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Anastasopoulos NA, Barbouti A, Goussia AC, Christodoulou DK, Glantzounis GK. Exploring the Role of Metabolic Hyperferritinaemia (MHF) in Steatotic Liver Disease (SLD) and Hepatocellular Carcinoma (HCC). Cancers (Basel) 2025; 17:842. [PMID: 40075688 PMCID: PMC11899477 DOI: 10.3390/cancers17050842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/24/2025] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
The increasing prevalence of the spectrum of Steatotic Liver Disease (SLD), including Metabolic-Associated Steatotic Liver Disease (MASLD), Metabolic-Associated Steatohepatitis (MASH), and progression to Cirrhosis and Hepatocellular Carcinoma (HCC) has led to intense research in disease pathophysiology, with many studies focusing on the role of iron. Iron overload, which is often observed in patients with SLD as a part of metabolic hyperferritinaemia (MHF), particularly in the reticuloendothelial system (RES), can exacerbate steatosis. This imbalance in iron distribution, coupled with a high-fat diet, can further promote the progression of SLD by means of oxidative stress triggering inflammation and activating hepatic stellate cells (HSCs), therefore leading to fibrosis and progression of simple steatosis to the more severe MASH. The influence of iron overload in disease progression has also been shown by the complex role of ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation. Ferroptosis depletes the liver's antioxidant capacity, further contributing to the development of MASH, while its role in MASH-related HCC is potentially linked to alternations in the tumour microenvironment, as well as ferroptosis resistance. The iron-rich steatotic hepatic environment becomes prone to hepatocarcinogenesis by activation of several pro-carcinogenic mechanisms including epithelial-to-mesenchymal transition and deactivation of DNA damage repair. Biochemical markers of iron overload and deranged metabolism have been linked to all stages of SLD and its associated HCC in multiple patient cohorts of diverse genetic backgrounds, enhancing our daily clinical understanding of this interaction. Further understanding could lead to enhanced therapies for SLD management and prevention.
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Affiliation(s)
- Nikolaos-Andreas Anastasopoulos
- HPB Unit, Department of Surgery, University Hospital of Ioannina, 45110 Ioannina, Greece
- Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, London W12 0HS, UK
| | - Alexandra Barbouti
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Anna C. Goussia
- Department of Pathology, University Hospital of Ioannina, 45110 Ioannina, Greece
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Zoller H, Tilg H. Ferritin-a promising biomarker in MASLD. Gut 2024; 73:720-721. [PMID: 38538068 DOI: 10.1136/gutjnl-2023-331848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 02/27/2024] [Indexed: 04/07/2024]
Affiliation(s)
- Heinz Zoller
- Department of Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Tirol, Austria
- Christian Doppler Laboratory on Iron and Phosphate Biology, Christian Doppler Forschungsgesellschaft, Innsbruck, Tirol, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medizinische Universitat Innsbruck, Innsbruck, Tirol, Austria
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3
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Liu Y, Qin X, Chen T, Chen M, Wu L, He B. Exploring the interactions between metabolic dysfunction-associated fatty liver disease and micronutrients: from molecular mechanisms to clinical applications. Front Nutr 2024; 11:1344924. [PMID: 38549744 PMCID: PMC10973017 DOI: 10.3389/fnut.2024.1344924] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 03/05/2024] [Indexed: 01/06/2025] Open
Abstract
Metabolic (dysfunction)-associated fatty liver disease (MAFLD) has emerged as a significant global health concern, representing a major cause of liver disease worldwide. This condition spans a spectrum of histopathologic stages, beginning with simple fatty liver (MAFL), characterized by over 5% fat accumulation, and advancing to metabolic (dysfunction)-associated steatohepatitis, potentially leading to hepatocellular carcinoma. Despite extensive research, there remains a substantial gap in effective therapeutic interventions. This condition's progression is closely tied to micronutrient levels, crucial for biological functions like antioxidant activities and immune efficiency. The levels of these micronutrients exhibit considerable variability among individuals with MAFLD. Moreover, the extent of deficiency in these nutrients can vary significantly throughout the different stages of MAFLD, with disease progression potentially exacerbating these deficiencies. This review focuses on the role of micronutrients, particularly vitamins A, D, E, and minerals like iron, copper, selenium, and zinc, in MAFLD's pathophysiology. It highlights how alterations in the homeostasis of these micronutrients are intricately linked to the pathophysiological processes of MAFLD. Concurrently, this review endeavors to harness the existing evidence to propose novel therapeutic strategies targeting these vitamins and minerals in MAFLD management and offers new insights into disease mechanisms and treatment opportunities in MAFLD.
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Affiliation(s)
- Yuan Liu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Xiang Qin
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Tianzhu Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Mengyao Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Liyan Wu
- Department of Gastroenterology, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Beihui He
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
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Inai Y, Izawa T, Kamei T, Fujiwara S, Tanaka M, Yamate J, Kuwamura M. Difference in the Mechanism of Iron Overload-Enhanced Acute Hepatotoxicity Induced by Thioacetamide and Carbon Tetrachloride in Rats. Toxicol Pathol 2024; 52:55-66. [PMID: 38528719 DOI: 10.1177/01926233241235623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Abstract
Iron overload has been recognized as a risk factor for liver disease; however, little is known about its pathological role in the modification of liver injury. The purpose of this study is to investigate the influence of iron overload on liver injury induced by two hepatotoxicants with different pathogenesis in rats. Rats were fed a control (Cont), 0.8% high-iron (0.8% Fe), or 1% high-iron diet (1% Fe) for 4 weeks and were then administered with saline, thioacetamide (TAA), or carbon tetrachloride (CCl4). Hepatic and systemic iron overload were seen in the 0.8% and 1% Fe groups. Twenty-four hours after administration, hepatocellular necrosis induced by TAA and hepatocellular necrosis, degeneration, and vacuolation induced by CCl4, as well as serum transaminase values, were exacerbated in the 0.8% and 1% Fe groups compared to the Cont group. On the other hand, microvesicular vacuolation induced by CCl4 was decreased in 0.8% and 1% Fe groups. Hepatocellular DNA damage was increased by iron overload in both models, whereas a synergistic effect of oxidative stress by excess iron and hepatotoxicant was only present in the CCl4 model. The data showed that dietary iron overload exacerbates TAA- and CCl4-induced acute liver injury with different mechanisms.
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Affiliation(s)
- Yohei Inai
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, Osaka, Japan
| | - Takeshi Izawa
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, Osaka, Japan
| | - Tomomi Kamei
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, Osaka, Japan
| | - Sho Fujiwara
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, Osaka, Japan
| | - Miyuu Tanaka
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, Osaka, Japan
| | - Jyoji Yamate
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, Osaka, Japan
| | - Mitsuru Kuwamura
- Laboratory of Veterinary Pathology, Osaka Metropolitan University, Osaka, Japan
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5
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Roeb E. [Nonalcoholic fatty liver disease : Hepatic manifestations of metabolic syndrome]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2023; 64:323-328. [PMID: 36580094 DOI: 10.1007/s00108-022-01448-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/28/2022] [Indexed: 12/30/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is nowadays the leading cause of chronic liver disease worldwide and shows a strong association with the metabolic syndrome. The NAFLD is a systemic disease associated with a plethora of extrahepatic manifestations and comorbidities, such as type 2 diabetes, obesity and dyslipidemia. These extrahepatic disorders are related either to secondary effects of the associated obesity or to pathophysiological effects of insulin resistance in NAFLD. The three most common causes of the observed increased morbidity and mortality associated with NAFLD are cardiovascular diseases, liver diseases, such as cirrhosis, and cancer. In this overview, cardiovascular diseases, type 2 diabetes mellitus and chronic kidney diseases in connection with NAFLD are discussed as examples, as well as tumor entities, in particular colon cancer, lung diseases (obstructive sleep apnea), endocrine diseases (hypothyroidism) and systemic phenomena associated with NAFLD (e.g. iron overload and thrombophilia). In addition to focusing on the pathogenesis of these extrahepatic manifestations, the clinical implications are highlighted. So far there are no drugs approved for the indication NAFLD in Germany. The new NAFLD S2k guidelines offer a way out of the current "therapeutic nihilism". Diagnostic and therapeutic algorithms based on the metabolic comorbidities and the stage of fibrosis are designed with practical relevance and can be used in everyday medical practice. Therefore, clear basic measures and drug recommendations can be given for NAFLD depending on the comorbidities and stage of fibrosis.
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Affiliation(s)
- Elke Roeb
- Schwerpunkt Gastroenterologie, Zentrum für Innere Medizin, Justus-Liebig-Universität & Universitätsklinikum Gießen, Klinikstr. 33, 35392, Gießen, Deutschland.
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Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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Malnick SDH, Alin P, Somin M, Neuman MG. Fatty Liver Disease-Alcoholic and Non-Alcoholic: Similar but Different. Int J Mol Sci 2022; 23:16226. [PMID: 36555867 PMCID: PMC9783455 DOI: 10.3390/ijms232416226] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
In alcohol-induced liver disease (ALD) and in non-alcoholic fatty liver disease (NAFLD), there are abnormal accumulations of fat in the liver. This phenomenon may be related to excessive alcohol consumption, as well as the combination of alcohol consumption and medications. There is an evolution from simple steatosis to steatohepatitis, fibrosis and cirrhosis leading to hepatocellular carcinoma (HCC). Hepatic pathology is very similar regarding non-alcoholic fatty liver disease (NAFLD) and ALD. Initially, there is lipid accumulation in parenchyma and progression to lobular inflammation. The morphological changes in the liver mitochondria, perivenular and perisinusoidal fibrosis, and hepatocellular ballooning, apoptosis and necrosis and accumulation of fibrosis may lead to the development of cirrhosis and HCC. Medical history of ethanol consumption, laboratory markers of chronic ethanol intake, AST/ALT ratio on the one hand and features of the metabolic syndrome on the other hand, may help in estimating the contribution of alcohol intake and the metabolic syndrome, respectively, to liver steatosis.
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Affiliation(s)
- Stephen D. H. Malnick
- Department of Internal Medicine, Kaplan Medical Center, Affiliated to Hebrew University, Rehovot 76100, Israel
| | - Pavel Alin
- Department of Internal Medicine, Kaplan Medical Center, Affiliated to Hebrew University, Rehovot 76100, Israel
| | - Marina Somin
- Department of Internal Medicine, Kaplan Medical Center, Affiliated to Hebrew University, Rehovot 76100, Israel
| | - Manuela G. Neuman
- In Vitro Drug Safety and Biotechnology, Department of Pharmacology and Toxicology, Temerity Faculty of Medicine, University of Toronto, Toronto, ON M5G OA3, Canada
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Liu C, Chen Y, Zhang Z, Xie J, Yu C, Xu L, Li Y. Iron Status and NAFLD among European Populations: A Bidirectional Two-Sample Mendelian Randomization Study. Nutrients 2022; 14:5237. [PMID: 36558395 PMCID: PMC9788387 DOI: 10.3390/nu14245237] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/05/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
Background and aim: Previous observational studies have suggested a paradoxical relationship between iron status and the risk of non-alcoholic fatty liver disease (NAFLD). Observed associations in these epidemiological studies fail to show sequential temporality and suffer from problems of confounding. Therefore, we performed a bidirectional two-sample Mendelian randomization (MR) to evaluate the relationship between serum iron status and NAFLD. Methods: The inverse weighted method (IVW) meta-analysis with the fixed-effect model was the main method to estimate the relationship between iron status, including serum ferritin, iron, transferrin saturation (TSAT) and total iron-binding capacity (TIBC), and NAFLD. Weighted median, penalized weighted median, and MR Robust Adjusted Profile Score (MR RAPS) methods were used as additional analyses. Sensitivity analyses were performed with Cochran's Q test, MR-Egger regression, Steiger filtering, and the MR PRESSO test. Results: Iron status, including serum ferritin, iron, and TSAT, was associated with an increased risk of NAFLD (odds ratio (OR) (95% confidence interval (CI)): 1.25 (1.06, 1.48); 1.24 (1.05, 1.46), 1.16 (1.02, 1.31), respectively). In contrast, minimal effects of NAFLD on serum ferritin, iron, TSAT, and TIBC were observed (OR (95% CI): 1.01 (1.00, 1.02), 1.01 (1.00, 1.02), 1.03 (1.01, 1.05), 1.03 (1.01, 1.05), respectively). Conclusions: Our findings corroborated the causal associations between serum ferritin, iron, TSAT, and NAFLD, which might suggest the potential benefits of iron-related therapy. In addition, NAFLD might, in turn, slightly affect iron homeostasis indicated as serum ferritin, iron, TSAT, and TIBC, but this needs to be further confirmed.
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Affiliation(s)
- Cenqin Liu
- Department of Gastroenterology, Ningbo Hospital, Zhejiang University, Ningbo 315010, China
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
- Department of Gastroenterology, Ningbo First Hospital, Ningbo 315010, China
| | - Yishu Chen
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Zhixin Zhang
- Department of Gastroenterology, Ningbo First Hospital, Ningbo 315010, China
- School of Medicine, Ningbo University, Ningbo 315010, China
| | - Jiarong Xie
- Department of Gastroenterology, Ningbo First Hospital, Ningbo 315010, China
- School of Medicine, Ningbo University, Ningbo 315010, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Lei Xu
- Department of Gastroenterology, Ningbo Hospital, Zhejiang University, Ningbo 315010, China
- Department of Gastroenterology, Ningbo First Hospital, Ningbo 315010, China
| | - Youming Li
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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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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10
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Xiong F, Zhou Q, Huang X, Cao P, Wang Y. Ferroptosis plays a novel role in nonalcoholic steatohepatitis pathogenesis. Front Pharmacol 2022; 13:1055793. [PMID: 36532757 PMCID: PMC9755204 DOI: 10.3389/fphar.2022.1055793] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/23/2022] [Indexed: 09/29/2023] Open
Abstract
Ferroptosis relies on iron, and ferroptotic cell death is triggered when the balance of the oxidation-reduction system is disrupted by excessive lipid peroxide accumulation. A close relationship between ferroptosis and nonalcoholic steatohepatitis (NASH) is formed by phospholipid peroxidation substrates, bioactive iron, and reactive oxygen species (ROS) neutralization systems. Recent studies into ferroptosis during NASH development might reveal NASH pathogenesis and drug targets. Our review summarizes NASH pathogenesis from the perspective of ferroptosis mechanisms. Further, we discuss the relationship between mitochondrial dysfunction, ferroptosis, and NASH. Finally, potential pharmacological therapies directed to ferroptosis in NASH are hypothesized.
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Affiliation(s)
- Fei Xiong
- Department of Gastroenterology, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, China
| | - Qiao Zhou
- Department of Rheumatology and Immunology, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, China
| | - Xiaobo Huang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Peng Cao
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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11
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Chen H. Iron metabolism in non-alcoholic fatty liver disease: A promising therapeutic target. LIVER RESEARCH 2022; 6:203-213. [PMID: 39957910 PMCID: PMC11791839 DOI: 10.1016/j.livres.2022.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/05/2022] [Accepted: 09/12/2022] [Indexed: 11/23/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide, and is closely associated with the increased risk of the prevalence of obesity and diabetes. NAFLD begins with the presence of >5% excessive lipid accumulation in the liver, and potentially develops into non-alcoholic steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. Therefore, insight into the pathogenesis of NAFLD is of key importance to its effective treatment. Iron is an essential element in the life of all mammalian organisms. However, the free iron deposition is positively associated with histological severity in NAFLD patients due to the production of reactive oxygen species via the Fenton reaction. Recently, several iron metabolism-targeted therapies, such as phlebotomy, iron chelators, nanotherapeutics. and ferroptosis, have shown their potential as a therapeutic option in the treatment of NAFLD and as a clinical strategy to intervene in the progression of NAFLD. Herein, we review the recent overall evidence on iron metabolism and provide the mechanism of hepatic iron overload-induced liver pathologies and the recent advances in iron metabolism-targeted therapeutics in the treatment of NAFLD.
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Affiliation(s)
- Hanqing Chen
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou Key Laboratory of Digestive Diseases, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
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12
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Fernandez M, Lokan J, Leung C, Grigg A. A critical evaluation of the role of iron overload in fatty liver disease. J Gastroenterol Hepatol 2022; 37:1873-1883. [PMID: 35906772 DOI: 10.1111/jgh.15971] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 07/16/2022] [Accepted: 07/27/2022] [Indexed: 12/09/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has been associated with a condition known as the dysmetabolic iron overload syndrome, but the frequency and severity of iron overload in NAFLD is not well described. There is emerging evidence that mild to moderate excess hepatic iron can aggravate the risk of progression of NAFLD to nonalcoholic steatohepatitis and eventually cirrhosis. Mechanisms are postulated to be via reactive oxygen species, inflammatory cytokines, lipid oxidation, and oxidative stress. The aim of this review is to assess the evidence for true hepatic iron overload in NAFLD, to discuss the pathogenesis by which excess iron may be toxic, and to critically evaluate the studies designed to deplete iron by regular venesection. In brief, the studies are inconclusive due to heterogeneity in eligibility criteria, sample size, randomization, hepatic iron measurement, serial histological endpoints, target ferritin levels, length of venesection, and degree of confounding lifestyle intervention. We propose a trial designed to overcome the limitations of these studies.
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Affiliation(s)
- Monique Fernandez
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Julie Lokan
- Department of Anatomical Pathology, Austin Health, Heidelberg, Victoria, Australia
| | - Christopher Leung
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.,Departments of Gastroenterology and Hepatology, Austin Health, Heidelberg, Victoria, Australia
| | - Andrew Grigg
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.,Department of Clinical Haematology, Austin Health, Heidelberg, Victoria, Australia
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13
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Hsu CC, Senussi NH, Fertrin KY, Kowdley KV. Iron overload disorders. Hepatol Commun 2022; 6:1842-1854. [PMID: 35699322 PMCID: PMC9315134 DOI: 10.1002/hep4.2012] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 04/06/2022] [Accepted: 04/16/2022] [Indexed: 01/19/2023] Open
Abstract
Iron overload disorders represent a variety of conditions that lead to increased total body iron stores and resultant end-organ damage. An elevated ferritin and transferrin-iron saturation can be commonly encountered in the evaluation of elevated liver enzymes. Confirmatory homeostatic iron regulator (HFE) genetic testing for C282Y and H63D, mutations most encountered in hereditary hemochromatosis, should be pursued in evaluation of hyperferritinemia. Magnetic resonance imaging with quantitative assessment of iron content or liver biopsy (especially if liver disease is a cause of iron overload) should be used as appropriate. A secondary cause for iron overload should be considered if HFE genetic testing is negative for the C282Y homozygous or C282Y/H63D compound heterozygous mutations. Differential diagnosis of secondary iron overload includes hematologic disorders, iatrogenic causes, or chronic liver diseases. More common hematologic disorders include thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, sickle cell disease, or pyruvate kinase deficiency. If iron overload has been excluded, evaluation for causes of hyperferritinemia should be pursued. Causes of hyperferritinemia include chronic liver disease, malignancy, infections, kidney failure, and rheumatic conditions, such as adult-onset Still's disease or hemophagocytic lymphohistiocytosis. In this review, we describe the diagnostic testing of patients with suspected hereditary hemochromatosis, the evaluation of patients with elevated serum ferritin levels, and signs of secondary overload and treatment options for those with secondary iron overload.
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Affiliation(s)
- Christine C Hsu
- Medstar Georgetown University HospitalMedstar Georgetown Transplant InstituteWashingtonDistrict of ColumbiaUSA
| | - Nizar H Senussi
- Gastroenterology and HepatologyUniversity of New MexicoAlbuquerqueNew MexicoUSA
| | - Kleber Y Fertrin
- Division of HematologyDepartment of MedicineUniversity of WashingtonWashingtonUSA
| | - Kris V Kowdley
- Liver Institute Northwest and Elson S. Floyd College of MedicineWashington State UniversityWashingtonUSA
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14
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Zoller H, Schaefer B, Vanclooster A, Griffiths B, Bardou-Jacquet E, Corradini E, Porto G, Ryan J, Cornberg M. EASL Clinical Practice Guidelines on haemochromatosis. J Hepatol 2022; 77:479-502. [PMID: 35662478 DOI: 10.1016/j.jhep.2022.03.033] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 03/29/2022] [Indexed: 12/15/2022]
Abstract
Haemochromatosis is characterised by elevated transferrin saturation (TSAT) and progressive iron loading that mainly affects the liver. Early diagnosis and treatment by phlebotomy can prevent cirrhosis, hepatocellular carcinoma, diabetes, arthropathy and other complications. In patients homozygous for p.Cys282Tyr in HFE, provisional iron overload based on serum iron parameters (TSAT >45% and ferritin >200 μg/L in females and TSAT >50% and ferritin >300 μg/L in males and postmenopausal women) is sufficient to diagnose haemochromatosis. In patients with high TSAT and elevated ferritin but other HFE genotypes, diagnosis requires the presence of hepatic iron overload on MRI or liver biopsy. The stage of liver fibrosis and other end-organ damage should be carefully assessed at diagnosis because they determine disease management. Patients with advanced fibrosis should be included in a screening programme for hepatocellular carcinoma. Treatment targets for phlebotomy are ferritin <50 μg/L during the induction phase and <100 μg/L during the maintenance phase.
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Jaccard E, Seyssel K, Gouveia A, Vergely C, Baratali L, Gubelmann C, Froissart M, Favrat B, Marques-Vidal P, Tappy L, Waeber G. Effect of acute iron infusion on insulin secretion: A randomized, double-blind, placebo-controlled trial. EClinicalMedicine 2022; 48:101434. [PMID: 35706490 PMCID: PMC9092517 DOI: 10.1016/j.eclinm.2022.101434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 04/01/2022] [Accepted: 04/14/2022] [Indexed: 11/29/2022] Open
Abstract
Background Chronic exposure to high iron levels increases diabetes risk partly by inducing oxidative stress, but the consequences of acute iron administration on beta cells are unknown. We tested whether the acute administration of iron for the correction of iron deficiency influenced insulin secretion and the production of reactive oxygen species. Methods Single-center, double-blinded, randomized controlled trial conducted between June 2017 and March 2020. 32 women aged 18 to 47 years, displaying symptomatic iron deficiency without anaemia, were recruited from a community setting and randomly allocated (1:1) to a single infusion of 1000 mg intravenous ferric carboxymaltose (iron) or saline (placebo). The primary outcome was the between group mean difference from baseline to day 28 in first and second phase insulin secretion, assessed by a two-step hyperglycaemic clamp. All analyses were performed by intention to treat. This trial was registered in ClinicalTrials.gov NCT03191201. Findings Iron infusion did not affect first and second phase insulin release. For first phase, the between group mean difference from baseline to day 28 was 0 μU × 10 min/mL [95% CI, -22 to 22, P = 0.99]. For second phase, it was -5 μUx10min/mL [95% CI, -161 to 151; P = 0.95] at the first plateau of the clamp and -249 μUx10min/mL [95% CI, -635 to 137; P = 0.20] at the second plateau. Iron infusion increased serum ascorbyl/ascorbate ratio, a marker of plasma oxidative stress, at day 14, with restoration of normal ratio at day 28 relative to placebo. Finally, high-sensitive C-reactive protein levels remained similar among groups. Interpretation In iron deficient women without anaemia, intravenous administration of 1000 mg of iron in a single sitting did not impair glucose-induced insulin secretion despite a transient increase in the levels of circulating reactive oxygen species. Funding The Swiss National Science Foundation, University of Lausanne and Leenaards, Raymond-Berger and Placide Nicod Foundations.
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Affiliation(s)
- Evrim Jaccard
- Department of Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, rue du Bugnon 46, Lausanne 1011, Switzerland
| | - Kévin Seyssel
- Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, rue du Bugnon 7a, Lausanne 1005, Switzerland
| | - Alexandre Gouveia
- Center for Primary Care and Public Health, University of Lausanne, rue du Bugnon 44, Lausanne, Switzerland
| | - Catherine Vergely
- Pathophysiology and Epidemiology of Cerebro-Cardiovascular Diseases (PEC2, EA7460),UFR des Sciences de Santé, University of Bourgogne Franche-Comté, 7 boulevard Jeanne d’ Arc, Dijon 21079, France
| | - Laila Baratali
- Department of Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, rue du Bugnon 46, Lausanne 1011, Switzerland
| | - Cédric Gubelmann
- Department of Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, rue du Bugnon 46, Lausanne 1011, Switzerland
| | - Marc Froissart
- Clinical Research Center, CHUV, University of Lausanne, Switzerland
| | - Bernard Favrat
- Center for Primary Care and Public Health, University of Lausanne, rue du Bugnon 44, Lausanne, Switzerland
| | - Pedro Marques-Vidal
- Department of Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, rue du Bugnon 46, Lausanne 1011, Switzerland
| | - Luc Tappy
- Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, rue du Bugnon 7a, Lausanne 1005, Switzerland
| | - Gérard Waeber
- Department of Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, rue du Bugnon 46, Lausanne 1011, Switzerland
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de Jesus RN, Callejas GH, David Mendonça Chaim F, Antonio Gestic M, Pimentel Utrini M, Callejas-Neto F, Adami Chaim E, Cazzo E. Roux-en-Y Gastric Bypass as a Treatment for Hepatic Iron Overload: An Exploratory Study. Obes Surg 2022; 32:2438-2444. [PMID: 35543890 DOI: 10.1007/s11695-022-06103-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/04/2022] [Accepted: 05/04/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Excess bodily iron content is commonly associated with obesity and metabolic associated medical conditions and is thought to lead to cardiovascular disease. The effect of Roux-en-Y gastric bypass (RYGB) on hepatic iron overload remains to be determined. OBJECTIVE To assess the evolution of histologically proven hepatic iron overload after RYGB. METHODS This is an exploratory historical cohort study in which 42 individuals who underwent RYGB, and then a second surgical procedure had paired liver biopsies collected. Hepatic iron overload and NAFLD features were assessed through histopathological examination. Biochemical iron metabolism parameters were also assessed. RESULTS The mean age at RYGB was 47 ± 10.2 years and 92.9% were female. The average time elapsed between RYGB and the second surgical procedure was 20.6 ± 15.4 months. The mean percentage of total weight loss between the two procedures was 26.7 ± 9.4%. Significant reductions in ferritin (220.8 ± 202.9 vs. 101.6 ± 116.7 ng/mL; p = 0.006), hemoglobin (13.7 ± 1.8 vs. 12.1 ± 2.6 g/dL; p = 0.01), and red blood cell count (4.7 ± 0.7 vs. 4.3 ± 0.5 106/mm3; p = 0.003) were observed, as well as reductions in the frequencies of steatosis (83.3% vs. 23.8%; p < 0.0001) and steatohepatitis (52.4% vs. 11.9%; p < 0.0001). The frequency of hepatic iron overload significantly decreased from 16.7 to 2.4% (p = 0.03). CONCLUSION RYGB led to a significant decrease in hepatic iron overload, emerging as a possible therapeutical tool for this condition in individuals with obesity and dysmetabolic iron overload syndrome.
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Affiliation(s)
| | | | | | | | | | | | - Elinton Adami Chaim
- Department of Surgery, State University of Campinas (UNICAMP), Campinas, Brazil
| | - Everton Cazzo
- Department of Surgery, State University of Campinas (UNICAMP), Campinas, Brazil.
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17
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Smirne C, Croce E, Di Benedetto D, Cantaluppi V, Comi C, Sainaghi PP, Minisini R, Grossini E, Pirisi M. Oxidative Stress in Non-Alcoholic Fatty Liver Disease. LIVERS 2022; 2:30-76. [DOI: 10.3390/livers2010003] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a challenging disease caused by multiple factors, which may partly explain why it still remains an orphan of adequate therapies. This review highlights the interaction between oxidative stress (OS) and disturbed lipid metabolism. Several reactive oxygen species generators, including those produced in the gastrointestinal tract, contribute to the lipotoxic hepatic (and extrahepatic) damage by fatty acids and a great variety of their biologically active metabolites in a “multiple parallel-hit model”. This leads to inflammation and fibrogenesis and contributes to NAFLD progression. The alterations of the oxidant/antioxidant balance affect also metabolism-related organelles, leading to lipid peroxidation, mitochondrial dysfunction, and endoplasmic reticulum stress. This OS-induced damage is at least partially counteracted by the physiological antioxidant response. Therefore, modulation of this defense system emerges as an interesting target to prevent NAFLD development and progression. For instance, probiotics, prebiotics, diet, and fecal microbiota transplantation represent new therapeutic approaches targeting the gut microbiota dysbiosis. The OS and its counter-regulation are under the influence of individual genetic and epigenetic factors as well. In the near future, precision medicine taking into consideration genetic or environmental epigenetic risk factors, coupled with new OS biomarkers, will likely assist in noninvasive diagnosis and monitoring of NAFLD progression and in further personalizing treatments.
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Affiliation(s)
- Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Eleonora Croce
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Davide Di Benedetto
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Vincenzo Cantaluppi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Cristoforo Comi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Pier Paolo Sainaghi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Elena Grossini
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
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Pădureanu V, Dop D, Drăgoescu AN, Pădureanu R, Mușetescu AE, Nedelcu L. Non-alcoholic fatty liver disease and hematologic manifestations (Review). Exp Ther Med 2021; 22:1355. [PMID: 34659501 PMCID: PMC8515549 DOI: 10.3892/etm.2021.10790] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 08/16/2021] [Indexed: 11/30/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multisystem disease, and it is associated with numerous extra-hepatic manifestations or additional co-occurring diseases. The aim of the present review was the identification and management of the hematologic manifestations of NAFLD. One of the triggers is considered to be iron abnormalities. Increased ferritin levels, hepatic iron deposits and iron overload are associated with NAFLD. The iron overload degree and severity are associated with the level of liver fibrosis and with the risk for hepatocellular carcinoma. Excess iron deposits refers to the dysmetabolic iron overload syndrome (DIOS) and it is characterized by steatosis associated with moderate tissue iron deposition and increased levels of serum ferritin, while the serum transferrin saturation was normal. Further prospective studies are necessary to determine whether NAFLD has an independent risk for hematologic symptoms, besides the known risk factors. Future studies are also needed in order to assess the increasing impact of NAFLD on the micro- and macro-vascular complications of this systemic disease.
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Affiliation(s)
- Vlad Pădureanu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dalia Dop
- Department of Pediatrics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Alice Nicoleta Drăgoescu
- Department of Anesthesiology and Intensive Care, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Rodica Pădureanu
- Department of Internal Medicine, Emergency Clinical County Hospital of Craiova, 200642 Craiova, Romania
| | - Anca Emanuela Mușetescu
- Department of Rheumatology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Laurențiu Nedelcu
- Department of Internal Medicine, Faculty of Medicine, Transylvania University Brasov, 500019 Brașov, Romania
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19
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Viveiros A, Schaefer B, Panzer M, Henninger B, Plaikner M, Kremser C, Franke A, Franzenburg S, Hoeppner MP, Stauder R, Janecke A, Tilg H, Zoller H. MRI-Based Iron Phenotyping and Patient Selection for Next-Generation Sequencing of Non-Homeostatic Iron Regulator Hemochromatosis Genes. Hepatology 2021; 74:2424-2435. [PMID: 34048062 PMCID: PMC8596846 DOI: 10.1002/hep.31982] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/13/2021] [Accepted: 05/13/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS High serum ferritin is frequent among patients with chronic liver disease and commonly associated with hepatic iron overload. Genetic causes of high liver iron include homozygosity for the p.Cys282Tyr variant in homeostatic iron regulator (HFE) and rare variants in non-HFE genes. The aims of the present study were to describe the landscape and frequency of mutations in hemochromatosis genes and determine whether patient selection by noninvasive hepatic iron quantification using MRI improves the diagnostic yield of next-generation sequencing (NGS) in patients with hyperferritinemia. APPROACH AND RESULTS A cohort of 410 unselected liver clinic patients with high serum ferritin (defined as ≥200 μg/L for women and ≥300 μg/L for men) was investigated by HFE genotyping and abdominal MRI R2*. Forty-one (10%) patients were homozygous for the p.Cys282Tyr variant in HFE. Of the remaining 369 patients, 256 (69%) had high transferrin saturation (TSAT; ≥45%) and 199 (53%) had confirmed hepatic iron overload (liver R2* ≥70 s-1 ). NGS of hemochromatosis genes was carried out in 180 patients with hepatic iron overload, and likely pathogenic variants were identified in 68 of 180 (38%) patients, mainly in HFE (79%), ceruloplasmin (25%), and transferrin receptor 2 (19%). Low spleen iron (R2* <50 s-1 ), but not TSAT, was significantly associated with the presence of mutations. In 167 patients (93%), no monogenic cause of hepatic iron overload could be identified. CONCLUSIONS In patients without homozygosity for p.Cys282Tyr, coincident pathogenic variants in HFE and non-HFE genes could explain hyperferritinemia with hepatic iron overload in a subset of patients. Unlike HFE hemochromatosis, this type of polygenic hepatic iron overload presents with variable TSAT. High ferritin in blood is an indicator of the iron storage disease, hemochromatosis. A simple genetic test establishes this diagnosis in the majority of patients affected. MRI of the abdomen can guide further genetic testing.
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Affiliation(s)
- André Viveiros
- Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate BiologyMedical University of InnsbruckInnsbruckAustria
| | - Benedikt Schaefer
- Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate BiologyMedical University of InnsbruckInnsbruckAustria
| | - Marlene Panzer
- Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate BiologyMedical University of InnsbruckInnsbruckAustria
| | | | - Michaela Plaikner
- Department of RadiologyMedical University of InnsbruckInnsbruckAustria
| | - Christian Kremser
- Department of RadiologyMedical University of InnsbruckInnsbruckAustria
| | - André Franke
- Institute of Clinical Molecular Biology (IKMB)Kiel UniversityKielGermany
| | - Sören Franzenburg
- Institute of Clinical Molecular Biology (IKMB)Kiel UniversityKielGermany
| | - Marc P. Hoeppner
- Institute of Clinical Molecular Biology (IKMB)Kiel UniversityKielGermany
| | - Reinhard Stauder
- Department of Medicine VMedical University of InnsbruckInnsbruckAustria
| | - Andreas Janecke
- Department of PediatricsMedical University of InnsbruckInnsbruckAustria
- Department of GeneticsMedical University of InnsbruckInnsbruckAustria
| | - Herbert Tilg
- Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate BiologyMedical University of InnsbruckInnsbruckAustria
| | - Heinz Zoller
- Department of Medicine I and Christian Doppler Laboratory on Iron and Phosphate BiologyMedical University of InnsbruckInnsbruckAustria
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20
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Gillespie J. "You Are What You Eat": The Role of Dietary Macronutrients and Micronutrients in MAFLD. Clin Liver Dis (Hoboken) 2021; 18:67-71. [PMID: 34584670 PMCID: PMC8450468 DOI: 10.1002/cld.1083] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 11/24/2020] [Accepted: 12/06/2020] [Indexed: 02/04/2023] Open
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21
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Lahaye C, Gladine C, Pereira B, Berger J, Chinetti-Gbaguidi G, Lainé F, Mazur A, Ruivard M. Does iron overload in metabolic syndrome affect macrophage profile? A case control study. J Trace Elem Med Biol 2021; 67:126786. [PMID: 34022567 DOI: 10.1016/j.jtemb.2021.126786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 04/28/2021] [Accepted: 05/10/2021] [Indexed: 12/31/2022]
Abstract
AIMS Dysmetabolic iron overload syndrome (DIOS) is common but the clinical relevance of iron overload is not understood. Macrophages are central cells in iron homeostasis and inflammation. We hypothesized that iron overload in DIOS could affect the phenotype of monocytes and impair macrophage gene expression. METHODS This study compared 20 subjects with DIOS to 20 subjects with metabolic syndrome (MetS) without iron overload, and 20 healthy controls. Monocytes were phenotyped by Fluorescence-Activated Cell Sorting (FACS) and differentiated into anti-inflammatory M2 macrophages in the presence of IL-4. The expression of 38 genes related to inflammation, iron metabolism and M2 phenotype was assessed by real-time PCR. RESULTS FACS showed no difference between monocytes across the three groups. The macrophagic response to IL-4-driven differentiation was altered in four of the five genes of M2 phenotype (MRC1, F13A1, ABCA1, TGM2 but not FABP4), in DIOS vs Mets and controls demonstrating an impaired M2 polarization. The expression profile of inflammatory genes was not different in DIOS vs MetS. Several genes of iron metabolism presented a higher expression in DIOS vs MetS: SCL11A2 (a free iron transporter, +76 %, p = 0.04), SOD1 (an antioxidant enzyme, +27 %, p = 0.02), and TFRC (the receptor 1 of transferrin, +59 %, p = 0.003). CONCLUSIONS In DIOS, macrophage polarization toward the M2 alternative phenotype is impaired but not associated with a pro-inflammatory profile. The up regulation of transferrin receptor 1 (TFRC) in DIOS macrophages suggests an adaptive role that may limit iron toxicity in DIOS.
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Affiliation(s)
- Clément Lahaye
- Université Clermont Auvergne, CHU Clermont-Ferrand, Service de Médecine interne Hôpital Estaing, INRAE, UNH, Unité de Nutrition Humaine, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
| | - Cécile Gladine
- Université Clermont Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
| | - Bruno Pereira
- Université Clermont Auvergne, CHU Clermont-Ferrand, Unité de biostatistiques, F-63000 Clermont-Ferrand, France.
| | - Juliette Berger
- Université Clermont Auvergne, CHU Clermont-Ferrand, Laboratoire d'Hématologie, Hôpital Estaing, F-63000 Clermont-Ferrand, France.
| | | | - Fabrice Lainé
- INSERM CIC 1414, and Liver Unit, CHU Rennes, 35000 Rennes, France.
| | - Andrzej Mazur
- Université Clermont Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
| | - Marc Ruivard
- Université Clermont Auvergne, CHU Clermont-Ferrand, Service de Médecine interne Hôpital Estaing, F-63000 Clermont-Ferrand, France.
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22
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Imajo K, Kessoku T, Honda Y, Hasegawa S, Tomeno W, Ogawa Y, Motosugi U, Saigusa Y, Yoneda M, Kirikoshi H, Yamanaka S, Utsunomiya D, Saito S, Nakajima A. MRI-Based Quantitative R2 * Mapping at 3 Tesla Reflects Hepatic Iron Overload and Pathogenesis in Nonalcoholic Fatty Liver Disease Patients. J Magn Reson Imaging 2021; 55:111-125. [PMID: 34184822 DOI: 10.1002/jmri.27810] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 06/16/2021] [Accepted: 06/18/2021] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND The role of hepatic iron overload (HIO) in nonalcoholic fatty liver disease (NAFLD) pathogenesis has not been fully elucidated. PURPOSE This study aimed to investigate the effect of HIO and examine the diagnostic usefulness of magnetic resonance imaging (MRI)-based R2* quantification in evaluating hepatic iron content (HIC) and pathological findings in NAFLD. STUDY TYPE Prospective and retrospective. POPULATION A prospective study of 168 patients (age, 57.2 ± 15.0; male/female, 80/88) and a retrospective validation study of 202 patients (age, 57.0 ± 14.4; male/female, 113/89) with liver-biopsy-confirmed NAFLD were performed. FIELD STRENGTH/SEQUENCE 3 T; chemical-shift encoded multi-echo gradient echo. ASSESSMENT Using liver tissues obtained by liver biopsy, HIC was prospectively evaluated in 168 patients by atomic absorption spectrometry. Diagnostic accuracies of HIC and R2* for grading hepatic inflammation plus ballooning (HIB) as an indicator of NAFLD activity were assessed. STATISTICAL TESTS Student's t-test and analysis of variance (ANOVA) with Scheffe's multiple testing correction for univariate comparisons; multivariate logistic analysis. P-value less than 0.05 is statistically significant. RESULTS HIC was significantly correlated with HIB grades (r = 0.407). R2* was significantly correlated with HIC (r = 0.557) and HIB grades (r = 0.569). R2* mapped an area under the receiver operating characteristic (AUROC; 0.774) for HIC ≥808 ng/mL (median value) with cutoff value of 62.5 s-1 . In addition, R2* mapped AUROC of HIB for grades ≥3 was 0.799 with cutoff value of 58.5 s-1 . When R2* was <62.5 s-1 , R2* correlated weakly with HIC (r = 0.372) as it was affected by fat deposition and did not correlate with HIB grades (P = 0.052). Conversely, when R2* was ≥62.5 s-1 , a significant correlation of R2* with HIC (r = 0.556) and with HIB grades was observed (P < 0.0001) with being less affected by fat deposition. DATA CONCLUSION R2* ≥ 62.5 s-1 is a promising modality for non-invasive diagnosis of clinically important high grades (≥3) of HIB associated with increased HIC. LEVEL OF EVIDENCE 1 TECHNICAL EFFICACY STAGE: 2.
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Affiliation(s)
- Kento Imajo
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takaomi Kessoku
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yasushi Honda
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Sho Hasegawa
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Wataru Tomeno
- Department of Gastroenterology, International University of Health and Welfare Atami Hospital, Atami, Japan
| | - Yuji Ogawa
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Utaroh Motosugi
- Department of Radiology, University of Yamanashi, Chuo, Japan
| | - Yusuke Saigusa
- Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan
| | - Masato Yoneda
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hiroyuki Kirikoshi
- Department of Clinical Laboratory, Yokohama City University Hospital, Yokohama, Japan
| | - Shoji Yamanaka
- Anatomic and Clinical Pathology Department, Yokohama City University Hospital, Yokohama, Japan
| | - Daisuke Utsunomiya
- Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Satoru Saito
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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23
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Hyperferritinemia-A Clinical Overview. J Clin Med 2021; 10:jcm10092008. [PMID: 34067164 PMCID: PMC8125175 DOI: 10.3390/jcm10092008] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/03/2021] [Accepted: 05/05/2021] [Indexed: 02/07/2023] Open
Abstract
Ferritin is one of the most frequently requested laboratory tests in primary and secondary care, and levels often deviate from reference ranges. Serving as an indirect marker for total body iron stores, low ferritin is highly specific for iron deficiency. Hyperferritinemia is, however, a non-specific finding, which is frequently overlooked in general practice. In routine medical practice, only 10% of cases are related to an iron overload, whilst the rest is seen as a result of acute phase reactions and reactive increases in ferritin due to underlying conditions. Differentiation of the presence or absence of an associated iron overload upon hyperferritinemia is essential, although often proves to be complex. In this review, we have performed a review of a selection of the literature based on the authors’ own experiences and assessments in accordance with international recommendations and guidelines. We address the biology, etiology, and epidemiology of hyperferritinemia. Finally, an algorithm for the diagnostic workup and management of hyperferritinemia is proposed, and general principles regarding the treatment of iron overload are discussed.
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Lonardo A, Arab JP, Arrese M. Perspectives on Precision Medicine Approaches to NAFLD Diagnosis and Management. Adv Ther 2021; 38:2130-2158. [PMID: 33829368 PMCID: PMC8107169 DOI: 10.1007/s12325-021-01690-1] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023]
Abstract
Precision medicine defines the attempt to identify the most effective approaches for specific subsets of patients based on their genetic background, clinical features, and environmental factors. Nonalcoholic fatty liver disease (NAFLD) encompasses the alcohol-like spectrum of liver disorders (steatosis, steatohepatitis with/without fibrosis, and cirrhosis and hepatocellular carcinoma) in the nonalcoholic patient. Recently, disease renaming to MAFLD [metabolic (dysfunction)-associated fatty liver disease] and positive criteria for diagnosis have been proposed. This review article is specifically devoted to envisaging some clues that may be useful to implementing a precision medicine-oriented approach in research and clinical practice. To this end, we focus on how sex and reproductive status, genetics, intestinal microbiota diversity, endocrine and metabolic status, as well as physical activity may interact in determining NAFLD/MAFLD heterogeneity. All these factors should be considered in the individual patient with the aim of implementing an individualized therapeutic plan. The impact of considering NAFLD heterogeneity on the development of targeted therapies for NAFLD subgroups is also extensively discussed.
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Affiliation(s)
- Amedeo Lonardo
- Department of Internal Medicine, Azienda Ospedaliero-Universitaria, Ospedale Civile di Baggiovara, 1135 Via Giardini, 41126, Modena, Italy.
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Biología Celular y Molecular, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Biología Celular y Molecular, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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Botta A, Barra NG, Lam NH, Chow S, Pantopoulos K, Schertzer JD, Sweeney G. Iron Reshapes the Gut Microbiome and Host Metabolism. J Lipid Atheroscler 2021; 10:160-183. [PMID: 34095010 PMCID: PMC8159756 DOI: 10.12997/jla.2021.10.2.160] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/12/2021] [Accepted: 02/21/2021] [Indexed: 12/12/2022] Open
Abstract
Compelling studies have established that the gut microbiome is a modifier of metabolic health. Changes in the composition of the gut microbiome are influenced by genetics and the environment, including diet. Iron is a potential node of crosstalk between the host-microbe relationship and metabolic disease. Although iron is well characterized as a frequent traveling companion of metabolic disease, the role of iron is underappreciated because the mechanisms of iron's influence on host metabolism are poorly characterized. Both iron deficiency and excessive amounts leading to iron overload can have detrimental effects on cardiometabolic health. Optimal iron homeostasis is critical for regulation of host immunity and metabolism in addition to regulation of commensal and pathogenic enteric bacteria. In this article we review evidence to support the notion that altering composition of the gut microbiome may be an important route via which iron impacts cardiometabolic health. We discuss reshaping of the microbiome by iron, the physiological significance and the potential for therapeutic interventions.
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Affiliation(s)
- Amy Botta
- Department of Biology, York University, Toronto, ON, Canada
| | - Nicole G. Barra
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
| | - Nhat Hung Lam
- Department of Biology, York University, Toronto, ON, Canada
| | - Samantha Chow
- Department of Biology, York University, Toronto, ON, Canada
| | - Kostas Pantopoulos
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, QC, Canada
| | - Jonathan D. Schertzer
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
| | - Gary Sweeney
- Department of Biology, York University, Toronto, ON, Canada
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Iron depletion attenuates steatosis in a mouse model of non-alcoholic fatty liver disease: Role of iron-dependent pathways. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166142. [PMID: 33839281 DOI: 10.1016/j.bbadis.2021.166142] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/23/2021] [Accepted: 04/01/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Iron has been proposed as influencing the progression of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD). We have previously shown that, in the Hfe-/- mouse model of hemochromatosis, feeding of a high-calorie diet (HCD) leads to increased liver injury. In this study we investigated whether the feeding of an iron deficient/HCD to Hfe-/- mice influenced the development of NAFLD. METHODS Liver histology was assessed in Hfe-/- mice fed a standard iron-containing or iron-deficient diet plus or minus a HCD. Hepatic iron concentration, serum transferrin saturation and free fatty acid were measured. Expression of genes implicated in iron regulation and fatty liver disease was determined by quantitative real-time PCR (qRT-PCR). RESULTS Standard iron/HCD-fed mice developed severe steatosis whereas NAS score was reduced in mice fed iron-deficient HCD. Mice fed iron-deficient HCD had lower liver weights, lower transferrin saturation and decreased ferroportin and hepcidin gene expression than HCD-fed mice. Serum non-esterified fatty acids were increased in iron-deficient HCD-fed mice compared with standard iron HCD. Expression analysis indicated that genes involved in fatty-acid binding and mTOR pathways were regulated by iron depletion. CONCLUSIONS Our results indicate that decreasing iron intake attenuates the development of steatosis resulting from a high calorie diet. These results also suggest that human studies of agents that modify iron balance in patients with NAFLD should be revisited.
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Tobita H, Yazaki T, Kataoka M, Kotani S, Oka A, Mishiro T, Oshima N, Kawashima K, Ishimura N, Naora K, Sato S, Ishihara S. Comparison of dapagliflozin and teneligliptin in nonalcoholic fatty liver disease patients without type 2 diabetes mellitus: a prospective randomized study. J Clin Biochem Nutr 2021; 68:173-180. [PMID: 33879970 PMCID: PMC8046003 DOI: 10.3164/jcbn.20-129] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 09/16/2020] [Indexed: 12/17/2022] Open
Abstract
There are no reports regarding the efficacy of sodium-glucose cotransporter 2 inhibitor (SGLT2i) and dipeptidyl peptidase 4 inhibitor (DPP4i) administrations in nonalcoholic fatty liver disease (NAFLD) patients without type 2 diabetes mellitus. The purpose of this study was to evaluate the efficacy of those drugs in such patients. NAFLD patients without type 2 diabetes mellitus were enrolled in this single center double-blind randomized prospective study, and allocated to receive either dapagliflozin (SGLT2i) or teneligliptin (DPP4i) for 12 weeks. Laboratory variables and body compositions were assessed at the baseline and end of treatment. The primary endpoint was alanine aminotransferase (ALT) reduction level at the end of treatment. Twenty-two eligible patients (dapagliflozin group, n = 12; teneligliptin group, n = 10) were analyzed. In both groups, the serum concentration of ALT was significantly decreased after treatment (p<0.05). Multiple regression analysis results showed that decreased body weight of patients with dapagliflozin administration was significantly related to changes in total body water and body fat mass. Administration of dapagliflozin or teneligliptin decreased the serum concentration of ALT in NAFLD patients without type 2 diabetes mellitus. With dapagliflozin, body weight decreased, which was related to changes in total body water and body fat mass (UMIN000027304).
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Affiliation(s)
- Hiroshi Tobita
- Division of Hepatology, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Department of Internal Medicine II, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Tomotaka Yazaki
- Division of Hepatology, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Department of Internal Medicine II, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Masatoshi Kataoka
- Division of Hepatology, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Department of Internal Medicine II, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Satoshi Kotani
- Department of Internal Medicine II, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Akihiko Oka
- Department of Internal Medicine II, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Tsuyoshi Mishiro
- Department of Internal Medicine II, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Naoki Oshima
- Department of Internal Medicine II, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Kousaku Kawashima
- Department of Internal Medicine II, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Norihisa Ishimura
- Department of Internal Medicine II, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Kohji Naora
- Department of Pharmacy, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Shuichi Sato
- Department of International Medicine, Izumo City General Medical Center, Izumo, Shimane 693-8501, Japan
| | - Shunji Ishihara
- Department of Internal Medicine II, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
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Anastasopoulos NAT, Lianos GD, Tatsi V, Karampa A, Goussia A, Glantzounis GK. Clinical heterogeneity in patients with non-alcoholic fatty liver disease-associated hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2020; 14:1025-1033. [PMID: 32746645 DOI: 10.1080/17474124.2020.1802244] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION The indisputable increase in nonalcoholic Fatty Liver Disease (NAFLD) prevalence (25% of population) has consequently led to an increase in Hepatocellular Carcinoma (HCC) and liver-related mortality worldwide. The characteristics of patients with HCC, secondary to NAFLD, are older age, large tumors due to late diagnosis, often without cirrhosis and high prevalence of the metabolic syndrome components, leading to an increased mortality rate. Although the mechanisms of disease remain partially obscure, insulin resistance, oxidative stress, apoptosis, iron overload, and excessive local and systemic inflammation are identified as culprits for hepatocarcinogenesis in the presence of NAFLD. AREA COVERED In this review, the authors report that there are no uniform guidelines for surveillance and early diagnosis in this patient group. Barcelona Clinic Liver Cancer staging is generally applicable to HCC due to NAFLD and management depends on liver function, tumor characteristics, and cardiovascular comorbidity. Evidence suggests that HCC due to NAFLD can be associated with worse survival due to late diagnosis. EXPERT OPINION The need for effective early diagnosis and management of NAFLD is urgent, considering the galloping incidence of the obesity and the fact that liver cirrhosis and HCC due to NAFLD will become the first indication for liver transplantation in foreseeable future.
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Affiliation(s)
- Nikolaos-Andreas T Anastasopoulos
- First Propaedeutic Department of General Surgery, National and Kapodistrian University of Athens, "Hippokrateion" General Hospital of Athens , Athens, Greece.,Department of Surgery, University Hospital of Ioannina and School of Medicine, University of Ioannina , Ioannina, Greece
| | - Georgios D Lianos
- Department of Surgery, University Hospital of Ioannina and School of Medicine, University of Ioannina , Ioannina, Greece
| | - Vera Tatsi
- Department of Surgery, University Hospital of Ioannina and School of Medicine, University of Ioannina , Ioannina, Greece
| | - Anastasia Karampa
- Department of Surgery, University Hospital of Ioannina and School of Medicine, University of Ioannina , Ioannina, Greece
| | - Anna Goussia
- Department of Pathology, University Hospital of Ioannina and School of Medicine, University of Ioannina , Ioannina, Greece
| | - Georgios K Glantzounis
- Department of Surgery, University Hospital of Ioannina and School of Medicine, University of Ioannina , Ioannina, Greece
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Robinson KE, Shah VH. Pathogenesis and pathways: nonalcoholic fatty liver disease & alcoholic liver disease. Transl Gastroenterol Hepatol 2020; 5:49. [PMID: 33073044 DOI: 10.21037/tgh.2019.12.05] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 11/29/2019] [Indexed: 12/16/2022] Open
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) account for the majority of hepatic morbidity and deaths due to cirrhosis in the United States. ALD is an umbrella term for a number of conditions linked to excessive alcohol consumption including simple steatosis, cirrhosis, acute alcoholic hepatitis (AH) with or without cirrhosis, and hepatocellular carcinoma (HCC) as a complication of cirrhosis. Although it presents with histological features resembling alcohol-induced liver injury, NAFLD occurs in patients with little or no history of alcohol consumption. NAFLD is a broad-spectrum term used to describe anything from fat accumulation in hepatocytes without inflammation or fibrosis (simple hepatic steatosis) to hepatic steatosis with a necroinflammatory component (steatohepatitis) with or without associated fibrosis. The pathogenesis is not fully understood for either disease. Development of severe liver disease is highly variable amongst chronic abusers of alcohol. Sex, age, genetics, host microbiome, and behavior are all factors linked to the development of ALD. These factors also contribute to NAFLD, but by contrast, insulin resistance is widely believed to be the main driver of nonalcoholic hepatic steatosis. The mechanism behind the transition from nonalcoholic steatosis to steatohepatitis remains a matter of debate with insulin resistance, oxidative injury, hepatic iron, gut hormones, antioxidant deficiency, and host microbiome all suspected to play part of the role.
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Affiliation(s)
- Kyle E Robinson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Kechagias S, Nasr P, Blomdahl J, Ekstedt M. Established and emerging factors affecting the progression of nonalcoholic fatty liver disease. Metabolism 2020; 111S:154183. [PMID: 32061907 DOI: 10.1016/j.metabol.2020.154183] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 02/07/2020] [Accepted: 02/11/2020] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease affecting approximately 25% of the global population. Although a majority of NAFLD patients will never experience liver-related symptoms it is estimated that 5-10% will develop cirrhosis-related complications with risk of death or need for liver transplantation. NAFLD is closely associated with cardiovascular disease and components of the metabolic syndrome. However, NAFLD is not uncommon in lean individuals and may in these subjects represent a different entity with separate pathophysiological mechanisms involved implying a higher risk for development of end-stage liver disease. There is considerable fluctuation in the histopathological course of NAFLD that may partly be attributed to lifestyle factors and dietary composition. Nutrients such as fructose, monounsaturated fatty acids, and trans-fatty acids may aggravate NAFLD. Presence of type 2 diabetes mellitus seems to be the most important clinical predictor of liver-related morbidity and mortality in NAFLD. Apart from severity of the metabolic syndrome, genetic polymorphisms and environmental factors, such as moderate alcohol consumption, may explain the variation in histopathological and clinical outcome among NAFLD patients.
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Affiliation(s)
- Stergios Kechagias
- Department of Gastroenterology and Hepatology, Linköping University, Linköping, Sweden; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
| | - Patrik Nasr
- Department of Gastroenterology and Hepatology, Linköping University, Linköping, Sweden; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
| | - Julia Blomdahl
- Department of Gastroenterology and Hepatology, Linköping University, Linköping, Sweden; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
| | - Mattias Ekstedt
- Department of Gastroenterology and Hepatology, Linköping University, Linköping, Sweden; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
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Decreased Physical Working Capacity in Adolescents With Nonalcoholic Fatty Liver Disease Associates With Reduced Iron Availability. Clin Gastroenterol Hepatol 2020; 18:1584-1591. [PMID: 31628998 DOI: 10.1016/j.cgh.2019.10.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 10/07/2019] [Accepted: 10/11/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is common and related to obesity and insulin resistance. Iron metabolism is impaired in obese individuals and iron deficiency has been associated with physical inactivity. We investigated whether iron bioavailability is reduced in patients with NAFLD and contributes to reduced cardiorespiratory fitness. METHODS We collected information on weight-adjusted, submaximal physical work capacity (PWC), ultrasound-determined hepatic steatosis, iron indices, and hematologic and metabolic parameters from 390 female and 458 male participants of the Raine Study-a longitudinal study of disease development in 2868 children in Western Australia. X2 and linear regression analyses were used to compare characteristics of study participants according to NAFLD status at age 17 years. RESULTS Fourteen percent of the cohort had NAFLD. PWC was significantly reduced in adolescents with NAFLD compared to adolescents without NAFLD (reduction of 0.17 W/kg, P = .0003, adjusted for sex and body mass index [BMI]). Iron bioavailability (assessed by mean corpuscular volume [MCV], mean corpuscular haemoglobin [MCH], transferrin saturation, and serum levels of iron) was inversely correlated with BMI in adolescents with NAFLD (P ≤ .01 for all, adjusted for sex) but not in adolescents without NAFLD (P > .30). MCV and MCH correlated with PWC (MCV, P = .002 for female and P = .0003 male participants; MCH, P = .004 for female and P = .01 for male participants), irrespective of NAFLD status. Reduced PWC was associated with lower transferrin saturation in adolescents with NAFLD (reduction of 0.012 W/kg per unit decrease in transferrin saturation, P = .007) but not in adolescents without NAFLD (reduction of 0.001 W/kg, P = .40), adjusted for sex. This association was independent of MCV or MCH. CONCLUSIONS In a well-defined cohort of adolescents, we found NAFLD to be associated with decreased cardiorespiratory fitness, independent of BMI. The relationship between transferrin saturation and PWC in adolescents with NAFLD indicates that functional iron deficiency might contribute to reductions in cardiorespiratory fitness.
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Macías-Rodríguez RU, Inzaugarat ME, Ruiz-Margáin A, Nelson LJ, Trautwein C, Cubero FJ. Reclassifying Hepatic Cell Death during Liver Damage: Ferroptosis-A Novel Form of Non-Apoptotic Cell Death? Int J Mol Sci 2020; 21:1651. [PMID: 32121273 PMCID: PMC7084577 DOI: 10.3390/ijms21051651] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 02/10/2020] [Accepted: 02/14/2020] [Indexed: 12/11/2022] Open
Abstract
Ferroptosis has emerged as a new type of cell death in different pathological conditions, including neurological and kidney diseases and, especially, in different types of cancer. The hallmark of this regulated cell death is the presence of iron-driven lipid peroxidation; the activation of key genes related to this process such as glutathione peroxidase-4 (gpx4), acyl-CoA synthetase long-chain family member-4 (acsl4), carbonyl reductase [NADPH] 3 (cbr3), and prostaglandin peroxidase synthase-2 (ptgs2); and morphological changes including shrunken and electron-dense mitochondria. Iron overload in the liver has long been recognized as both a major trigger of liver damage in different diseases, and it is also associated with liver fibrosis. New evidence suggests that ferroptosis might be a novel type of non-apoptotic cell death in several liver diseases including non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), drug-induced liver injury (DILI), viral hepatitis, and hemochromatosis. The interaction between iron-related lipid peroxidation, cellular stress signals, and antioxidant systems plays a pivotal role in the development of this novel type of cell death. In addition, integrated responses from lipidic mediators together with free iron from iron-containing enzymes are essential to understanding this process. The presence of ferroptosis and the exact mechanisms leading to this non-apoptotic type of cell death in the liver remain scarcely elucidated. Recognizing ferroptosis as a novel type of cell death in the liver could lead to the understanding of the complex interaction between different types of cell death, their role in progression of liver fibrosis, the development of new biomarkers, as well as the use of modulators of ferroptosis, allowing improved theranostic approaches in the clinic.
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Affiliation(s)
- Ricardo U. Macías-Rodríguez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico;
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (M.E.I.); (C.T.)
- MICTLÁN-Network (Mechanisms of Liver Injury, Cell Death and Translational Nutrition in Liver Diseases Research Network), Mexico City 14080, Mexico
- Liver Fibrosis and Nutrition Lab (LFN Lab), Mexico City 14080, Mexico
| | - María Eugenia Inzaugarat
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (M.E.I.); (C.T.)
- MICTLÁN-Network (Mechanisms of Liver Injury, Cell Death and Translational Nutrition in Liver Diseases Research Network), Mexico City 14080, Mexico
| | - Astrid Ruiz-Margáin
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico;
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (M.E.I.); (C.T.)
- MICTLÁN-Network (Mechanisms of Liver Injury, Cell Death and Translational Nutrition in Liver Diseases Research Network), Mexico City 14080, Mexico
- Liver Fibrosis and Nutrition Lab (LFN Lab), Mexico City 14080, Mexico
| | - Leonard J. Nelson
- Institute for Bioengineering (IBioE), School of Engineering, Faraday Building, The University of Edinburgh, Edinburgh EH9 3 JL, UK;
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (M.E.I.); (C.T.)
| | - Francisco Javier Cubero
- MICTLÁN-Network (Mechanisms of Liver Injury, Cell Death and Translational Nutrition in Liver Diseases Research Network), Mexico City 14080, Mexico
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), 28041 Madrid, Spain
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Tariq R, Axley P, Singal AK. Extra-Hepatic Manifestations of Nonalcoholic Fatty Liver Disease: A Review. J Clin Exp Hepatol 2020; 10:81-87. [PMID: 32025167 PMCID: PMC6995895 DOI: 10.1016/j.jceh.2019.07.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 07/17/2019] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease worldwide with a strong association with metabolic syndrome. NAFLD is truly a systemic disease and is associated with a plethora of extra-hepatic manifestations or comorbidities. These are either related to secondary effects of associated obesity or from pathophysiological effects of insulin resistance in NAFLD. Three most common causes of increased morbidity and mortality associated with NAFLD are cardiovascular disease, liver disease, and cancer. In this narrative review, we will discuss comprehensively on cardiovascular disease, type 2 diabetes mellitus, and chronic kidney disease and will also highlight on malignancy especially colorectal cancer, pulmonary disorders including obstructive sleep apnea, endocrine disorders such as hypothyroidism and polycystic ovarian syndrome, dermatological disorders especially psoriasis, and hematological associations including iron overload and susceptibility to thrombosis. In addition to focusing on pathogenesis of these extrahepatic manifestations, we will highlight their clinical implications for physicians in routine clinical practice. Further, there remains an unmet need for safe and effective therapies and examining their benefits on these extra-hepatic manifestations among patients with NAFLD.
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Key Words
- CKD, chronic kidney disease
- CT, computed tomography
- CVD, cardiovascular disease
- HCC
- MetS, metabolic syndrome
- NAFL, nonalcoholic fatty liver
- NAFLD, nonalcoholic fatty liver disease
- NASH
- NASH, nonalcoholic steatohepatitis
- OSA, obstructive sleep apnea
- PCOS, polycystic ovarian syndrome
- T2DM, type 2 diabetes mellitus
- insulin resistance
- metabolic syndrome
- steatosis
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Affiliation(s)
- Raseen Tariq
- Department of Medicine, University of Rochester, Rochester, NY, USA
| | - Page Axley
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ashwani K. Singal
- Division of Gastroenterology and Hepatology, University of South Dakota Sanford School of Medicine, Transplant Hepatologist Avera University Hospital & Transplant Institute, Chief Clinical Research Affairs, Transplant Hepatology & Institute of Human Genetics Research, Sioux Falls, SD, 57105, USA,Address for correspondence: Ashwani K. Singal, MD Associate Professor of Medicine, Division of Gastroenterology and Hepatology, University of South Dakota Sanford School of Medicine, Transplant Hepatologist Avera University Hospital & Transplant Institute, Chief Clinical Research Affairs, Transplant Hepatology & Institute of Human Genetics Research, Sioux Falls, SD, 57105, USA.
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Castiella A, Urreta I, Zapata E, Zubiaurre L, Alústiza JM, Otazua P, Salvador E, Letamendi G, Arrizabalaga B, Rincón ML, Emparanza JI. Liver iron concentration in dysmetabolic hyperferritinemia: Results from a prospective cohort of 276 patients. Ann Hepatol 2020; 19:31-35. [PMID: 31587985 DOI: 10.1016/j.aohep.2019.07.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 06/30/2019] [Accepted: 07/02/2019] [Indexed: 02/08/2023]
Abstract
INTRODUCTION AND OBJECTIVES We aimed to study the liver iron concentration in patients referred for hyperferritinemia to six hospitals in the Basque Country and to determine if there were differences between patients with or without metabolic syndrome. PATIENTS AND METHODS Metabolic syndrome was defined by accepted criteria. Liver iron concentration was determined by magnetic resonance imaging. RESULTS We obtained the data needed to diagnose metabolic syndrome in 276 patients; a total of 135 patients (49%), 115/240 men (48%), and 20/36 women (55.6%) presented metabolic syndrome. In all 276 patients, an MRI for the determination of liver iron concentration (mean±SD) was performed. The mean liver iron concentration was 30.83±19.38 for women with metabolic syndrome, 38.84±25.50 for men with metabolic syndrome, and 37.66±24.79 (CI 95%; 33.44-41.88) for the whole metabolic syndrome group. In 141 patients (51%), metabolic syndrome was not diagnosed: 125/240 were men (52%) and 16/36 were women (44.4%). The mean liver iron concentration was 34.88±16.18 for women without metabolic syndrome, 44.48±38.16 for men without metabolic syndrome, and 43.39±36.43 (CI 95%, 37.32-49.46) for the whole non-metabolic syndrome group. Comparison of the mean liver iron concentration from both groups (metabolic syndrome vs non-metabolic syndrome) revealed no significant differences (p=0.12). CONCLUSIONS Patients with hyperferritinemia and metabolic syndrome presented a mildly increased mean liver iron concentration that was not significantly different to that of patients with hyperferritinemia and non-metabolic syndrome.
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Affiliation(s)
- Agustin Castiella
- Gastroenterology Service, Mendaro Hospital, Mendaro, Spain; Gastroenterology Service, Donostia University Hospital, Donostia, Spain.
| | - Iratxe Urreta
- Clinical Epidemiology Unit, CASPe, CIBER-ESP, Donostia University Hospital, Donostia, Spain
| | - Eva Zapata
- Gastroenterology Service, Mendaro Hospital, Mendaro, Spain; Gastroenterology Service, Donostia University Hospital, Donostia, Spain
| | | | | | - Pedro Otazua
- Gastroenterology Service, Mondragon Hospital, Mondragon, Spain
| | | | | | | | | | - José I Emparanza
- Clinical Epidemiology Unit, CASPe, CIBER-ESP, Donostia University Hospital, Donostia, Spain
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Martin-Rodriguez JL, Gonzalez-Cantero J, Gonzalez-Cantero A, Martí-Bonmatí L, Alberich-Bayarri Á, Gonzalez-Cejudo T, Gonzalez-Calvin JL. Insulin resistance and NAFLD: Relationship with intrahepatic iron and serum TNF-α using 1H MR spectroscopy and MRI. DIABETES & METABOLISM 2019; 45:473-479. [PMID: 30660761 DOI: 10.1016/j.diabet.2019.01.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 12/18/2018] [Accepted: 01/09/2019] [Indexed: 02/07/2023]
Abstract
AIM The association of non-alcoholic fatty liver disease (NAFLD) with insulin resistance (IR) is well established, yet little is known of their possible relationship with intrahepatic iron and serum tumour necrosis factor (TNF)-α concentrations in adults without diabetes. Thus, this study looked at the relationship of intrahepatic iron and serum TNF-α with intrahepatic triglycerides and IR in non-diabetic adults. METHODS In this cross-sectional study of 104 healthy non-diabetic Caucasians, a quantitative magnetic resonance (MR) imaging T2 gradient-echo technique was used to measure hepatic iron, with 1H-MR spectroscopy used to measure hepatic triglycerides. HOMA-IR was calculated to determine IR. RESULTS The prevalence of hepatic iron overload (HIOL) was 26.6% in individuals with NAFLD vs. 0% in those without. IR was present in 87.5% of subjects with both NAFLD and HIOL, in 45.4% of those with NAFLD but not HIOL, and in 4.5% of those with neither. HOMA-IR was positively correlated with hepatic triglycerides (r = 0.56, P < 0.001) and hepatic iron (r = 0.52, P < 0.001), whereas serum TNF-α concentrations correlated with intrahepatic triglyceride levels (r = 0.28, P < 0.04), but not with intrahepatic iron. Hepatic triglycerides, serum TNF-α and age were the only significant determinants of IR in regression analyses. CONCLUSION IR is closely associated with intrahepatic triglycerides and, to a lesser extent, intrahepatic iron, with some interplay between them. High serum TNF-α concentrations may contribute to the association between NAFLD and IR, while increased hepatic triglycerides appear to be a determinant of the development of HIOL in non-diabetic subjects without haemochromatosis.
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Affiliation(s)
| | - J Gonzalez-Cantero
- Department of Radiology, HGU Gregorio Marañon Madrid, and University of Granada, Spain.
| | | | - L Martí-Bonmatí
- Medical Imaging Department and Biomedical Imaging Research Group, Hospital Universitario y Politécnico La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Á Alberich-Bayarri
- Grupo de Investigación Biomédica en Imagen, Instituto de Investigación Sanitaria La Fe and Quantitative Imaging Biomarkers in Medicine (QUIBIM), Valencia, Spain
| | - T Gonzalez-Cejudo
- Servicio Laboratorio Clínico, University Hospital San Cecilio, Granada, Spain
| | - J L Gonzalez-Calvin
- Department of Gastroenterology, University Hospital San Cecilio, Department of Medicine, University of Granada, Spain
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Salaye L, Bychkova I, Sink S, Kovalic AJ, Bharadwaj MS, Lorenzo F, Jain S, Harrison AV, Davis AT, Turnbull K, Meegalla NT, Lee SH, Cooksey R, Donati GL, Kavanagh K, Bonkovsky HL, McClain DA. A Low Iron Diet Protects from Steatohepatitis in a Mouse Model. Nutrients 2019; 11:nu11092172. [PMID: 31510077 PMCID: PMC6769937 DOI: 10.3390/nu11092172] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 08/31/2019] [Accepted: 09/06/2019] [Indexed: 02/07/2023] Open
Abstract
High tissue iron levels are a risk factor for multiple chronic diseases including type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). To investigate causal relationships and underlying mechanisms, we used an established NAFLD model-mice fed a high fat diet with supplemental fructose in the water ("fast food", FF). Iron did not affect excess hepatic triglyceride accumulation in the mice on FF, and FF did not affect iron accumulation compared to normal chow. Mice on low iron are protected from worsening of markers for non-alcoholic steatohepatitis (NASH), including serum transaminases and fibrotic gene transcript levels. These occurred prior to the onset of significant insulin resistance or changes in adipokines. Transcriptome sequencing revealed the major effects of iron to be on signaling by the transforming growth factor beta (TGF-β) pathway, a known mechanistic factor in NASH. High iron increased fibrotic gene expression in vitro, demonstrating that the effect of dietary iron on NASH is direct. Conclusion: A lower tissue iron level prevents accelerated progression of NAFLD to NASH, suggesting a possible therapeutic strategy in humans with the disease.
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Affiliation(s)
- Lipika Salaye
- Center on Diabetes, Obesity and Metabolism, Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27101, USA
| | - Ielizaveta Bychkova
- Department of Internal Medicine, University of Utah Medical Center, Salt Lake City, UT 84112, USA
| | - Sandy Sink
- Center on Diabetes, Obesity and Metabolism, Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27101, USA
| | - Alexander J Kovalic
- Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Manish S Bharadwaj
- Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
- Agilent Technologies, 121 Hartwell Ave, Lexington, MA 02421, USA
| | - Felipe Lorenzo
- Center on Diabetes, Obesity and Metabolism, Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27101, USA
| | - Shalini Jain
- Center on Diabetes, Obesity and Metabolism, Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27101, USA
| | - Alexandria V Harrison
- Center on Diabetes, Obesity and Metabolism, Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27101, USA
| | - Ashley T Davis
- Department of Comparative Medicine, Wake Forest University, Winston-Salem, NC 27157, USA
| | - Katherine Turnbull
- Center on Diabetes, Obesity and Metabolism, Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27101, USA
- Department of Comparative Medicine, Wake Forest University, Winston-Salem, NC 27157, USA
| | - Nuwan T Meegalla
- Center on Diabetes, Obesity and Metabolism, Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27101, USA
- Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Soh-Hyun Lee
- Department of Internal Medicine, University of Utah Medical Center, Salt Lake City, UT 84112, USA
| | - Robert Cooksey
- Department of Internal Medicine, University of Utah Medical Center, Salt Lake City, UT 84112, USA
- VA Medical Center, Salt Lake City, UT 84148, USA
| | - George L Donati
- Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USA
| | - Kylie Kavanagh
- Department of Comparative Medicine, Wake Forest University, Winston-Salem, NC 27157, USA
- Department of Biomedicine, University of Tasmania, Hobart, Tasmania 7000, Australia
| | - Herbert L Bonkovsky
- Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Donald A McClain
- Center on Diabetes, Obesity and Metabolism, Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC 27101, USA.
- VA Medical Center, Salt Lake City, UT 84148, USA.
- VA Medical Center, Salisbury, NC 28144, USA.
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Atarashi M, Izawa T, Kuwamura M, Yamate J. [The role of iron overload in the progression of nonalcoholic steatohepatitis (NASH)]. Nihon Yakurigaku Zasshi 2019; 154:61-65. [PMID: 31406044 DOI: 10.1254/fpj.154.61] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Non-alcoholic steatohepatitis (NASH), one of the most common chronic liver diseases (CLD), is getting the most important cause of cirrhosis and hepatocellular carcinoma. Iron is an essential micronutrient for organisms. Once excess iron is accumulated in vital organs, dysfunctions of these organs can occur via the generation of reactive oxygen species. Hepatic iron overload is often seen in CLD patients. In NASH patients, iron accumulation in the liver is positively correlated with histological severity. Thus iron overload can contribute to progression of nonalcoholic fatty liver disease (NAFLD) to NASH. In a rat model of NASH, feeding of high-fat and high-iron diet increases hepatic inflammation with increased hepatic cytokine expression compared with feeding of high-fat diet only. In this model, iron is intensely accumulated in Kupffer cells/macrophages within the lesion, raising the possibility that iron-laden Kupffer cells/macrophages can play a key role in the enhancement of hepatic inflammation in NASH condition. On the other hand, in a rat model of liver cirrhosis, dietary iron overload clearly abrogates the development and progression of liver cirrhosis induced by repeated administration of thioacetamide (TAA). These findings suggest that iron overload can promote or suppress chronic liver diseases depending on the tissue microenvironment. Here we review and introduce the recent findings on the pathological roles of iron overload in the development and progression of NAFLD/NASH.
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Affiliation(s)
- Machi Atarashi
- Researcher Pharmacology dept. Research & Development center FUSO Pharm., Ltd.,Laboratory of Veterinary Pathology, Division of Veterinary Science, Osaka Prefecture University Graduate School of Life and Environmental Sciences
| | - Takeshi Izawa
- Laboratory of Veterinary Pathology, Division of Veterinary Science, Osaka Prefecture University Graduate School of Life and Environmental Sciences
| | - Mitsuru Kuwamura
- Laboratory of Veterinary Pathology, Division of Veterinary Science, Osaka Prefecture University Graduate School of Life and Environmental Sciences
| | - Jyoji Yamate
- Laboratory of Veterinary Pathology, Division of Veterinary Science, Osaka Prefecture University Graduate School of Life and Environmental Sciences
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Abstract
Hereditary hemochromatosis (HH) is one of the most common genetic disorders among persons of northern European descent. There have been recent advances in the diagnosis, management, and treatment of HH. The availability of molecular diagnostic testing for HH has made possible confirmation of the diagnosis for most patients. Several genotype-phenotype correlation studies have clarified the differences in clinical features between patients with the C282Y homozygous genotypes and other HFE mutation patterns. The increasing use of noninvasive tests such as MRI T2* has made quantification of hepatic iron deposition easier and eliminated the need for liver biopsy in most patients. Serum ferritin of <1,000 ng/mL at diagnosis remains an important diagnostic test to identify patients with a low risk of advanced hepatic fibrosis and should be used routinely as part of the initial diagnostic evaluation. Genetic testing for other types of HH is available but is expensive and generally not useful in most clinical settings. Serum ferritin may be elevated among patients with nonalcoholic fatty liver disease and in those with alcoholic liver disease. These diagnoses are more common than HH among patients with elevated serum ferritin who are not C282Y homozygotes or C282Y/H63D compound heterozygotes. A secondary cause for liver disease should be excluded among patients with suspected iron overload who are not C282Y homozygotes. Phlebotomy remains the mainstay of therapy, but emerging novel therapies such as new chelating agents may have a role for selected patients.
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Buzzetti E, Petta S, Manuguerra R, Luong TV, Cabibi D, Corradini E, Craxì A, Pinzani M, Tsochatzis E, Pietrangelo A. Evaluating the association of serum ferritin and hepatic iron with disease severity in non-alcoholic fatty liver disease. Liver Int 2019; 39:1325-1334. [PMID: 30851216 DOI: 10.1111/liv.14096] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 02/25/2019] [Accepted: 02/28/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Hyperferritinemia, with or without increased hepatic iron, represents a common finding in non-alcoholic fatty liver disease (NAFLD). However, it is unclear whether it reflects hepatic inflammation or true iron-overload and, in case the latter is confirmed, whether this influences disease progression. We therefore explored the association between serum ferritin, degree and pattern of hepatic iron deposition and liver disease severity in patients with NAFLD. METHODS We selected 468 patients with biopsy-proven NAFLD from 2 European centres. Iron, hepatic and metabolic parameters were collected at the time of liver biopsy. Iron deposits in hepatocytes and reticuloendothelial cells were assessed and graded. Diagnosis of non-alcoholic steatohepatitis (NASH) and fibrosis staging were performed. RESULTS A total of 122 (26%) patients had hyperferritinemia, whereas stainable hepatic iron was found in 116 (25%) patients (38% predominantly in hepatocytes, 20% in reticuloendothelial cells and 42% in both). Subjects with stainable hepatic iron, particularly those with a mixed pattern, had higher serum ferritin and transaminases but only a mixed pattern of iron deposition was among the variables significantly associated with presence of NASH. Serum ferritin was not associated with presence of NASH, however it increased with worsening fibrosis stage (F3 compared to F0-F1), and significantly decreased in stage F4. CONCLUSIONS A mixed pattern of hepatic iron deposition is associated with the presence of steatohepatitis, while serum ferritin increases with worsening fibrosis up to pre-cirrhotic stage. In individual NAFLD patients, serum ferritin could be evaluated as part of non-invasive diagnostic panels but not on its own.
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Affiliation(s)
- Elena Buzzetti
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Modena, Italy
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Salvatore Petta
- Section of Gastroenterology and Hepatology, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | | | - Tu Vinh Luong
- Department of Cellular Pathology, Royal Free Hospital, London, UK
| | - Daniela Cabibi
- Department of Sciences for the Promotion of Health and Mother and Child Care, Anatomic Pathology, University of Palermo, Palermo, Italy
| | - Elena Corradini
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonio Craxì
- Section of Gastroenterology and Hepatology, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Emmanuel Tsochatzis
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Antonello Pietrangelo
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Modena, Italy
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Marchisello S, Di Pino A, Scicali R, Urbano F, Piro S, Purrello F, Rabuazzo AM. Pathophysiological, Molecular and Therapeutic Issues of Nonalcoholic Fatty Liver Disease: An Overview. Int J Mol Sci 2019; 20:ijms20081948. [PMID: 31010049 PMCID: PMC6514656 DOI: 10.3390/ijms20081948] [Citation(s) in RCA: 130] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 04/18/2019] [Accepted: 04/20/2019] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) represents the leading cause of liver disease in developed countries but its diffusion is currently also emerging in Asian countries, in South America and in other developing countries. It is progressively becoming one of the main diseases responsible for hepatic insufficiency, hepatocarcinoma and the need for orthotopic liver transplantation. NAFLD is linked with metabolic syndrome in a close and bidirectional relationship. To date, NAFLD is a diagnosis of exclusion, and liver biopsy is the gold standard for diagnosis. NAFLD pathogenesis is complex and multifactorial, mainly involving genetic, metabolic and environmental factors. New concepts are constantly arising in the literature promising new diagnostic and therapeutic tools. One of the challenges will be to better characterize not only NAFLD development but overall NAFLD progression, in order to better identify NAFLD patients at higher risk of metabolic, cardiovascular and neoplastic complications. This review analyses NAFLD epidemiology and the different prevalence of the disease in distinct groups, particularly according to sex, age, body mass index, type 2 diabetes and dyslipidemia. Furthermore, the work expands on the pathophysiology of NAFLD, examining multiple-hit pathogenesis and the role of different factors in hepatic steatosis development and progression: genetics, metabolic factors and insulin resistance, diet, adipose tissue, gut microbiota, iron deposits, bile acids and circadian clock. In conclusion, the current available therapies for NAFLD will be discussed.
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Affiliation(s)
- Simona Marchisello
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Antonino Di Pino
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Roberto Scicali
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Francesca Urbano
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Salvatore Piro
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Francesco Purrello
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Agata Maria Rabuazzo
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
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Handa P, Thomas S, Morgan-Stevenson V, Maliken BD, Gochanour E, Boukhar S, Yeh MM, Kowdley KV. Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis. J Leukoc Biol 2019; 105:1015-1026. [PMID: 30835899 DOI: 10.1002/jlb.3a0318-108r] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 01/21/2019] [Accepted: 02/14/2019] [Indexed: 12/12/2022] Open
Abstract
We have previously demonstrated that iron overload in hepatic reticuloendothelial system cells (RES) is associated with severe nonalcoholic steatohepatitis (NASH) and advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Recruited myeloid-derived macrophages have gained a pivotal position as drivers of NASH progression and fibrosis. In this study, we used bone marrow-derived macrophages (BMDM) from C57Bl6 mice as surrogates for recruited macrophages and examined the effect of iron on macrophage polarization. Treatment with iron (ferric ammonium citrate, FAC) led to increased expression levels of M1 markers: CCL2, CD14, iNOS, IL-1β, IL-6, and TNF-α; it also increased protein levels of CD68, TNF-α, IL-1β, and IL-6 by flow cytometry. This effect could be reversed by desferrioxamine, an iron chelator. Furthermore, iron loading of macrophages in the presence of IL-4 led to the down-regulation of M2 markers: arginase-1, Mgl-1, and M2-specific transcriptional regulator, KLF4. Iron loading of macrophages with IL-4 also resulted in reduced phosphorylation of STAT6, another transcriptional regulator of M2 activation. Dietary iron overload of C57Bl6 mice led to hepatic macrophage M1 activation. Iron overload also stimulated hepatic fibrogenesis. Histologic analysis revealed that iron overload resulted in steatohepatitis. Furthermore, NAFLD patients with hepatic RES iron deposition had increased hepatic gene expression levels of M1 markers, IL-6, IL-1β, and CD40 and reduced gene expression of an M2 marker, TGM2, relative to patients with hepatocellular iron deposition pattern. We conclude that iron disrupts the balance between M1/M2 macrophage polarization and leads to macrophage-driven inflammation and fibrogenesis in NAFLD.
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Affiliation(s)
- Priya Handa
- Organ Care Research and Liver Care Network, Seattle, Washington, USA
| | - Sunil Thomas
- University of Washington, School of Medicine, Seattle, Washington, USA
| | | | - Bryan D Maliken
- University of Cincinnati College of Medicine, Medical Scientist Training Program, Cincinnati, Ohio, USA
| | - Eric Gochanour
- Organ Care Research and Liver Care Network, Seattle, Washington, USA
| | - Sarag Boukhar
- University of Washington, School of Medicine, Seattle, Washington, USA
| | - Matthew M Yeh
- University of Washington, School of Medicine, Seattle, Washington, USA
| | - Kris V Kowdley
- Organ Care Research and Liver Care Network, Seattle, Washington, USA
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Rates of and Factors Associated With Placebo Response in Trials of Pharmacotherapies for Nonalcoholic Steatohepatitis: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2019; 17:616-629.e26. [PMID: 29913275 DOI: 10.1016/j.cgh.2018.06.011] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 06/06/2018] [Accepted: 06/09/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS It is important to know the extent of the placebo effect in designing randomized controlled trials for patients with nonalcoholic steatohepatitis (NASH), to accurately calculate sample size and define treatment endpoints. METHODS We performed a systematic review and meta-analysis of the placebo groups from randomized controlled trials of adults with NASH that provided histologic and/or magnetic resonance image-based assessments. We identified trials through a comprehensive search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus, from each database's inception through January 2, 2018. RESULTS We identified 39 randomized controlled trials, comprising 1463 patients who received placebo. Histologic assessment data (the nonalcoholic fatty liver disease activity scores, NAS) were available from 956 patients; magnetic resonance spectroscopy data were available from 295 patients and magnetic resonance proton density fat fraction measurements from 61 patients. Overall, 25% of patients given placebo had an improvement in NAS by 2 or more points (95% CI, 21%-29%) with a small amount of heterogeneity (I2 = 27%). There were improvements by at least 1 point in steatosis scores of 33% ± 3% of patients, in hepatocyte ballooning scores of 30% ± 3% of patients, in lobular inflammation scores of 32% ± 3% of patients, and in fibrosis scores of 21% ± 3% of patients, with a moderate amount of heterogeneity among trials (I2 range, 51%-63%). Patients given placebo had a statistically significant improvement in NAS (by 0.72 ± 0.19), with a large amount of heterogeneity (I2 = 96%). Univariate and multivariate meta-regression showed that trials with a higher baseline NAS, those conducted in South America, and those in which patients had a decrease in body mass index, were associated with greater improvements in NAS among patients given placebo. Patients given placebo had significant reductions in intrahepatic triglyceride, measured by magnetic resonance spectroscopy (by 1.45% ± 0.54%) with moderate heterogeneity (I2 = 40%), and in magnetic resonance proton density fat fraction (by 2.43 ± 0.89), without heterogeneity (I2 = 0). Mean serum levels of alanine and aspartate aminotransferases decreased significantly (by 11.7 ± 3.8 U/L and 5.9 ± 2.1 U/L, respectively; P < .01 for both). CONCLUSIONS In a meta-analysis of randomized controlled trials of NASH, patients given placebo have significant histologic, radiologic, and biochemical responses. The placebo response should be considered in designing trials of agents for treatment of NASH.
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Miyanishi K, Tanaka S, Sakamoto H, Kato J. The role of iron in hepatic inflammation and hepatocellular carcinoma. Free Radic Biol Med 2019; 133:200-205. [PMID: 30017991 DOI: 10.1016/j.freeradbiomed.2018.07.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 07/08/2018] [Accepted: 07/10/2018] [Indexed: 02/06/2023]
Abstract
Iron is an essential for organisms and the liver plays a major role in its storage. In pathologic conditions, where iron absorption from the intestine or iron uptake into the hepatocytes is increased, excess iron accumulates in the hepatocytes, leading to hepatocyte injury through the production of free radicals. Iron exerts its toxicity by catalyzing the generation of reactive oxygen species (ROS). ROS causes cell injury by inducing damage to the lysosomal, cytoplasmic, nuclear and mitochondrial membranes, apoptosis through activation of the caspase cascade, and hyperoxidation of fatty chains. In this manuscript, we reviewed the articles regarding role of iron in hepatic inflammation and hepatocellular carcinoma.
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Affiliation(s)
- Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan.
| | - Shingo Tanaka
- Department of Medical Oncology, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan; Department of Infection Control, and Laboratory Medicine, Sapporo Medical University, School of Medicine, Japan
| | - Hiroki Sakamoto
- Department of Medical Oncology, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan
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Effect of procyanidin on dietary iron absorption in hereditary hemochromatosis and in dysmetabolic iron overload syndrome: A crossover double-blind randomized controlled trial. Clin Nutr 2019; 39:97-103. [PMID: 30792142 DOI: 10.1016/j.clnu.2019.02.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/31/2019] [Accepted: 02/01/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS Type I hereditary hemochromatosis (HH) and dysmetabolic iron overload syndrome (DIOS) are the two most prevalent iron overload diseases. Although many food components, particularly polyphenols, reduce iron bioavailability, there is no clinically validated nutritional strategy to reduce food-iron absorption in patients with these diseases. We aimed to determine whether supplementation with 100 mg of procyanidins during a meal reduces dietary iron absorption in patients with HH or DIOS. METHODS 20 HH and 20 DIOS patients were enrolled in a double-blind three-period crossover randomized study. Basal serum iron level was measured following an overnight fast. Each patient consumed a standardized test iron-rich meal containing 43 mg of iron with two capsules of placebo or procyanidin supplementation. Each period was separated by a 3-day wash-out period. The primary objective was a reduction of dietary iron absorption, assessed by a reduction of serum-iron area under the curve (AUC) corrected for baseline serum iron. RESULTS All patients completed the study. The meal and the procyanidin supplements were well tolerated. In both HH and DIOS patients, the iron-rich meal induced a significant increase of serum iron compared with baseline at 120, 180, 240 min, from 8 to 9.1% (p = 0.002, 0.001 and 0.003, respectively) in DIOS and from 15.8 to 25.7% (p < 0.001) in HH. Iron absorption was 3.5-fold higher in HH than in DIOS (p < 0.001). Procyanidin supplementation did not significantly modify iron absorption in DIOS (AUC of added iron 332.87 ± 649.55 vs 312.61 ± 678.61 μmol.h/L, p = 0.916) or in HH (1168.62 ± 652.87 vs 1148.54 μmol.h/L ± 1290.05, p = 0.917). CONCLUSIONS An iron-rich test meal led to a marked increase in iron absorption in HH but a mild increase in DIOS. Procyanidin supplementation does not significantly reduce dietary iron absorption in either disease. CLINICAL TRIAL REGISTRY: clinicaltrials.gov (NCT03453918).
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Mehta KJ, Farnaud SJ, Sharp PA. Iron and liver fibrosis: Mechanistic and clinical aspects. World J Gastroenterol 2019; 25:521-538. [PMID: 30774269 PMCID: PMC6371002 DOI: 10.3748/wjg.v25.i5.521] [Citation(s) in RCA: 193] [Impact Index Per Article: 32.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/02/2019] [Accepted: 01/10/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore, understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly, highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis.
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Affiliation(s)
- Kosha J Mehta
- School of Population Health and Environmental Sciences, Faculty of Life Sciences and Medicine, King’s College London, London SE1 1UL, United Kingdom
- Division of Human Sciences, School of Applied Sciences, London South Bank University, London SE1 0AA, United Kingdom
| | - Sebastien Je Farnaud
- Faculty Research Centre for Sport, Exercise and Life Sciences, Coventry University, Coventry CV1 2DS, United Kingdom
| | - Paul A Sharp
- Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 9NH, United Kingdom
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46
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Assimakopoulos K, Karaivazoglou K, Tsermpini EE, Diamantopoulou G, Triantos C. Quality of life in patients with nonalcoholic fatty liver disease: A systematic review. J Psychosom Res 2018; 112:73-80. [PMID: 30097139 DOI: 10.1016/j.jpsychores.2018.07.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 07/10/2018] [Accepted: 07/11/2018] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent medical condition, which may lead to severe complications including cirrhosis and hepatocellular carcinoma. Its chronic course and its association with obesity and diabetes mellitus augment the long-term impact of NAFLD on patients' health and quality of life (QoL) and put great strain on healthcare systems worldwide. Research is growingly focusing on NAFLD patients' QoL in an attempt to describe the full spectrum of disease burden and tackle its future consequences. Relevant studies are characterized by sample heterogeneity and provide conflicting findings which should be interpreted with the use of a systematic and integrative approach. In this context, our aim was to conduct a systematic literature review on the topic of NAFLD patients' QoL. METHODS We performed a systematic search of PubMed, ScienceDirect and GoogleScholar databases according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol. RESULTS Our search yielded 14 suitable articles reporting data from almost 5000 patients. All authors agree that NAFLD patients' QoL is impaired especially in the physical sub-domain. In addition, several demographic, clinical and histopathological parameters have emerged as major determinants of patients' QoL. However, future studies are needed to further clarify these issues. CONCLUSIONS NAFLD patients report poor physical QoL. QoL impairment is associated with a variety of disease-related parameters, mostly the presence of fatigue and cirrhosis.
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Affiliation(s)
| | | | - Evangelia-Eirini Tsermpini
- Department of Pharmacy, Laboratory of Molecular Biology and Immunology, School of Health Science, University of Patras, Rion Patras, Greece
| | - Georgia Diamantopoulou
- Department of Gastroenterology, School of Medicine, University of Patras, Rion Patras, Greece
| | - Christos Triantos
- Department of Gastroenterology, School of Medicine, University of Patras, Rion Patras, Greece.
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47
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Pickett-Blakely O, Young K, Carr RM. Micronutrients in Nonalcoholic Fatty Liver Disease Pathogenesis. Cell Mol Gastroenterol Hepatol 2018; 6:451-462. [PMID: 30294653 PMCID: PMC6170520 DOI: 10.1016/j.jcmgh.2018.07.004] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 07/19/2018] [Indexed: 02/06/2023]
Abstract
Micronutrients include electrolytes, minerals, vitamins, and carotenoids, and are required in microgram or milligram quantities for cellular metabolism. The liver plays an important role in micronutrient metabolism and this metabolism often is altered in chronic liver diseases. Here, we review how the liver contributes to micronutrient metabolism; how impaired micronutrient metabolism may be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a systemic disorder of energy, glucose, and lipid homeostasis; and how insights gained from micronutrient biology have informed NAFLD therapeutics. Finally, we highlight some of the challenges and opportunities that remain with investigating the contribution of micronutrients to NAFLD pathology and suggest strategies to incorporate our understanding into the care of NAFLD patients.
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Affiliation(s)
| | | | - Rotonya M. Carr
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania
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48
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Mateo-Gallego R, Lacalle L, Pérez-Calahorra S, Marco-Benedí V, Recasens V, Padrón N, Lamiquiz-Moneo I, Baila-Rueda L, Jarauta E, Calmarza P, Cenarro A, Civeira F. Efficacy of repeated phlebotomies in hypertriglyceridemia and iron overload: A prospective, randomized, controlled trial. J Clin Lipidol 2018; 12:1190-1198. [PMID: 30049591 DOI: 10.1016/j.jacl.2018.06.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 06/21/2018] [Accepted: 06/27/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND High ferritin concentration is associated with hypertriglyceridemia, although it is not elucidated if iron overload has a causal role. OBJECTIVE To evaluate the efficacy of repeated phlebotomies in patients with iron overload and hypertriglyceridemia. METHODS Twelve weeks, 1:1 randomized, parallel-groups trial conducted at a University Hospital Lipid Clinic, including 86 subjects aged 18-70 years with serum ferritin >300 ng/mL in men or >200 ng/mL in women and triglycerides >200 mg/dL. Participants underwent: (1) three phlebotomies (every 3 weeks) and lipid-lowering dietary counseling or (2) lipid-lowering dietary counseling. The main outcome measured was the mean difference in percent change in triglyceride concentration between groups after the intervention. The mean differences in percent change of other clinical and biochemical variables (including cytokines and proinflammatory markers) after the intervention were also evaluated. RESULTS Subjects who received phlebotomies showed a significant improvement in iron metabolism. The mean percent change in triglycerides between groups was -4.68 [-20.8, 11.4]%, P = .721. Retinol-binding protein 4 decreased by 9.98 ± 21.7% after phlebotomies, with a mean percent change between groups of -14.2 [-25.8, -2.73]%, P = .017, and correlated to gamma glutamyl transferase, alanine aminotransferase and aspartate aminotransferase change. Subjects with a large reduction in hepcidin showed a large improvement in liver enzymes and proinflammatory markers. CONCLUSIONS A lipid-lowering diet plus a substantial reduction in iron deposits with repeated phlebotomies in subjects with hyperferritinemia and hypertriglyceridemia did not reduce triglyceride concentration in comparison with a lipid-lowering diet. Iron depletion for lipid management in these patients is not supported.
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Affiliation(s)
- Rocío Mateo-Gallego
- Lipid Unit, Hospital Universitario Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain; Universidad de Zaragoza, Zaragoza, Spain
| | - Laura Lacalle
- Hematology Department, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Sofía Pérez-Calahorra
- Lipid Unit, Hospital Universitario Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain
| | - Victoria Marco-Benedí
- Lipid Unit, Hospital Universitario Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain
| | - Valle Recasens
- Universidad de Zaragoza, Zaragoza, Spain; Hematology Department, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Noelia Padrón
- Hematology Department, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Itziar Lamiquiz-Moneo
- Lipid Unit, Hospital Universitario Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain
| | - Lucía Baila-Rueda
- Lipid Unit, Hospital Universitario Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain
| | - Estíbaliz Jarauta
- Lipid Unit, Hospital Universitario Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain
| | - Pilar Calmarza
- Biochemistry Department, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Ana Cenarro
- Lipid Unit, Hospital Universitario Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain
| | - Fernando Civeira
- Lipid Unit, Hospital Universitario Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain; Universidad de Zaragoza, Zaragoza, Spain.
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49
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Pirasteh A, Yuan Q, Hernando D, Reeder SB, Pedrosa I, Yokoo T. Inter-method reproducibility of biexponential R 2 MR relaxometry for estimation of liver iron concentration. Magn Reson Med 2018; 80:2691-2701. [PMID: 29770484 DOI: 10.1002/mrm.27348] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 04/03/2018] [Accepted: 04/16/2018] [Indexed: 12/17/2022]
Abstract
PURPOSE To assess the reproducibility of biexponential R2 -relaxometry MRI for estimation of liver iron concentration (LIC) between proprietary and nonproprietary analysis methods. METHODS This single-center retrospective study, approved by investigational review board and compliant with the Health Insurance Portability and Accountability Act, included 40 liver MRI exams in 38 subjects with suspected or known iron overload. From spin-echo images of the liver, acquired at 5 different echo times (TE = 6-18 ms), biexponential R2 maps were calculated using 1 proprietary (FerriScan, Resonance Health Ltd., Claremont WA, Australia) and 3 nonproprietary (simulated annealing, nonlinear least squares, dictionary search) analysis methods. Each subject's average liver R2 value was converted to LIC using a previously validated calibration curve. Inter-method reproducibility for liver R2 and LIC were assessed for linearity using linear regression analysis and absolute agreement using intraclass correlation and Bland-Altman analysis. For point estimates, 95% confidence intervals were calculated; P values < 0.05 were considered statistically significant. RESULTS Linearity between the proprietary and nonproprietary methods was excellent across the observed range for R2 (20-312 s-1 ) and LIC (0.4-52.2 mg/g), with all coefficients of determination (R2 ) ≥ 0.95. No statistically significant bias was found (slope estimates ∼ 1; intercept estimates ∼ 0; P values > 0.05). Agreement between the 4 methods was excellent for both liver R2 and LIC (intraclass correlations ≥ 0.97). Bland-Altman 95% limits of agreement in % difference between the proprietary and nonproprietary methods were ≤ 9% and ≤ 16% for R2 and LIC, respectively. CONCLUSION Biexponential R2 -relaxometry MRI for LIC estimation is reproducible between proprietary and nonproprietary analysis methods.
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Affiliation(s)
- Ali Pirasteh
- Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Qing Yuan
- Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Diego Hernando
- Radiology, Medical Physics, University of Wisconsin, Madison, Wisconsin
| | - Scott B Reeder
- Radiology, Medical Physics, Biomedical Engineering, Medicine, Emergency Medicine, University of Wisconsin, Madison, Wisconsin
| | - Ivan Pedrosa
- Radiology, University of Texas Southwestern Medical Center, Dallas, Texas.,Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Takeshi Yokoo
- Radiology, University of Texas Southwestern Medical Center, Dallas, Texas.,Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas
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50
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Britton L, Bridle K, Reiling J, Santrampurwala N, Wockner L, Ching H, Stuart K, Subramaniam VN, Jeffrey G, St Pierre T, House M, Gummer J, Trengove R, Olynyk J, Crawford D, Adams L. Hepatic iron concentration correlates with insulin sensitivity in nonalcoholic fatty liver disease. Hepatol Commun 2018; 2:644-653. [PMID: 29881816 PMCID: PMC5983226 DOI: 10.1002/hep4.1190] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 03/23/2018] [Accepted: 04/01/2018] [Indexed: 01/01/2023] Open
Abstract
Rodent and cell‐culture models support a role for iron‐related adipokine dysregulation and insulin resistance in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); however, substantial human data are lacking. We examined the relationship between measures of iron status, adipokines, and insulin resistance in patients with NAFLD in the presence and absence of venesection. This study forms part of the Impact of Iron on Insulin Resistance and Liver Histology in Nonalcoholic Steatohepatitis (IIRON2) study, a prospective randomized controlled trial of venesection for adults with NAFLD. Paired serum samples at baseline and 6 months (end of treatment) in controls (n = 28) and patients who had venesection (n = 23) were assayed for adiponectin, leptin, resistin, retinol binding protein‐4, tumor necrosis factor α, and interleukin‐6, using a Quantibody, customized, multiplexed enzyme‐linked immunosorbent assay array. Hepatic iron concentration (HIC) was determined using MR FerriScan. Unexpectedly, analysis revealed a significant positive correlation between baseline serum adiponectin concentration and HIC, which strengthened after correction for age, sex, and body mass index (rho = 0.36; P = 0.007). In addition, there were significant inverse correlations between HIC and measures of insulin resistance (adipose tissue insulin resistance (Adipo‐IR), serum insulin, serum glucose, homeostasis model assessment of insulin resistance, hemoglobin A1c, and hepatic steatosis), whereas a positive correlation was noted with the insulin sensitivity index. Changes in serum adipokines over 6 months did not differ between the control and venesection groups. Conclusion: HIC positively correlates with serum adiponectin and insulin sensitivity in patients with NAFLD. Further study is required to establish causality and mechanistic explanations for these associations and their relevance in the pathogenesis of insulin resistance and NAFLD. (Hepatology Communications 2018;2:644‐653)
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Affiliation(s)
- Laurence Britton
- Gallipoli Medical Research Institute Greenslopes Private Hospital Greenslopes Australia.,University of Queensland Herston Australia.,Department of Gastroenterology Princess Alexandra Hospital Woolloongabba Australia.,QIMR Berghofer Medical Research Institute Brisbane Australia
| | - Kim Bridle
- Gallipoli Medical Research Institute Greenslopes Private Hospital Greenslopes Australia.,University of Queensland Herston Australia
| | - Janske Reiling
- Gallipoli Medical Research Institute Greenslopes Private Hospital Greenslopes Australia.,University of Queensland Herston Australia.,Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht University Maastricht the Netherlands
| | - Nishreen Santrampurwala
- Gallipoli Medical Research Institute Greenslopes Private Hospital Greenslopes Australia.,University of Queensland Herston Australia.,QIMR Berghofer Medical Research Institute Brisbane Australia
| | - Leesa Wockner
- QIMR Berghofer Medical Research Institute Brisbane Australia
| | - Helena Ching
- Medical School, Faculty of Health Sciences University of Western Australia Crawley Australia
| | - Katherine Stuart
- Gallipoli Medical Research Institute Greenslopes Private Hospital Greenslopes Australia.,Department of Gastroenterology Princess Alexandra Hospital Woolloongabba Australia
| | - V Nathan Subramaniam
- QIMR Berghofer Medical Research Institute Brisbane Australia.,Institute of Health and Biomedical Innovation and School of Biomedical Sciences Queensland University of Technology Kelvin Grove Australia
| | - Gary Jeffrey
- Medical School, Faculty of Health Sciences University of Western Australia Crawley Australia.,Department of Hepatology Sir Charles Gairdner Hospital Perth Australia
| | - Tim St Pierre
- School of Physics University of Western Australia Crawley Australia
| | - Michael House
- School of Physics University of Western Australia Crawley Australia
| | - Joel Gummer
- Separation Science and Metabolomics Laboratory (Metabolomics Australia, Western Australia node) Murdoch University Murdoch Australia
| | - Robert Trengove
- Separation Science and Metabolomics Laboratory (Metabolomics Australia, Western Australia node) Murdoch University Murdoch Australia
| | - John Olynyk
- Department of Gastroenterology Fiona Stanley and Fremantle Hospital Group Murdoch Australia.,School of Health and Medical Sciences Edith Cowan University Joondalup Australia
| | - Darrell Crawford
- Gallipoli Medical Research Institute Greenslopes Private Hospital Greenslopes Australia.,University of Queensland Herston Australia
| | - Leon Adams
- Medical School, Faculty of Health Sciences University of Western Australia Crawley Australia.,Department of Hepatology Sir Charles Gairdner Hospital Perth Australia
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