated by receptor-interacting protein (RIP) 3, may mediate cell death and inflammation in the liver. We aimed to investigate the role of necroptosis in mediating deleterious processes associated with cholestatic liver disease. Hallmarks of necroptosis were evaluated in liver biopsies of primary biliary cholangitis (PBC) patients and in wild-type and RIP3-deficient (RIP3−/−) mice subjected to common bile duct ligation (BDL). The functional link between RIP3, heme oxygenase-1 (HO-1) and antioxidant response was investigated in vivo after BDL and in vitro. We demonstrate increased RIP3 expression and mixed lineage kinase domain-like protein (MLKL) phosphorylation in liver samples of human PBC patients, coincident with thioflavin T labeling, suggesting activation of necroptosis. BDL resulted in evident hallmarks of necroptosis, concomitant with progressive bile duct hyperplasia, multifocal necrosis, fibrosis and inflammation. MLKL phosphorylation was increased and insoluble aggregates of RIP3, MLKL and RIP1 formed in BLD liver tissue samples. Furthermore, RIP3 deficiency blocked BDL-induced necroinflammation at 3 and 14 days post-BDL. Serum hepatic enzymes, fibrogenic liver gene expression and oxidative stress decreased in RIP3−/− mice at 3 days after BDL. However, at 14 days, cholestasis aggravated and fibrosis was not halted. RIP3 deficiency further associated with increased hepatic expression of HO-1 and accumulation of iron in BDL mice. The functional link between HO-1 activity and bile acid toxicity was established in RIP3-deficient primary hepatocytes. Necroptosis is triggered in PBC patients and mediates hepatic necroinflammation in BDL-induced acute cholestasis. Targeting necroptosis may represent a therapeutic strategy for acute cholestasis, although complementary approaches may be required to control progression of chronic cholestatic liver disease.
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Affiliation(s)
- Marta B Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Pedro M Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - André L Simão
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Dimitry Ofengeim
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Tânia Carvalho
- Histology and Comparative Pathology Laboratory, Instituto de Medicina Molecular, Lisbon, Portugal
| | - Joana D Amaral
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Maria M Gaspar
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Helena Cortez-Pinto
- Department of Gastrenterology, Hospital Santa Maria, Lisbon, Portugal.,Faculty of Medicine, Universidade de Lisboa, Lisbon, Portugal
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Junying Yuan
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Cecília M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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Pelucchi S, Galimberti S, Greni F, Rametta R, Mariani R, Pelloni I, Girelli D, Busti F, Ravasi G, Valsecchi MG, Valenti L, Piperno A. Proprotein convertase 7 rs236918 associated with liver fibrosis in Italian patients with HFE-related hemochromatosis. J Gastroenterol Hepatol 2016; 31:1342-8. [PMID: 26868056 DOI: 10.1111/jgh.13315] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 01/26/2016] [Accepted: 02/06/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM p.Cys282Tyr homozygosity is the prevalent genotype in (HFE)-related Hereditary Hemochromatosis with low penetrance and variable expression. However, liver cirrhosis and hepatocellular carcinoma remain the main causes of mortality in these patients. Detection of genetic modifiers identifying patients at risk for liver damage would be relevant for their clinical management. We evaluated proprotein convertase 7 (PCSK7) rs236918 as genetic marker of risk of liver fibrosis in an Italian cohort of p.Cys282Tyr homozygotes. METHODS Liver fibrosis was histologically assessed by Ishak score. We evaluated PCSK7 alleles and genotypes frequencies according to single or grouped staging scores: absent/mild fibrosis (stage: 0-2), moderate (stage: 3-4), and severe fibrosis/cirrhosis (stage: 5-6). Single nucleotide polymorphism genotyping was performed by restriction fragment length polymorphism or Taqman 5'-nuclease assays. RESULTS The rs236918 allele C frequency increased from stages 0-2 to 5-6 (7.1% vs 13.6%, vs 21.9%, P = 0.003). The wild-type genotype was significantly more frequent in the absent/mild fibrosis group (54.2%) compared with only 17% in patients with severe fibrosis/cirrhosis. At univariate proportional odds model, patients with GC + CC genotypes were 2.77 times (P = 0.0018) more likely to have worse liver staging scores than wild-type patients. In the adjusted analysis, odds ratio was 2.37 (P = 0.0218), and 2.56 (P = 0.0233) when the analysis was restricted to males. An exploratory mediation analysis suggested a direct effect of genotype on severe fibrosis/cirrhosis (odds ratio = 3.11, P = 0.0157), and a mild non-significant indirect effect mediated through iron accounting for 28%. CONCLUSIONS These findings confirm that PCSK7 rs236918 C allele is a risk factor for cirrhosis development in Italian patients with HFE-Hemochromatosis.
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Affiliation(s)
- Sara Pelucchi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Stefania Galimberti
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,Centre of Biostatistics for Clinical Epidemiology, University of Milano-Bicocca, Monza, Italy
| | - Federico Greni
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Raffaela Rametta
- Department of Medicine, Second Division of Gastroenterology, IRCCS, Ospedale Maggiore Policlinico, University of Milano, Milano, Italy
| | - Raffaella Mariani
- Centre for disorder of iron metabolism, S.Gerardo Hospital, Monza, Italy
| | - Irene Pelloni
- Centre for disorder of iron metabolism, S.Gerardo Hospital, Monza, Italy
| | - Domenico Girelli
- Department of Medicine Policlinico GB Rossi, University of Verona, Verona, Italy
| | - Fabiana Busti
- Department of Medicine Policlinico GB Rossi, University of Verona, Verona, Italy
| | - Giulia Ravasi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Maria Grazia Valsecchi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,Centre of Biostatistics for Clinical Epidemiology, University of Milano-Bicocca, Monza, Italy
| | - Luca Valenti
- Department of Medicine, Second Division of Gastroenterology, IRCCS, Ospedale Maggiore Policlinico, University of Milano, Milano, Italy
| | - Alberto Piperno
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,Centre for disorder of iron metabolism, S.Gerardo Hospital, Monza, Italy.,Consortium of Human Molecular Genetics, Monza, Italy
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Saliba AN, Taher AT. Morbidities in non-transfusion-dependent thalassemia. Ann N Y Acad Sci 2016; 1368:82-94. [DOI: 10.1111/nyas.13083] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 04/06/2016] [Accepted: 04/07/2016] [Indexed: 01/19/2023]
Affiliation(s)
- Antoine N. Saliba
- Department of Medicine; Indiana University School of Medicine; Indianapolis Indiana
| | - Ali T. Taher
- Department of Internal Medicine; American University of Beirut Medical Center; Beirut Lebanon
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Harb AR, Saliba AN, Taher AT. Non-Transfusion Dependent Thalassemia: Translating Evidence to Guidelines. THALASSEMIA REPORTS 2014. [DOI: 10.4081/thal.2014.4863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
The thalassemias are a group of inherited disorders of hemoglobin synthesis characterized by various degrees of defective production of the α- or β-globin chains of adult hemoglobin A. Non-transfusion- dependent thalassemia (NTDT) includes a group of thalassemia patients who do not require regular RBC transfusions for survival, but may require occasional transfusions due to infection or pregnancy or may require more regular transfusions later in life due to splenomegaly or other complications. Due to the rising phenomenon of global migration, this previously well-localized entity is currently spreading more and more worldwide reaching Northern America and Northern Europe. The clinical picture of NTDT is governed by the severity of the ineffective erythropoiesis and the chronic hemolytic anemia, which, in turn, lead to iron overload, hypercoagulability, and an array of clinical complications involving almost every organ system. Patients with NTDT suffer from complications that are distinct from those encountered in patients with transfusion- dependent thalassemia (TDT) in addition to the complications shared by both TDT and NTDT. As a consequence, patients with NTDT deserve a care specifically tailored to their needs. In the care of patients with NTDT, aiming at a standardized yet personalized care is not an easy task especially that NTDT patients lie on a heterogeneous spectrum with a wide variability in their clinical presentation and response to therapy. Therefore, guidelines emerge as a necessity to answer the specific needs of NTDT patients and the clinicians caring for them. In this article, we summarize the complications most commonly associated with NTDT and the recommendations of the guidelines for the management of patients with NTDT, based on the best available evidence.
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Lee SM, Loguinov A, Fleming RE, Vulpe CD. Effects of strain and age on hepatic gene expression profiles in murine models of HFE-associated hereditary hemochromatosis. GENES AND NUTRITION 2014; 10:443. [PMID: 25427953 DOI: 10.1007/s12263-014-0443-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 11/15/2014] [Indexed: 12/20/2022]
Abstract
Hereditary hemochromatosis is an iron overload disorder most commonly caused by a defect in the HFE gene. While the genetic defect is highly prevalent, the majority of individuals do not develop clinically significant iron overload, suggesting the importance of genetic modifiers. Murine hfe knockout models have demonstrated that strain background has a strong effect on the severity of iron loading. We noted that hepatic iron loading in hfe-/- mice occurs primarily over the first postnatal weeks (loading phase) followed by a timeframe of relatively static iron concentrations (plateau phase). We thus evaluated the effects of background strain and of age on hepatic gene expression in Hfe knockout mice (hfe-/-). Hepatic gene expression profiles were examined using cDNA microarrays in 4- and 8-week-old hfe-/- and wild-type mice on two different genetic backgrounds, C57BL/6J (C57) and AKR/J (AKR). Genes differentially regulated in all hfe-/- mice groups, compared with wild-type mice, including those involved in cell survival, stress and damage responses and lipid metabolism. AKR strain-specific changes in lipid metabolism genes and C57 strain-specific changes in cell adhesion and extracellular matrix protein genes were detected in hfe-/- mice. Mouse strain and age are each significantly associated with hepatic gene expression profiles in hfe-/- mice. These affects may underlie or reflect differences in iron loading in these mice.
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Affiliation(s)
- Seung-Min Lee
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, South Korea,
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Abstract
Hepatocellular carcinoma is one of the major malignant tumors in the world today. The number of new cases of the tumor increases year by year, and hepatocellular carcinoma almost always runs a fulminant course and carries an especially grave prognosis. It has a low resectability rate and a high recurrence rate after surgical intervention, and responds poorly to anticancer drugs and radiotherapy. Hepatocellular carcinoma does not have a uniform geographical distribution: rather, very high incidences occur in Eastern and Southeastern Asia and in sub-Saharan Black Africans. In these regions and populations, the tumor shows a distinct shift in age distribution toward the younger ages, seen to greatest extent in sub-Saharan Black Africans. In all populations, males are more commonly affected. The most common risk factors for hepatocellular carcinoma in resource-poor populations with a high incidence of the tumor are chronic hepatitis B virus infection and dietary exposure to the fungal hepatocarcinogen aflatoxin B1. These two causative agents act either singly or synergistically. Both the viral infection and exposure to the fungus occur from early childhood, and the tumor typically presents at an early age. Chronic hepatitis C virus infection is an important cause of hepatocellular carcinoma in resource-rich countries with a low incidence of the tumor. The infection is acquired in adulthood and hepatocellular carcinoma occurs later than it does with hepatitis B virus-induced tumors. In recent years, obesity and the metabolic syndrome have increased markedly in incidence and importance as a cause of hepatocellular carcinoma in some resource-rich regions. Chronic alcohol abuse remains an important risk factor for malignant transformation of hepatocytes, frequently in association with alcohol-induced cirrhosis. Excessive iron accumulation in hereditary hemochromatosis and dietary iron overload in the Black African population and membranous obstruction of the inferior cava cause the tumor in a few countries.
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Affiliation(s)
- Michael C Kew
- Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
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Abstract
In recent years it has become increasingly evident that excess body iron may be complicated by the supervention of hepatocellular carcinoma (HCC). Hereditary hemochromatosis (HH) was the first condition in which hepatic iron overload was shown to predispose to the development of HCC. The inherited predisposition to excessive absorption of dietary iron in HH is almost always the result of homozygosity of the C282Y mutation of the HFE gene, which causes inappropriately low secretion of hepcidin. HCC develops in 8-10% of patients with HH and is responsible for approximately 45% of deaths in the HCC patients. Cirrhosis is almost always present when HCC is diagnosed. Dietary iron overload is a condition which occurs in rural-dwelling Black Africans in southern Africa as a result of the consumption, over time, of large volumes of alcohol home-brewed in iron containers and having, as a consequence, a high iron content. Iron loading of the liver results and may be complicated by malignant transformation of the liver (relative risk of approximately 10.0). Accompanying cirrhosis does occur but is less common than that in HH. The development of HCC as a consequence of increased dietary iron, and the fact that it may develop in the absence of cirrhosis, has been confirmed in an animal model. Drinking water with a high iron content might contribute to the high incidence of HCC in parts of Taiwan. The metabolic syndrome [obesity, insulin resistance type 2 (or diabetes mellitus type 2), non-alcoholic fatty liver or non-alcoholic steatohepatitis] has in recent years become a major public health problem in some resource-rich countries. A link between excess body iron and insulin resistance or the metabolic syndrome has become apparent. The metabolic syndrome may be complicated by the supervention of HCC, and recent evidence suggests that increased body iron may contribute to this complication.
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Affiliation(s)
- Michael C. Kew
- Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, Africa
- Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
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Rossi E, Olynyk JK, Jeffrey GP. Clinical penetrance of C282Y homozygousHFEhemochromatosis. Expert Rev Hematol 2014; 1:205-16. [DOI: 10.1586/17474086.1.2.205] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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McKinnon EJ, Rossi E, Beilby JP, Trinder D, Olynyk JK. Factors that affect serum levels of ferritin in Australian adults and implications for follow-up. Clin Gastroenterol Hepatol 2014; 12:101-108.e4. [PMID: 23906872 DOI: 10.1016/j.cgh.2013.07.019] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 07/08/2013] [Accepted: 07/08/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Serum levels of ferritin are commonly measured to assess iron stores but are affected by factors such as obesity and chronic disease. Published reference ranges have not changed in decades, and the number of patients whose levels exceed the upper limits has been increasing. As a result, more patients are evaluated for iron overload. METHODS We compared serum levels of ferritin in 1188 Australian adults who participated in the 2005 Busselton Population Survey with levels from the 1995 survey. Parametric regression was used to assess the effects of body weight and biochemical parameters on serum level of ferritin to derive contemporary population-appropriate reference ranges. RESULTS In 2005, age-adjusted levels of ferritin were 21% higher in men (P < .0001) and 10% higher in women (P = .01) than in 1995; 31% of men exceeded levels of 300 μg/L, compared with 23% in 1995. Body mass index (BMI) ≥25 kg/m(2) was associated with higher levels of ferritin in men ≥35 years old and in postmenopausal women (P ≤ .002). Serum level of γ-glutamyltransferase (GGT) correlated with serum level of ferritin (P < .0001). In men, the estimated 95th percentiles ranged from 353 to 495 μg/L (<35 years), from 350 to 511 μg/L (≥35 years, BMI <25 kg/m(2)), and from 413 to 696 μg/L (≥35 years, BMI ≥25 kg/m(2)) when GGT levels were 10-75 IU/L. In women, the 95th percentiles ranged from 106 to 235 μg/L (premenopausal), from 222 to 323 μg/L (postmenopausal, BMI <25 kg/m(2)), and from 249 to 422 μg/L (postmenopausal, BMI ≥25 kg/m(2)) when GGT levels were 8-45 IU/L. CONCLUSION Serum levels of ferritin increased significantly between 1995 and 2005. Reference ranges that accommodate demographic and biomedical variations will assist clinicians in identifying individuals who require further evaluation for iron overload.
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Affiliation(s)
- Elizabeth J McKinnon
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia
| | | | - John P Beilby
- PathWest, Perth, Western Australia, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia, Australia
| | - Debbie Trinder
- School of Medicine and Pharmacology, Fremantle Hospital, University of Western Australia, Fremantle, Western Australia, Australia; Western Australian Institute of Medical Research, Perth, Western Australia, Australia
| | - John K Olynyk
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia; Department of Gastroenterology, Fremantle Hospital, Fremantle, Western Australia, Australia; Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia.
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Castiella A, Alústiza JM, Zapata E, Emparanza JI. Is MRI becoming the new gold standard for diagnosing iron overload in hemochromatosis and other liver iron disorders? IMAGING IN MEDICINE 2013; 5:515-524. [DOI: 10.2217/iim.13.60] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Paparo F, Cevasco L, Zefiro D, Biscaldi E, Bacigalupo L, Balocco M, Pongiglione M, Banderali S, Forni GL, Rollandi GA. Diagnostic value of real-time elastography in the assessment of hepatic fibrosis in patients with liver iron overload. Eur J Radiol 2013; 82:e755-61. [PMID: 24050879 DOI: 10.1016/j.ejrad.2013.08.038] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Revised: 07/12/2013] [Accepted: 08/18/2013] [Indexed: 01/11/2023]
Abstract
OBJECTIVE The objective of our prospective monocentric work was to determine the diagnostic value of real-time elastography (RTE) in the assessment of liver fibrosis in patients with iron overload, using transient elastography (TE) as reference standard. METHODS Sixty-seven consecutive patients with MRI detectable iron overload (T2*<6.3 ms) were enrolled. TE and RTE were performed on the same day as MRI. Elastograms were acquired by an experienced operator and analyzed by calculating the elastic ratio between perihepatic soft tissues and liver parenchyma. An elliptical ROI of 1cm(2) (Z1) was positioned in the liver parenchyma and a smaller elliptical ROI of 2mm(2) (Z2) was positioned in a homogeneously soft (red) region of the diaphragm, which was considered as internal control to calculate the elastic ratio Z2/Z1. RESULTS Seven patients were excluded because of invalid TE or RTE examinations. The remaining 60 patients were 57% males and 43% females (mean age: 42 [21-76] years), including 37 homozygous-β-thalassemics, 13 patients with β-thalassemia intermedia, 6 with primary hemochromatosis, and 4 with myelodysplastic syndrome. Increasing elastic ratios were significantly correlated with increasing TE values (r=0.645, 95% CI 0.468-0.772, P<0.0001). The mean elastic ratios for each METAVIR group were as follows: F0/1 = 1.9 ± 0.4; F2 = 2.2 ± 0.4; F3 = 2.9 ± 0.5; F4 = 3.2 ± 0.4. The diagnostic accuracy of RTE for F ≥ 2 evaluated by AUC-ROC analysis was 0.798 (95% CI 0.674-0.890). The diagnostic accuracy of RTE for F ≥ 3 was 0.909 (95% CI 0.806-0.968). At a cut-off ≥ 2.75, RTE showed a sensitivity of 70% (95% CI 45.7-88.1) and a specificity of 97.5% (95% CI 86.8-99.9). CONCLUSIONS In patients with MRI-detectable liver iron-overload RTE allows to discriminate between F0/1-F2 and F3-F4 with a reasonable diagnostic accuracy.
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Affiliation(s)
- Francesco Paparo
- Department of Radiology, E.O. Ospedali Galliera, Mura della Cappuccine 14, 16128 Genoa, Italy
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Wang QM, Du JL, Duan ZJ, Guo SB, Sun XY, Liu Z. Inhibiting heme oxygenase-1 attenuates rat liver fibrosis by removing iron accumulation. World J Gastroenterol 2013; 19:2921-2934. [PMID: 23704825 PMCID: PMC3660817 DOI: 10.3748/wjg.v19.i19.2921] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2013] [Revised: 03/08/2013] [Accepted: 03/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of the heme oxygenase (HO)-1/carbon monoxide system on iron deposition and portal pressure in rats with hepatic fibrosis induced by bile duct ligation (BDL).
METHODS: Male Sprague-Dawley rats were divided randomly into a Sham group, BDL group, Fe group, deferoxamine (DFX) group, zinc protoporphyrin (ZnPP) group and cobalt protoporphyrin (CoPP) group. The levels of HO-1 were detected using different methods. The serum carboxyhemoglobin (COHb), iron, and portal vein pressure (PVP) were also quantified. The plasma and mRNA levels of hepcidin were measured. Hepatic fibrosis and its main pathway were assessed using Van Gieson’s stain, hydroxyproline, transforming growth factor-β1 (TGF-β1), nuclear factor-E2-related factor 2 (Nrf2), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1).
RESULTS: Serum COHb and protein and mRNA expression levels of HO-1 and Nrf2 were increased in the BDL group compared with the Sham group and were much higher in the CoPP group. The ZnPP group showed lower expression of HO-1 and Nrf2 and lower COHb. The levels of iron and PVP were enhanced in the BDL group but were lower in the ZnPP and DFX groups and were higher in the CoPP and Fe groups. Hepcidin levels were higher, whereas superoxide dismutase levels were increased and malonaldehyde levels were decreased in the ZnPP and DFX groups. The ZnPP group also showed inhibited TGF-β1 expression and regulated TIMP-1/MMP-2 expression, as well as obviously attenuated liver fibrosis.
CONCLUSION: Reducing hepatic iron deposition and CO levels by inhibiting HO-1 activity though the Nrf2/Keap pathway could be helpful in improving hepatic fibrosis and regulating PVP.
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Taylor BA, Loeffler RB, Song R, McCarville MB, Hankins JS, Hillenbrand CM. Simultaneous field and R2 mapping to quantify liver iron content using autoregressive moving average modeling. J Magn Reson Imaging 2011; 35:1125-32. [PMID: 22180325 DOI: 10.1002/jmri.23545] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Accepted: 11/29/2011] [Indexed: 12/14/2022] Open
Abstract
PURPOSE To investigate the use of a complex multigradient echo (mGRE) acquisition and an autoregressive moving average (ARMA) model for simultaneous susceptibility and R 2 measurements for the assessment of liver iron content (LIC) in patients with iron overload. MATERIALS AND METHODS Fifty magnetic resonance imaging (MRI) exams with magnitude and phase mGRE images were processed using the ARMA model, which provides fat-separated field maps, R 2 maps, and T(1) -W imaging. The LIC was calculated by measuring the susceptibility between the liver and the right transverse abdominal muscle from the field maps. The relationship between LIC derived from susceptibility measurements and LIC from R 2 measurements was determined using linear least-squares regression analysis. RESULTS LIC measured from R 2 is highly correlated to the LIC with the susceptibility method (mg/g dry = 8.99 ± 0.15 × [mg Fe/mL of wet liver] -2.38 ± 0.29, R(2) = 0.94). The field inhomogeneity in the liver is correlated with R 2 (R(2) = 0.85). CONCLUSION By using the ARMA model on complex mGRE images, both susceptibility and R 2-based LIC measurements can be made simultaneously. The susceptibility measurement can be used to help verify R 2 measurements in the assessment of iron overload.
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Affiliation(s)
- Brian A Taylor
- Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
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Cosme Á, Ojeda E, Bujanda L, De Juan MD, Alustiza JM, Castiella A, Zapata E, Gómez A. Características clínicas y evolutivas de una familia con hemocromatosis hereditaria tipo 1. GACETA MÉDICA DE BILBAO 2011; 108:42-48. [DOI: 10.1016/j.gmb.2010.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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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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Ageing, telomeres, senescence, and liver injury. J Hepatol 2010; 53:950-61. [PMID: 20739078 DOI: 10.1016/j.jhep.2010.06.009] [Citation(s) in RCA: 132] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2010] [Revised: 06/24/2010] [Accepted: 06/26/2010] [Indexed: 02/08/2023]
Abstract
Populations in developed countries continue to grow older and an understanding of the ageing process to allow healthy ageing carries important medical implications. Older individuals are more susceptible to most acquired liver disorders and more vulnerable to the consequences of liver disease. Accordingly, age is a critical determinant of outcome for hepatitis C virus infection and liver transplantation. In this review we describe changes in the ageing liver and discuss mechanisms of senescence at the cellular level. In particular, we focus on mechanisms by which inflammation, oxidative stress, and oncogenic stress accelerate cellular senescence. In the setting of chronic hepatic injury and inflammation, cellular senescence functions as an essential stress-response mechanism to limit the proliferation of damaged cells and reduce the risk of malignancy, but this benefit is achieved at the expense of senescence-related organ dysfunction. The dual role of cell senescence in chronic liver disease will make this an intriguing but challenging area for future clinical interventions.
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Ferroportin disease: a systematic meta-analysis of clinical and molecular findings. J Hepatol 2010; 53:941-9. [PMID: 20691492 PMCID: PMC2956830 DOI: 10.1016/j.jhep.2010.05.016] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2009] [Revised: 05/09/2010] [Accepted: 05/15/2010] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS Classical ferroportin disease is characterized by hyperferritinemia, normal transferrin saturation, and iron overload in macrophages. A non-classical form is characterized by additional hepatocellular iron deposits and a high transferrin saturation. Both forms demonstrate autosomal dominant transmission and are associated with ferroportin gene (SLC40A1) mutations. SLC40A1 encodes a cellular iron exporter expressed in macrophages, enterocytes, and hepatocytes. The aim of the analysis is to determine the penetrance of SLC40A1 mutations and to evaluate in silico tools to predict the functional impairment of ferroportin mutations as an alternative to in vitro studies. METHODS We conducted a systematic review of the literature and meta-analysis of the biochemical presentation, genetics, and pathology of ferroportin disease. RESULTS Of the 176 individuals reported with SLC40A1 mutations, 80 were classified as classical phenotype with hyperferritinemia and normal transferrin saturation. The non-classical phenotype with hyperferritinemia and elevated transferrin saturation was present in 53 patients. The remaining patients had normal serum ferritin or the data were reported incompletely. Despite an increased hepatic iron concentration in all biopsied patients, significant fibrosis or cirrhosis was present in only 11%. Hyperferritinemia was present in 86% of individuals with ferroportin mutations. Bio-informatic analysis of ferroportin mutations showed that the PolyPhen score has a sensitivity of 99% and a specificity of 67% for the discrimination between ferroportin mutations and polymorphisms. CONCLUSIONS In contrast to HFE hemochromatosis, ferroportin disease has a high penetrance, is genetically heterogeneous and is rarely associated with fibrosis. Non-classical ferroportin disease is associated with a higher risk of fibrosis and a more severe overload of hepatic iron.
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Castiella A, Zapata E, Alústiza JM. Non-invasive methods for liver fibrosis prediction in hemochromatosis: One step beyond. World J Hepatol 2010; 2:251-255. [PMID: 21161006 PMCID: PMC2999291 DOI: 10.4254/wjh.v2.i7.251] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2010] [Revised: 07/07/2010] [Accepted: 07/14/2010] [Indexed: 02/06/2023] Open
Abstract
Advances in recent years in the understanding of, and the genetic diagnosis of hereditary hemochromatosis (HH) have changed the approach to iron overload hereditary diseases. The ability to use a radiologic tool (MRI) that accurately provides liver iron concentration determination, and the presence of non-invasive serologic markers for fibrosis prediction (serum ferritin, platelet count, transaminases, etc), have diminished the need for liver biopsy for diagnosis and prognosis of this disease. Consequently, the role of liver biopsy in iron metabolism disorders is changing. Furthermore, the irruption of transient elastography to assess liver stiffness, and, more recently, the ability to determine liver fibrosis by means of MRI elastography will change this role even more, with a potential drastic decline in hepatic biopsies in years to come. This review will provide a brief summary of the different non-invasive methods available nowadays for diagnosis and prognosis in HH, and point out potential new techniques that could come about in the next years for fibrosis prediction, thus avoiding the need for liver biopsy in a greater number of patients. It is possible that liver biopsy will remain useful for the diagnosis of associated diseases, where other non-invasive means are not possible, or for those rare cases displaying discrepancies between radiological and biochemical markers.
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Affiliation(s)
- Agustin Castiella
- Agustin Castiella, Eva Zapata, Gastroenterology Service, Mendaro Hospital, Mendaro 20850, Spain
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