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Gomes NBN, Torres US, Ferraz MLCG, D'Ippolito G. Advanced Magnetic Resonance Imaging for Detection of Liver Fibrosis and Inflammation in Autoimmune Hepatitis: A State-of-the-Art Review. Semin Ultrasound CT MR 2024; 45:464-475. [PMID: 39069278 DOI: 10.1053/j.sult.2024.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Autoimmune hepatitis is a rare chronic liver disease, associated with a high level of morbidity and high mortality; approximately 40% of patients with severe untreated disease die within 6 months of diagnosis. It should be treated to achieve complete biochemical and histologic resolution of the disease using corticosteroids and immunosuppression to prevent further progression to cirrhosis. The use of invasive liver biopsy is recommended for the staging and assessment of inflammation and fibrosis for treatment decision-making in the face of an unsatisfactory response or clinical remission, including being a determinant for withdrawal of immunosuppression. On the other hand, liver biopsy is invasive, costly, and not free of complications. It also has potential sampling error and poor interobserver agreement. The limitations of liver biopsy highlight the importance of developing new imaging biomarkers that allow accurate and non-invasive assessment of autoimmune hepatitis in terms of liver inflammation and fibrosis, developing the virtual biopsy concept. Therefore, we review the state-of-the-art of Magnetic Resonance Imaging sequences for the noninvasive evaluation of autoimmune hepatitis, including historical advances and future directions.
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Affiliation(s)
- Natália B N Gomes
- Department of Radiology, Grupo Fleury, São Paulo, São Paulo, Brazil; Department of Diagnostic Imaging, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, São Paulo, Brazil
| | - Ulysses S Torres
- Department of Radiology, Grupo Fleury, São Paulo, São Paulo, Brazil; Department of Diagnostic Imaging, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, São Paulo, Brazil.
| | - Maria Lucia C G Ferraz
- Department of Gastroenterology, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, São Paulo, Brazil
| | - Giuseppe D'Ippolito
- Department of Radiology, Grupo Fleury, São Paulo, São Paulo, Brazil; Department of Diagnostic Imaging, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, São Paulo, Brazil
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Jo S, Kim JM, Li M, Kim HS, An YJ, Park S. TAT as a new marker and its use for noninvasive chemical biopsy in NASH diagnosis. Mol Med 2024; 30:232. [PMID: 39592957 PMCID: PMC11590374 DOI: 10.1186/s10020-024-00992-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND Early diagnosis of Nonalcoholic steatohepatitis (NASH) is crucial to prevent its progression to hepatocellular carcinoma, but its gold standard diagnosis still requires invasive biopsy. Here, a new marker-based noninvasive chemical biopsy approach is introduced that uses urine-secreted tyrosine metabolites. METHODS We first identified NASH-specific decrease in TAT expression, the first enzyme in the tyrosine degradation pathway (TDP), by employing exometabolome-transcriptome correlations, single-cell RNA -seq, and tissue staining on human NASH patient samples. A selective extrahepatic monitoring of the TAT activity was established by the chemical biopsy exploiting the enzyme's metabolic conversion of D2-tyrosine into D2-4HPP. The approach was applied to a NASH mouse model using the methionine-choline deficient diet, where urine D2-4HPP level was measured with a specific LC-MS detection, following oral administration of D2-tyrosine. RESULTS The noninvasive urine chemical biopsy approach could effectively differentiate NASH from normal mice (normal = 14, NASH = 15, p = 0.0054), correlated with the NASH pathology and TAT level decrease observed with immunostaining on the liver tissue. In addition, we showed that the diagnostic differentiation could be enhanced by measuring the downstream metabolites of TDP. The specificity of the TAT and the related TDP enzymes in NASH were also addressed in other settings employing high fat high fructose mouse NASH model and human obesity vs. NASH cohort. CONCLUSIONS Overall, we propose TAT and TDP as pathology-relevant markers for NASH and present the urine chemical biopsy as a noninvasive modality to evaluate the NASH-specific changes in urine that may help the NASH diagnosis.
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Affiliation(s)
- Sihyang Jo
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak- Ro 1, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Jin-Mo Kim
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak- Ro 1, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Minshu Li
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak- Ro 1, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Han Sun Kim
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak- Ro 1, Gwanak-gu, Seoul, 08826, Republic of Korea
- Department of Biochemistry, College of Medicine, Dongguk University, Gyeongju, 38066, Republic of Korea
| | - Yong Jin An
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak- Ro 1, Gwanak-gu, Seoul, 08826, Republic of Korea.
| | - Sunghyouk Park
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak- Ro 1, Gwanak-gu, Seoul, 08826, Republic of Korea.
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Yu Z, Fan X, Zhao X, He T, Li X, Du H, Zhao M, Zhu R, Li M, Zhang Z, Han F. Polystyrene Nanoplastics Induce Lipid Metabolism Disorder by Activating the PERK-ATF4 Signaling Pathway in Mice. ACS APPLIED MATERIALS & INTERFACES 2024; 16:34524-34537. [PMID: 38926154 DOI: 10.1021/acsami.4c04416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/28/2024]
Abstract
In recent years, the study of microplastics (MPs) and nanoplastics (NPs) and their effects on human health has gained significant attention. The impacts of NPs on lipid metabolism and the specific mechanisms involved remain poorly understood. To address this, we utilized high-throughput sequencing and molecular biology techniques to investigate how endoplasmic reticulum (ER) stress might affect hepatic lipid metabolism in the presence of polystyrene nanoplastics (PS-NPs). Our findings suggest that PS-NPs activate the PERK-ATF4 signaling pathway, which in turn upregulates the expression of genes related to lipid synthesis via the ATF4-PPARγ/SREBP-1 pathway. This activation leads to an abnormal accumulation of lipid droplets in the liver. 4-PBA, a known ER stress inhibitor, was found to mitigate the PS-NPs-induced lipid metabolism disorder. These results demonstrate the hepatotoxic effects of PS-NPs and clarify the mechanisms of abnormal lipid metabolism induced by PS-NPs.
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Affiliation(s)
- Ziteng Yu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Xingpei Fan
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Xinyi Zhao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Tianyue He
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Xiaoyan Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Haining Du
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Meimei Zhao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Ruijiao Zhu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Mengcong Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Ziyi Zhang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
| | - Fang Han
- School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China
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Chu R, Wang Y, Kong J, Pan T, Yang Y, He J. Lipid nanoparticles as the drug carrier for targeted therapy of hepatic disorders. J Mater Chem B 2024; 12:4759-4784. [PMID: 38682294 DOI: 10.1039/d3tb02766j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2024]
Abstract
The liver, a complex and vital organ in the human body, is susceptible to various diseases, including metabolic disorders, acute hepatitis, cirrhosis, and hepatocellular carcinoma. In recent decades, these diseases have significantly contributed to global morbidity and mortality. Currently, liver transplantation remains the most effective treatment for hepatic disorders. Nucleic acid therapeutics offer a selective approach to disease treatment through diverse mechanisms, enabling the regulation of relevant genes and providing a novel therapeutic avenue for hepatic disorders. It is expected that nucleic acid drugs will emerge as the third generation of pharmaceuticals, succeeding small molecule drugs and antibody drugs. Lipid nanoparticles (LNPs) represent a crucial technology in the field of drug delivery and constitute a significant advancement in gene therapies. Nucleic acids encapsulated in LNPs are shielded from the degradation of enzymes and effectively delivered to cells, where they are released and regulate specific genes. This paper provides a comprehensive review of the structure, composition, and applications of LNPs in the treatment of hepatic disorders and offers insights into prospects and challenges in the future development of LNPs.
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Affiliation(s)
- Runxuan Chu
- National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, P. R. China.
| | - Yi Wang
- Department of Chemistry, Hong Kong Baptist University, Kowloon Tung, Hong Kong SAR, P. R. China.
| | - Jianglong Kong
- Department of Chemistry, Hong Kong Baptist University, Kowloon Tung, Hong Kong SAR, P. R. China.
| | - Ting Pan
- National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, P. R. China.
- Department of Pharmaceutics School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Yani Yang
- National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, P. R. China.
| | - Jun He
- National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, P. R. China.
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Liu J, Liu X, Shan Y, Ting HJ, Yu X, Wang JW, Liu B. Targeted platelet with hydrogen peroxide responsive behavior for non-alcoholic steatohepatitis detection. Biomaterials 2024; 306:122506. [PMID: 38354517 DOI: 10.1016/j.biomaterials.2024.122506] [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] [Received: 09/28/2023] [Revised: 02/05/2024] [Accepted: 02/08/2024] [Indexed: 02/16/2024]
Abstract
The most common chronic liver illness, non-alcoholic fatty liver disease (NAFLD), refers to a range of abnormalities of the liver with varying degrees of steatosis. When the clinical symptoms including liver damage, inflammation, and fibrosis, are added to the initial steatosis, NAFLD becomes non-alcoholic steatohepatitis (NASH), the problematic and severe stage. The diagnosis of NASH at the right time could therefore effectively prevent deterioration of the disease. Considering that platelets (PLTs) could migrate to the sites of inflamed liver sinusoids with oxidative stress during the development of NASH, we purified the PLTs from fresh blood and engineered their surface with hydrogen peroxide (H2O2) responsive fluorescent probe (5-DP) through lipid fusion. The engineered PLT-DPs were recruited and trapped in the inflammation foci of the liver with NASH through interaction with the extracellular matrix, including hyaluronan and Kupffer cells. Additionally, the fluorescence of 5-DP on the surface of PLT-DP was significantly enhanced upon reacting with the elevated level of H2O2 in the NASH liver. Thus, PLT-DP has great promise for NASH fluorescence imaging with high selectivity and sensitivity.
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Affiliation(s)
- Jingjing Liu
- Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117585, Singapore; Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, 225001, China
| | - Xingang Liu
- Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117585, Singapore
| | - Yi Shan
- Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117585, Singapore
| | - Hui Jun Ting
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Nanomedicine Translational Research Program, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117609, Singapore
| | - Xiaodong Yu
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Nanomedicine Translational Research Program, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117609, Singapore
| | - Jiong-Wei Wang
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Nanomedicine Translational Research Program, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117609, Singapore; Cardiovascular Research Institute, National University Heart Centre Singapore, Singapore 117599, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore
| | - Bin Liu
- Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117585, Singapore.
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Barazesh M, Jalili S, Akhzari M, Faraji F, Khorramdin E. Recent Progresses on Pathophysiology, Diagnosis, Therapeutic Modalities,
and Management of Non-alcoholic Fatty Liver Disorder. CURRENT DRUG THERAPY 2024; 19:20-48. [DOI: 10.2174/1574885518666230417111247] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/30/2023] [Accepted: 02/06/2023] [Indexed: 01/03/2025]
Abstract
Abstract:
Non-alcoholic fatty liver disease (NAFLD) is currently the utmost common chronic liver
disorder that happens through all age groups and is identified to occur in 14%-30% of the general
population, demonstrating a critical and grossing clinical issue because of the growing incidence of
obesity and overweight. From the histological aspect, it looks like alcoholic liver damage, but it happens in patients who avoid remarkable alcohol usage. NAFLD comprises a broad spectrum, ranging
from benign hepatocellular steatosis to inflammatory nonalcoholic steatohepatitis (NASH), different
levels of fibrosis, and cirrhosis. Patients with NASH are more susceptible to more rapid progression to
cirrhosis and hepatocellular carcinoma. There is no single factor that drives proceeding from simple
steatosis to NASH. However, a combination of multi parameters such as genetic background, gut microflora, intake of high fat/ fructose dietary contents or methionine/choline-deficient diet, and consequently accumulated hepatocellular lipids mainly including triglycerides and also other bio-analytes,
such as free fatty acids, cholesterol, and phospholipids display a crucial role in disease promotion.
NAFLD is related to overweight and insulin resistance (IR) and is regarded as the hepatic presentation
of the metabolic syndrome, an amalgamation of medical statuses such as hyperlipidemia, hypertension, type 2 diabetes, and visceral obesity. Despite the increasing prevalence of this disease, which
imposes a remarkable clinical burden, most affected patients remain undiagnosed in a timely manner,
largely related to the asymptomatic entity of NAFLD patients and the unavailability of accurate and
efficient noninvasive diagnostic tests. However, liver biopsy is considered a gold standard for NAFLD
diagnosis, but due to being expensive and invasiveness is inappropriate for periodic disease screening.
Some noninvasive monitoring approaches have been established recently for NAFLD assessment. In
addition to the problem of correct disease course prediction, no effective therapeutic modalities are
approved for disease treatment. Imaging techniques can commonly validate the screening and discrimination of NAFLD; nevertheless, staging the disease needs a liver biopsy. The present therapeutic approaches depend on weight loss, sports activities, and dietary modifications, although different insulin-sensitizing drugs, antioxidants, and therapeutic agents seem hopeful. This review aims to focus on
the current knowledge concerning epidemiology, pathogenesis, and different biochemical experiments
and imaging modalities applied to diagnose the different grades of NAFLD and its management, as
well as new data about pharmacological therapies for this disorder.
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Affiliation(s)
- Mahdi Barazesh
- School of Paramedical, Gerash University of Medical Sciences, Gerash, Iran
| | - Sajad Jalili
- Department of Orthopedics, School of
Medicine, Ahvaz Jundishapour University of Medical Sciences, Ahvaz, Iran
| | - Morteza Akhzari
- School of Nursing, Larestan University of
Medical Sciences, Larestan, Iran
| | - Fouzieyeh Faraji
- School of Paramedical, Gerash University of Medical Sciences, Gerash, Iran
| | - Ebrahim Khorramdin
- Department of Orthopedics, School of
Medicine, Ahvaz Jundishapour University of Medical Sciences, Ahvaz, Iran
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Kirkil C, Aydin I, Yur M, Ag O, Bozcan MY. Comparison of the ABCD Score's Accuracy in Predicting Remission of Type 2 Diabetes Mellitus One Year After Sleeve Gastrectomy, One Anastomosis Gastric Bypass, and Sleeve Gastrectomy with Transit Bipartition. Obes Surg 2024; 34:133-140. [PMID: 37985569 DOI: 10.1007/s11695-023-06950-3] [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] [Received: 09/08/2023] [Revised: 11/05/2023] [Accepted: 11/13/2023] [Indexed: 11/22/2023]
Abstract
PURPOSE ABCD score is one of the scoring systems that predicts the probability of T2DM remission after bariatric surgery. Its success in determining T2DM remission after sleeve gastrectomy with transit bipartition (TB) has not yet been validated. The aim of this study was to evaluate the predictive value of ABCD score in TB. MATERIALS AND METHODS Of 438 patients with T2DM, 191 underwent sleeve gastrectomy (SG), 136 underwent one anastomosis gastric bypass (OAGB), and 111 underwent TB. Retrospective analysis of ABCD scores, 1-year postoperative remission rates, and the predictive accuracy of ABCD scores for these were conducted. RESULTS In the SG, OAGB, and TB groups, respectively, median ABCD scores were 7, 6, and 4, while complete remission rates were 95.3%, 84.6%, and 76.6% (p < 0.001). The area under curves (AUCs) for SG, OAGB, and TB were 0.829 (95% CI = 0.768 to 0.879, p < 0.0001), 0.801 (95% CI = 0.724 to 0.865, p < 0.0001), and 0.840 (95% CI = 0.758 to 0.902, p < 0.0001), respectively. There was no statistically significant difference between AUCs. CONCLUSION ABCD score predicts the probability of remission at 1-year follow-up in T2DM patients undergoing TB as accurately as in patients receiving SG or OAGB.
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Affiliation(s)
- Cuneyt Kirkil
- School of Medicine, Department of General Surgery, University of Firat, 23119, Elazig, Turkey.
| | - Ilayda Aydin
- Faculty of Health Sciences, Department of Nutrition and Dietetics, Ataturk University, 25240, Erzurum, Turkey
| | - Mesut Yur
- School of Medicine, Department of General Surgery, University of Firat, 23119, Elazig, Turkey
| | - Onur Ag
- School of Medicine, Department of General Surgery, University of Firat, 23119, Elazig, Turkey
| | - Muhammed Yusuf Bozcan
- School of Medicine, Department of General Surgery, University of Firat, 23119, Elazig, Turkey
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Tiniakos DG, Anstee QM, Brunt EM, Burt AD. Fatty Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:330-401. [DOI: 10.1016/b978-0-7020-8228-3.00005-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Ji X, Ma Q, Wang X, Ming H, Bao G, Fu M, Wei C. Digeda-4 decoction and its disassembled prescriptions improve dyslipidemia and apoptosis by regulating AMPK/SIRT1 pathway on tyloxapol-induced nonalcoholic fatty liver disease in mice. JOURNAL OF ETHNOPHARMACOLOGY 2023; 317:116827. [PMID: 37348794 DOI: 10.1016/j.jep.2023.116827] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/17/2023] [Accepted: 06/19/2023] [Indexed: 06/24/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Nonalcoholic fatty liver disease (NAFLD) is a manifestation of metabolic syndrome in the liver and the leading cause of chronic liver disease worldwide. Digeda-4 decoction (DGD-4) is a commonly prescribed Mongolian herbal drug for treating acute and chronic liver injury and fatty liver. However, the mechanisms underlying the improvement of dislipidemia and liver injury via treatment with DGD-4 remain unclear. Disassembling a prescription is an effective approach to studying the effects and mechanisms underlying Mongolian medicine prescriptions. By disassembling a prescription, it is feasible to discover effective combinations of individual herbs to optimize a given prescription. Accordingly, we disassembled DGD-4 into two groups: the single Lomatogonium rotatum (L.) Fries ex Nym (LR) (DGD-1) and non-LR (DGD-3). AIM OF THIS STUDY To study whether DGD-4 and its disassembled prescriptions have protective effects against tyloxapol (TY)-induced NAFLD and to explore the underlying mechanisms of action and compatibility of prescriptions. MATERIAL AND METHODS NAFLD mice were developed by TY induction. Biochemical horizontal analyses, enzyme-linked immunosorbent assay, and liver histological staining were performed to explore the protective effects of DGD-4 and its disassembled prescriptions DGD-3 and DGD-1. Furthermore, we performed immunohistochemical analyses and Western blotting to further explore the expression of target proteins. RESULTS DGD-4 and its disassembled prescriptions could inhibit TY-induced dislipidemia and liver injury. In addition, DGD-4 and its disassembled prescriptions increased the levels of p-AMPKα and p-ACC, but decreased the levels of SREBP1c, SCD-1, SREBP-2, and HMGCS1 proteins. The activation of lipid metabolic pathways SIRT1, PGC-1α, and PPARα improved lipid accumulation in the liver. Moreover, DGD-4 could inhibit hepatocyte apoptosis and treat TY-induced liver injury by upregulating the Bcl-2 expression, downregulating the expression of Bax, caspase-3, caspase-8, and the ratio of Bax/Bcl-2, and positively regulating the imbalance of oxidative stress (OxS) markers (such as superoxide dismutase [SOD], catalase [CAT], malondialdehyde [MDA], and myeloperoxidase [MPO]). DGD-1 was superior to DGD-3 in regulating lipid synthesis-related proteins such as SREBP1c, SCD-1, SREBP-2, and HMGCS1. DGD-3 significantly affected the expression of lipid metabolic proteins SIRT1, PGC-1α, PPARα, apoptotic proteins Bcl-2, Bax, caspase-3, caspase-8, and the regulation of Bax/Bcl-2 ratio. However, DGD-1 showed no regulatory effects on Bax and Bcl-2 proteins. CONCLUSION This study demonstrates the protective effects of DGD-4 in the TY-induced NAFLD mice through a mechanism involving improvement of dyslipidemia and apoptosis by regulating the AMPK/SIRT1 pathway. Although the Monarch drug DGD-1 reduces lipid accumulation and DGD-3 inhibits apoptosis and protects the liver from injury, DGD-4 can be more effective overall as a therapy when compared to DGD-1 and DGD-3.
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Affiliation(s)
- Xiaoping Ji
- School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao, 028000, China; Institute of Pharmaceutical Chemistry and Pharmacology, Inner Mongolia Minzu University, Tongliao, 028000, China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Inner Mongolia Minzu University, Tongliao, 028000, China.
| | - Qianqian Ma
- Institute of Pharmaceutical Chemistry and Pharmacology, Inner Mongolia Minzu University, Tongliao, 028000, China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Inner Mongolia Minzu University, Tongliao, 028000, China.
| | - Xuan Wang
- Institute of Pharmaceutical Chemistry and Pharmacology, Inner Mongolia Minzu University, Tongliao, 028000, China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Inner Mongolia Minzu University, Tongliao, 028000, China.
| | - Hui Ming
- Institute of Pharmaceutical Chemistry and Pharmacology, Inner Mongolia Minzu University, Tongliao, 028000, China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Inner Mongolia Minzu University, Tongliao, 028000, China.
| | - Guihua Bao
- School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao, 028000, China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Inner Mongolia Minzu University, Tongliao, 028000, China.
| | - Minghai Fu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou, 571199, China.
| | - Chengxi Wei
- School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao, 028000, China; Institute of Pharmaceutical Chemistry and Pharmacology, Inner Mongolia Minzu University, Tongliao, 028000, China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Inner Mongolia Minzu University, Tongliao, 028000, China.
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Wang Y, Chen Q, Wu S, Sun X, Yin R, Ouyang Z, Yin H, Wei Y. Amelioration of ethanol-induced oxidative stress and alcoholic liver disease by in vivo RNAi targeting Cyp2e1. Acta Pharm Sin B 2023; 13:3906-3918. [PMID: 37719371 PMCID: PMC10502278 DOI: 10.1016/j.apsb.2023.01.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/16/2022] [Accepted: 12/10/2022] [Indexed: 09/19/2023] Open
Abstract
Alcoholic liver disease (ALD) results from continuous and heavy alcohol consumption. The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention, which is a long process with poor efficacy and low patient compliance. Alcohol-induced CYP2E1 upregulation has been demonstrated as a key regulator of ALD, but CYP2E1 knockdown in humans was impractical, and pharmacological inhibition of CYP2E1 by a clinically relevant approach for treating ALD was not shown. In this study, we developed a RNAi therapeutics delivered by lipid nanoparticle, and treated mice fed on Lieber-DeCarli ethanol liquid diet weekly for up to 12 weeks. This RNAi-based inhibition of Cyp2e1 expression reduced reactive oxygen species and oxidative stress in mouse livers, and contributed to improved ALD symptoms in mice. The liver fat accumulation, hepatocyte inflammation, and fibrosis were reduced in ALD models. Therefore, this study suggested the feasibility of RNAi targeting to CYP2E1 as a potential therapeutic tool to the development of ALD.
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Affiliation(s)
- Yalan Wang
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Qiubing Chen
- Department of Urology, Frontier Science Centre for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Shuang Wu
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Xinyu Sun
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Runting Yin
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Zhen Ouyang
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Hao Yin
- Department of Urology, Frontier Science Centre for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- RNA Institute, Wuhan University, Wuhan 430072, China
- Wuhan Research Centre for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430010, China
| | - Yuan Wei
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
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Bawden SJ, Hoad C, Kaye P, Stephenson M, Dolman G, James MW, Wilkes E, Austin A, Guha IN, Francis S, Gowland P, Aithal GP. Comparing magnetic resonance liver fat fraction measurements with histology in fibrosis: the difference between proton density fat fraction and tissue mass fat fraction. MAGMA (NEW YORK, N.Y.) 2023; 36:553-563. [PMID: 36538248 PMCID: PMC10468948 DOI: 10.1007/s10334-022-01052-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 11/22/2022] [Accepted: 11/23/2022] [Indexed: 06/17/2023]
Abstract
OBJECTIVE Magnetic resonance spectroscopy (MRS) provides a powerful method of measuring fat fraction. However, previous studies have shown that MRS results give lower values compared with visual estimates from biopsies in fibrotic livers. This study investigated these discrepancies and considered whether a tissue water content correction, as assessed by MRI relaxometry, could provide better agreement. MATERIALS AND METHODS 110 patients were scanned in a 1.5 T Philips scanner and biopsies were obtained. Multiple echo MRS (30 × 30 × 30 mm volume) was used to determine Proton Density Fat Fraction (PDFF). Biopsies were assessed by visual assessment for fibrosis and steatosis grading. Digital image analysis (DIA) was also used to quantify fat fraction within tissue samples. T1 relaxation times were then used to estimate tissue water content to correct PDFF for confounding factors. RESULTS PDFF values across the four visually assessed steatosis grades were significantly less in the higher fibrosis group (F3-F4) compared to the lower fibrosis group (F0-F2). The slope of the linear regression of PDFF vs DIA fat fraction was ~ 1 in the low fibrosis group and 0.77 in the high fibrosis group. Correcting for water content based on T1 increased the gradient but it did not reach unity. DISCUSSION In fibrotic livers, PDFF underestimated fat fraction compared to DIA methods. Values were improved by applying a water content correction, but fat fractions were still underestimated.
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Affiliation(s)
- Stephen James Bawden
- Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, NG7 2RD, UK.
- Sir Peter Mansfield Imaging Centre, SPMIC, University Park, Physics and Astronomy, University of Nottingham, Nottingham, UK.
| | - Caroline Hoad
- Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, NG7 2RD, UK
| | - Philip Kaye
- Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, NG7 2RD, UK
- Department of Cellular Pathology, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Mary Stephenson
- Clinical Imaging Research Centre (CIRC), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Grace Dolman
- Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, NG7 2RD, UK
| | - Martin W James
- Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, NG7 2RD, UK
| | - Emilie Wilkes
- Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, NG7 2RD, UK
| | | | - Indra Neil Guha
- Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, NG7 2RD, UK
| | - Susan Francis
- Sir Peter Mansfield Imaging Centre, SPMIC, University Park, Physics and Astronomy, University of Nottingham, Nottingham, UK
| | - Penny Gowland
- Sir Peter Mansfield Imaging Centre, SPMIC, University Park, Physics and Astronomy, University of Nottingham, Nottingham, UK
| | - Guruprasad P Aithal
- Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, NG7 2RD, UK
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12
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Shamsa EH, Song Z, Kim H, Shamsa F, Hazlett LD, Zhang K. The links of fine airborne particulate matter exposure to occurrence of cardiovascular and metabolic diseases in Michigan, USA. PLOS GLOBAL PUBLIC HEALTH 2022; 2:e0000707. [PMID: 36962575 PMCID: PMC10021276 DOI: 10.1371/journal.pgph.0000707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 07/13/2022] [Indexed: 11/18/2022]
Abstract
Air pollutants, particularly airborne particulate matter with aerodynamic diameter < 2.5μm (PM2.5), have been linked to the increase in mortality and morbidity associated with cardiovascular and metabolic diseases. In this study, we investigated the dose-risk relationships between PM2.5 concentrations and occurrences of cardiovascular and metabolic diseases as well as the confounding socioeconomic factors in Michigan, USA, where PM2.5 levels are generally considered acceptable. Multivariate linear regression analyses were performed to investigate the relationship between health outcome and annual ground-level PM2.5 concentrations of 82 counties in Michigan. The analyses revelated significant linear dose-response associations between PM2.5 concentrations and cardiovascular disease (CVD) hospitalization. A 10 μg/m3 increase in PM2.5 exposure was found to be associated with a 3.0% increase in total CVD, 0.45% increase in Stroke, and a 0.3% increase in Hypertension hospitalization rates in Medicare beneficiaries. While the hospitalization rates of Total Stroke, Hemorrhagic Stroke, and Hypertension in urbanized counties were significantly higher than those of rural counties, the death rates of coronary heart disease and ischemic stroke in urbanized counties were significantly lower than those of rural counties. These results were correlated with the facts that PM2.5 levels in urbanized counties were significantly higher than that in rural counties and that the percentage of the population with health insurance and the median household income in rural counties were significantly lower. While obesity prevalence showed evidence of a weak positive correlation (ρ = 0.20, p-value = 0.078) with PM2.5 levels, there was no significant dose-response association between county diabetes prevalence rates and PM2.5 exposure in Michigan. In summary, this study revealed strong dose-response associations between PM2.5 concentrations and CVD incidence in Michigan, USA. The socioeconomic factors, such as access to healthcare resources and median household income, represent important confounding factors that could override the impact of PM2.5 exposure on CVD mortality.
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Affiliation(s)
- El Hussain Shamsa
- Center for Molecular Medicine & Genetics, The Wayne State University School of Medicine, Detroit, MI, United States of America
| | - Zhenfeng Song
- Center for Molecular Medicine & Genetics, The Wayne State University School of Medicine, Detroit, MI, United States of America
| | - Hyunbae Kim
- Center for Molecular Medicine & Genetics, The Wayne State University School of Medicine, Detroit, MI, United States of America
| | - Falah Shamsa
- Cancer Coalition of Georgia, Atlanta, GA, United States of America
| | - Linda D. Hazlett
- Ophthalmology, Visual and Anatomical Sciences, The Wayne State University School of Medicine, Detroit, MI, United States of America
| | - Kezhong Zhang
- Center for Molecular Medicine & Genetics, The Wayne State University School of Medicine, Detroit, MI, United States of America
- Department of Immunology and Microbiology, The Wayne State University School of Medicine, Detroit, MI, United States of America
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13
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Todo Y, Miyake T, Furukawa S, Matsuura B, Ishihara T, Miyazaki M, Shiomi A, Nakaguchi H, Kanzaki S, Yamamoto Y, Koizumi Y, Yoshida O, Tokumoto Y, Hirooka M, Takeshita E, Kumagi T, Ikeda Y, Abe M, Iwata T, Hiasa Y. Combined evaluation of Fibrosis-4 index and fatty liver for stratifying the risk for diabetes mellitus. J Diabetes Investig 2022; 13:1577-1584. [PMID: 35437902 PMCID: PMC9434594 DOI: 10.1111/jdi.13812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/29/2022] [Accepted: 04/13/2022] [Indexed: 11/29/2022] Open
Abstract
Aims/Introduction To investigate whether the Fibrosis‐4 index can help stratify the risk of diabetes mellitus in patients with fatty liver disease. Materials and Methods Based on fatty liver disease and Fibrosis‐4 index (cut‐off value 1.3), we retrospectively divided 9,449 individuals, who underwent at least two annual health checkups, into four groups stratified by sex: normal; high Fibrosis‐4 index without fatty liver disease; low Fibrosis‐4 index with fatty liver disease; and high Fibrosis‐4 index with fatty liver disease. Results Onset rates for diabetes mellitus in the normal, high Fibrosis‐4 index without fatty liver disease, low Fibrosis‐4 index with fatty liver disease and high Fibrosis‐4 index with fatty liver disease groups were 1.6%, 4.3%, 6.8% and 10.2%, respectively, in men, and 0.6%, 0.9%, 5.3% and 7.0%, respectively, in women. Compared with the normal group, the high Fibrosis‐4 index without fatty liver disease, low Fibrosis‐4 index with fatty liver disease and high Fibrosis‐4 index with fatty liver disease groups were at a significant risk for diabetes mellitus onset in both male and female participants. Furthermore, in both sexes, high Fibrosis‐4 index with fatty liver disease remained a significant risk factor on multivariate analysis (high fibrosis‐4 index with fatty liver disease group: adjusted hazard ratio 4.03, 95% confidence interval 2.19–7.42 [men] and adjusted hazard ratio 6.40, 95% confidence interval 1.77–23.14 [women]). Conclusions Individuals with fatty liver disease and high Fibrosis‐4 index had a higher risk of diabetes mellitus onset. Therefore, Fibrosis‐4 index can help stratify the risk of diabetes mellitus in patients with fatty liver disease and identify patients requiring intervention.
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Affiliation(s)
- Yasuhiko Todo
- Department of Diabetes and Endocrinology, Uwajima City Hospital, Gotenmachi, Uwajima, Ehime, Japan
| | - Teruki Miyake
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Shinya Furukawa
- Health Services Center, Ehime University, Bunkyo, Matsuyama, Ehime, Japan
| | - Bunzo Matsuura
- Department of Lifestyle-Related Medicine and Endocrinology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Toru Ishihara
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan.,Ehime General Health Care Association, Misake, Matsuyama, Ehime, Japan
| | - Masumi Miyazaki
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Akihito Shiomi
- Department of Diabetes and Endocrinology, Uwajima City Hospital, Gotenmachi, Uwajima, Ehime, Japan
| | - Hironobu Nakaguchi
- Health Services Center, Ehime University, Bunkyo, Matsuyama, Ehime, Japan
| | - Sayaka Kanzaki
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Yasunori Yamamoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Eiji Takeshita
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Teru Kumagi
- Postgraduate Medical Education Center, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yoshio Ikeda
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Takeru Iwata
- Ehime General Health Care Association, Misake, Matsuyama, Ehime, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
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14
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Miyake T, Matsuura B, Furukawa S, Ishihara T, Yoshida O, Miyazaki M, Watanebe K, Shiomi A, Nakaguchi H, Yamamoto Y, Koizumi Y, Tokumoto Y, Hirooka M, Takeshita E, Kumagi T, Abe M, Ikeda Y, Iwata T, Hiasa Y. Fatty liver with metabolic disorder, such as metabolic dysfunction-associated fatty liver disease, indicates high risk for developing diabetes mellitus. J Diabetes Investig 2022; 13:1245-1252. [PMID: 35167194 PMCID: PMC9248428 DOI: 10.1111/jdi.13772] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/27/2022] [Accepted: 02/13/2022] [Indexed: 11/26/2022] Open
Abstract
Introduction Nonalcoholic fatty liver disease (NAFLD) is diagnosed after excluding other liver diseases. The pathogenesis of NAFLD when complicated by other liver diseases has not been established completely. Metabolic dysfunction‐associated fatty liver disease (MAFLD) involves more metabolic factors than NAFLD, regardless of complications with other diseases. This study aimed to clarify the effects of fatty liver occurring with metabolic disorders, such as MAFLD without diabetes mellitus (DM), on the development of DM. Materials and Methods We retrospectively assessed 9,459 participants who underwent two or more annual health check‐ups. The participants were divided into the MAFLD group (fatty liver disease with overweight/obesity or non‐overweight/obesity complicated by metabolic disorders), simple fatty liver group (fatty liver disease other than MAFLD group), metabolic disorder group (metabolic disorder without fatty liver disease), and normal group (all other participants). Results The DM onset rates in the normal, simple fatty liver, metabolic disorder, and MAFLD groups were 0.51, 1.85, 2.52, and 7.36%, respectively. In the multivariate analysis, the MAFLD group showed a significantly higher risk of DM onset compared with other three groups (P < 0.01). Additionally, the risk of DM onset was significantly increased in fatty liver disease with overweight/obesity or pre‐diabetes (P < 0.01). Conclusions Fatty liver with metabolic disorders, such as MAFLD, can be used to identify patients with fatty liver disease who are at high risk of developing DM. Additionally, patients with fatty liver disease complicated with overweight/obesity or prediabetes are at an increased risk of DM onset and should receive more attention.
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Affiliation(s)
- Teruki Miyake
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Bunzo Matsuura
- Department of Lifestyle-Related Medicine and Endocrinology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Shinya Furukawa
- Health Services Center, Ehime University, Bunkyo, Matsuyama, Ehime, Japan
| | - Toru Ishihara
- Ehime General Health Care Association, Misake, Matsuyama, Ehime, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Masumi Miyazaki
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Kyoko Watanebe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Akihito Shiomi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Hironobu Nakaguchi
- Department of Lifestyle-Related Medicine and Endocrinology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Yasunori Yamamoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Eiji Takeshita
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Teru Kumagi
- Postgraduate Medical Education Center, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Yoshio Ikeda
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
| | - Takeshi Iwata
- Ehime General Health Care Association, Misake, Matsuyama, Ehime, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan
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15
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Mahmoudi A, Butler AE, Jamialahmadi T, Sahebkar A. The role of exosomal miRNA in nonalcoholic fatty liver disease. J Cell Physiol 2022; 237:2078-2094. [PMID: 35137416 DOI: 10.1002/jcp.30699] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 01/21/2022] [Accepted: 01/25/2022] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) impacts more than one-third of the population and is linked with other metabolic diseases. The term encompasses a wide spectrum of diseases, from modest steatosis to nonalcoholic steatohepatitis, fibrosis and, ultimately, cirrhosis with the potential for development of hepatocellular carcinoma. Currently, available methods for diagnosing NAFLD are invasive or lack accuracy, and monitoring to determine response to therapeutic interventions is challenging. Exosomes are nano-scaled extracellular vesicles that are secreted by a variety of cells. They convey proteins, mRNA, miRNA, and other bioactive molecules between cells and are involved in an extensive range of biological processes, particularly cell-cell communication. Several reports suggest that exosomes mediate miRNAs and, thus, they have potential clinical utility for diagnosis, prognosis, and therapeutics in liver diseases. In view of the vital role of exosomal microRNA in disease, we here synthesized current knowledge about the biogenesis of exosomal miRNA and exosome-mediated microRNA transfer. We then discuss the potential of exosomal miRNA in diagnosis and therapeutics of NAFLD.
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Affiliation(s)
- Ali Mahmoudi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Tannaz Jamialahmadi
- Surgical Oncology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Medicine, The University of Western Australia, Perth, Australia.,Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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16
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Kim H, Zhang D, Song Z, Tong X, Zhang K. Analysis of Insulin Resistance in Nonalcoholic Steatohepatitis. Methods Mol Biol 2022; 2455:233-241. [PMID: 35212998 PMCID: PMC9053411 DOI: 10.1007/978-1-0716-2128-8_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Insulin resistance is a major phenotype observed in nonalcoholic steatohepatitis (NASH), the advanced stage of nonalcoholic fatty liver disease (NAFLD). Insulin resistance in NASH is characterized by reductions in whole body, hepatic, and adipose tissue insulin sensitivity. The mechanisms underlying hepatic insulin resistance is primarily associated with hepatic glucose production (HGP) rate. Hepatic insulin resistance can also be a consequence or a driving factor of hepatic lipid accumulation by increasing free fatty acid synthesis, delivery, and catabolism. The common method to assess hepatic insulin resistance is to measure hepatic glucose production (HGP) using isotope tracer distribution technique. However, non-radioactive approaches have been developed to assess hepatic insulin resistance in the context of NASH. In this chapter, we describe the methods to evaluate hepatic insulin resistance in animal models of NASH by examining insulin sensitivity and glucose tolerance as well as the key molecules in hepatic insulin signaling pathways.
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Affiliation(s)
- Hyunbae Kim
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
| | - Deqiang Zhang
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Zhenfeng Song
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
| | - Xin Tong
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Kezhong Zhang
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA.
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI, USA.
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17
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The promising role of CCL2 as a noninvasive marker for nonalcoholic steatohepatitis diagnosis in Egyptian populations. Eur J Gastroenterol Hepatol 2021; 33:e954-e960. [PMID: 34907983 DOI: 10.1097/meg.0000000000002324] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a common liver problem, including both nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). In this study, we investigated the role of CCL2 and IL6 as a noninvasive tool for the diagnosis of NASH in clinical practice and to establish criteria for discrimination NASH from NAFL in Egyptian populations with NAFLD. METHOD In addition to 30 healthy controls, serum samples from 66 NAFLD patients histologically diagnosed by biopsy (32 NAFL and 34 NASH) were analyzed for serum IL6, CCL2, liver biomarkers, complete blood count and lipid profile. Serum IL6 or CCL2 levels were tested for correlation with the NASH activity score (NAS score). RESULT Both IL6 and CCL2 were significantly upregulated in NASH patients compared with NAFL patients or control. Serum CCL2 was significantly correlated with the degree of hepatocytes ballooning (the diagnostic endpoint for NASH) without any significant correlation with steatosis or lobular inflammation. Serum IL6 was not correlated with the NAS score. The ROC curve analysis of CCL2 for NASH diagnosis revealed an area under curve (AUROC) of 0.959 at cutoff ≥227 pg/ml. While IL6 revealed an (AUROC) of 0.790. CONCLUSION Serum CCL2 but not IL6 is a promising noninvasive tool for NASH diagnosis and CCL2 can provide a reliable, validated scoring system to discriminate NAFL from NASH in the Egyptian population confirming the role of CCL2 in NASH pathogenesis. These findings will aid in the development of innovative NASH treatment strategies in Egypt and improve the quality of clinical care.
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18
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Predictive value of cytokeratin-18 fragment levels for diagnosing steatohepatitis in patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2021; 33:1451-1458. [PMID: 34334708 DOI: 10.1097/meg.0000000000002176] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Several noninvasive markers have been developed to predict nonalcoholic steatohepatitis (NASH). We investigated the predictive value of the cytokeratin-18 fragment (CK18-F) level and FIB-4 index for diagnosing NASH in patients with nonalcoholic fatty liver disease (NAFLD). METHODS A total of 246 patients histologically diagnosed with NASH (n = 185) or nonalcoholic fatty liver (n = 61) were enrolled. We analyzed weighted receiver operating characteristic (ROC) curves for the prediction of NASH and determined the relationship between the CK18-F level and the histological features of NASH. In addition, we investigated the predictive value of the combination of the CK18-F level and FIB-4 index for diagnosing NASH. RESULTS The area under the ROC curve (AUROC) value of the CK18-F level was 0.77. With a CK18-F cutoff level of 260 U/L, the sensitivity and specificity for diagnosing NASH were 82.7 and 57.4%, respectively. Multiple comparisons showed that the CK18-F level did not differ among fibrosis stages but did significantly differ among hepatocyte ballooning grades. Overall, 95.7% (66/69) of patients with a FIB-4 index of ≥2.67 had NASH. In patients with a FIB-4 index of <2.67, the AUROC value of the CK18-F level for predicting NASH was 0.77 and a CK18-F cutoff level of 260 U/L resulted in a sensitivity and specificity of 82.4 and 56.9%. CONCLUSIONS The CK18-F level had a good predictive ability for diagnosing NASH in patients with NAFLD. Additionally, the combination of the CK18-F level and FIB-4 index accurately and noninvasively predicted NASH, even those with a low FIB-4 index.
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19
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Pang S, Dong W, Liu N, Gao S, Li J, Zhang X, Lu D, Zhang L. Diallyl sulfide protects against dilated cardiomyopathy via inhibition of oxidative stress and apoptosis in mice. Mol Med Rep 2021; 24:852. [PMID: 34651661 PMCID: PMC8532119 DOI: 10.3892/mmr.2021.12492] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/26/2021] [Indexed: 11/21/2022] Open
Abstract
Cytochrome P450 family 2 subfamily E member 1 (CYP2E1) is a member of the cytochrome P450 enzyme family and catalyzes the metabolism of various substrates. CYP2E1 is upregulated in multiple heart diseases and causes damage mainly via the production of reactive oxygen species (ROS). In mice, increased CYP2E1 expression induces cardiac myocyte apoptosis, and knockdown of endogenous CYP2E1 can attenuate the pathological development of dilated cardiomyopathy (DCM). Nevertheless, targeted inhibition of CYP2E1 via the administration of drugs for the treatment of DCM remains elusive. Therefore, the present study aimed to investigate whether diallyl sulfide (DAS), a competitive inhibitor of CYP2E1, can be used to inhibit the development of the pathological process of DCM and identify its possible mechanism. Here, cTnTR141W transgenic mice, which developed typical DCM phenotypes, were used. Following treatment with DAS for 6 weeks, echocardiography, histological analysis and molecular marker detection were conducted to investigate the DAS-induced improvement on myocardial function and morphology. Biochemical analysis, western blotting and TUNEL assays were used to detected ROS production and myocyte apoptosis. It was found that DAS improved the typical DCM phenotypes, including chamber dilation, wall thinning, fibrosis, poor myofibril organization and decreased ventricular blood ejection, as determined using echocardiographic and histopathological analyses. Furthermore, the regulatory mechanisms, including inhibition both of the oxidative stress levels and the mitochondria-dependent apoptosis pathways, were involved in the effects of DAS. In particular, DAS showed advantages in terms of improved chamber dilation and dysfunction in model mice, and the improvement occurred in the early stage of the treatment compared with enalaprilat, an angiotensin-converting enzyme inhibitor that has been widely used in the clinical treatment of DCM and HF. The current results demonstrated that DAS could protect against DCM via inhibition of oxidative stress and apoptosis. These findings also suggest that inhibition of CYP2E1 may be a valuable therapeutic strategy to control the development of heart diseases, especially those associated with CYP2E1 upregulation. Moreover, the development of DAS analogues with lower cytotoxicity and metabolic rate for CYP2E1 may be beneficial.
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Affiliation(s)
- Shuo Pang
- Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, P.R. China
| | - Wei Dong
- Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, P.R. China
| | - Ning Liu
- Beijing Engineering Research Center for Experimental Animal Models of Human Diseases, Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, P.R. China
| | - Shan Gao
- Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, P.R. China
| | - Jing Li
- Beijing Engineering Research Center for Experimental Animal Models of Human Diseases, Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, P.R. China
| | - Xu Zhang
- Beijing Engineering Research Center for Experimental Animal Models of Human Diseases, Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, P.R. China
| | - Dan Lu
- Beijing Engineering Research Center for Experimental Animal Models of Human Diseases, Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, P.R. China
| | - Lianfeng Zhang
- Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, P.R. China
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20
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Miyake T, Matsuura B, Furukawa S, Yoshida O, Hirooka M, Kumagi T, Ishihara T, Kanzaki S, Nakaguchi H, Miyazaki M, Nakamura Y, Yamamoto Y, Koizumi Y, Tokumoto Y, Takeshita E, Ikeda Y, Abe M, Kitai K, Hiasa Y. Nonalcoholic fatty liver disease is a risk factor for glucose intolerance onset in men regardless of alanine aminotransferase status. J Diabetes Investig 2021; 12:1890-1898. [PMID: 33742744 PMCID: PMC8504916 DOI: 10.1111/jdi.13548] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 02/21/2021] [Accepted: 03/17/2021] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Fatty liver disease (FLD) is a surrogate condition for glucose intolerance development. FLD may involve normal or abnormal liver enzyme levels. Whether FLD is a risk factor for glucose intolerance, regardless of liver enzyme levels, remains unknown. We assessed relationships between the development of impaired fasting glucose (IFG) and FLD, liver enzyme abnormalities, and alcohol consumption. MATERIALS AND METHODS We retrospectively evaluated 8,664 participants with more than two annual health check-ups. Participants were classified according to sex, alcohol consumption, alanine aminotransferase (ALT) levels, and fatty liver status. RESULTS In univariate analyses, IFG onset among men was related to normal or high ALT levels with FLD in the nonalcoholic and alcoholic groups (P-trend < 0.01). In multivariate analyses, IFG onset among nonalcoholic men was associated with normal or high ALT levels with FLD, independent of potential confounding factors (P-trend < 0.01). However, IFG onset was non-independently associated with any condition among alcoholic men. In univariate analyses, IFG onset among women was related to normal or high ALT levels with FLD in the nonalcoholic group (P-trend < 0.01) and high ALT levels with FLD in the alcoholic group (P-trend < 0.05). In multivariate analyses, IFG onset was independently associated with only normal ALT levels in nonalcoholic FLD women. CONCLUSIONS Among nonalcoholic men and women, FLD was a risk factor for IFG onset, including normal ALT concentrations. Care is needed for individuals with nonalcoholic FLD, regardless of liver injury, possibly helping reduce glucose intolerance risk.
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Affiliation(s)
- Teruki Miyake
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Bunzo Matsuura
- Department of Lifestyle‐Related Medicine and EndocrinologyEhime University Graduate School of MedicineToonEhimeJapan
| | | | - Osamu Yoshida
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Masashi Hirooka
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Teru Kumagi
- Postgraduate Medical Education CenterEhime University Graduate School of MedicineToonEhimeJapan
| | - Toru Ishihara
- Ehime General Health Care AssociationMatsuyamaEhimeJapan
| | - Sayaka Kanzaki
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Hironobu Nakaguchi
- Department of Lifestyle‐Related Medicine and EndocrinologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Masumi Miyazaki
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Yoshiko Nakamura
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Yasunori Yamamoto
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Yohei Koizumi
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Yoshio Tokumoto
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Eiji Takeshita
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Yoshio Ikeda
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Masanori Abe
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | | | - Yoichi Hiasa
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
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Yefimenko T, Mykytyuk M. Non-alcoholic fatty liver disease: time for changes. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (UKRAINE) 2021; 17:334-345. [DOI: 10.22141/2224-0721.17.4.2021.237350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The review contains updated information on the epidemiology, etiology, pathogenesis, diagnosis, treatment and prevention of non-alcoholic fatty liver disease (NAFLD). We searched for terms including NAFLD, non-alcoholic steatohepatitis (NASH), metabolic syndrome and type 2 diabetes mellitus in literature published over the past 5 years using the Scopus, Web of Science, CyberLeninka, PubMed databases. The concept of NAFLD includes two morphological forms of the disease with different prognosis: non-alcoholic fatty hepatosis and NASH. The severity of NASH is quite variable, including fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD, a spectrum of fatty liver disorders of viral, autoimmune, drug-induced, and genetic origin, which are not caused by alcohol abuse, has recently been renamed as metabolic (dysfunction) associated fatty liver disease (MAFLD). The average prevalence of NAFLD is approximately 25% among the adult population worldwide, and in some regions exceeds 30%. An increase in the prevalence of this pathology is in parallel with the global epidemic of obesity and type 2 diabetes mellitus in the world. It is time to reach a general consensus in the scientific community on changing the nomenclature and moving from a negative to a positive definition of NAFLD/NASH. The new nomenclature points to the “positive” determinants of the disease, namely the close relationship with metabolic disorders, instead of defining it as what it is not (ie. non-alcoholic). The MAFLD abbreviation more accurately discloses existing knowledge about fatty liver diseases associated with metabolic dysfunction and should replace NAFLD/NASH, as this will stimulate the research community’s efforts to update the disease nomenclature and subphenotype and accelerate the transition to new treatments. It is important that primary care physicians, endocrinologists, and other specialists are aware of the extent and long-term consequences of NAFLD. Early identification of patients with NASH can help improve treatment outcomes, avoid liver transplantation in patients with decompensated cirrhosis. There are currently no effective treatments for NAFLD, so it is important to follow a multidisciplinary approach, which means using measures to improve prognosis, reduce the risk of death associated with NAFLD, the development of cirrhosis or hepatocellular carcinoma. Epidemiological data suggest a close relationship between unhealthy lifestyles and NAFLD, so lifestyle adjustments are needed to all patients. Insulin sensitizers, statins, ezetimibe, a cholesterol absorption inhibitor, hepatoprotectors, antioxidants, incretin analogues, dipeptidyl peptidase 4 inhibitors, pentoxifylline, probiotics, angiotensin-converting enzyme inhibitors, and endocannabinoid antagonists are used in the treatment of NAFLD.
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Huang H, Wang J, Xu L, Miao M, Xu C. Association between High-Density Lipoprotein Cholesterol to Apolipoprotein A-I Ratio and Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study. Int J Endocrinol 2021; 2021:6676526. [PMID: 34194492 PMCID: PMC8203372 DOI: 10.1155/2021/6676526] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/22/2021] [Accepted: 05/29/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND This study aimed to explore the association between high-density lipoprotein cholesterol to apolipoprotein A-I ratio (HDL-C/apo A-I) and nonalcoholic fatty liver disease (NAFLD). METHODS A total of 9025 Chinese adults were enrolled in this cross-sectional study, who presented their annual health checkups at Zhenhai Lianhua Hospital, Ningbo, during 2017. RESULTS The NAFLD prevalence was 33.7%, and HDL-C/apo A-I was significantly decreased in NAFLD patients, as well as in lean NAFLD and in patients with NAFLD-related advanced fibrosis (all P < 0.001). The prevalence of NAFLD and components of metabolic syndrome are inversely associated with HDL-C/apo A-I (P < 0.001). Multivariate logistic regression analysis show that HDL-C/apo A-I is inversely associated with the risk of NAFLD (odds ratio: 0.353, 95% confidence interval: 0.257-0.486; P < 0.001). CONCLUSIONS Our results suggested that increased HDL-C/apo A-I is significantly associated with a decreased risk of NAFLD.
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Affiliation(s)
- Hangkai Huang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jinghua Wang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lei Xu
- Department of Gastroenterology, Zhejiang University Ningbo Hospital, Ningbo 315010, China
| | - Min Miao
- Department of Internal Medicine, Zhenhai Lianhua Hospital, Ningbo 315207, China
| | - Chengfu Xu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
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Bc B, Jaiswal RK, Gupta PK, Paudel R, Subedi RK. Carotid Intima-media Thickness in Patients with Non-alcoholic Fatty Liver Disease Attending a Tertiary Care Center: A Descriptive Cross-sectional Study. JNMA J Nepal Med Assoc 2021; 59:454-459. [PMID: 34508436 DOI: 10.31729/jnma.5719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Indexed: 11/01/2022] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease is fatty infiltration of the liver in the absence of other causes of steatosis. It is strongly associated with central adiposity, high body mass index, insulin resistance states, hypertension, hyperlipidemia which are features of metabolic syndrome. The objective of study is to find out the carotid intima-media thickness of non alcoholic fatty liver disease patients attending a tertiary care center. METHODS This was a descriptive cross sectional study conducted at National Academy of Medical Sciences, Bir Hospital from July 2018 to June 2019 among 70 diagnosed cases of non alcoholic fatty liver disease based on ultrasound findings. Data collection was started after receiving ethical approval from Institutional Review Board of the Institute. Convenience sampling method was used. Data were entered using Microsoft Excel. The carotid intima-media thickness of both sides were measured by ultrasound. Statistical Package for Social Sciences version 20 was used for analysis. RESULTS Out of 70 cases, the mean carotid intima-media thickness was 0.7140±0.1796mm on right and 0.7161±0.1828mm on left side. Among 70 cases 45 (64.3%) were Grade II non alcoholic fatty liver disease and 25 (35.7%) were Grade I. It was 0.5720±0.1275mm and 0.7929±0.1546mm in Grade I and II non alcoholic fatty liver disease cases respectively on right side whereas it was 0.5676±0.1259mm and 0.7987±0.1557mm respectively on left side. CONCLUSIONS This study showed increased carotid intima-media thickness in non alcoholic fatty liver disease cases.
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Affiliation(s)
- Bom Bc
- Department of Radiology, Rapti Academy of Health Sciences, Dang, Nepal
| | | | | | - Rajan Paudel
- Central Department of Public Health, Institute of Medicine, Tribhuwan University, Kathmandu, Nepal
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Zhang Z, Chen X, Cui B. Modulation of the fecal microbiome and metabolome by resistant dextrin ameliorates hepatic steatosis and mitochondrial abnormalities in mice. Food Funct 2021; 12:4504-4518. [PMID: 33885128 DOI: 10.1039/d1fo00249j] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Targeting the gut-liver axis by manipulating the intestinal microbiome is a promising therapy for nonalcoholic fatty liver disease (NAFLD). This study modulated the intestinal microbiota to explore whether resistant dextrin, as a potential prebiotic, could ameliorate high-fat diet (HFD)-induced hepatic steatosis in C57BL/6J mice. After two months of feeding, significant hepatic steatosis with mitochondrial dysfunction was observed in the HFD-fed mice. However, the concentrations of triglycerides and malondialdehyde in liver tissue and the levels of alanine aminotransferase and aspartate aminotransferase in the serum of mice fed an HFD plus resistant dextrin diet (HFID) were significantly decreased compared to the HFD-fed mice. Additionally, hepatic mitochondrial integrity and reactive oxygen species accumulation were improved in HFID-fed mice, ameliorating hepatic steatosis. The fecal microbiome of HFD-fed mice was enriched in Bifidobacterium, Lactobacillus, and Globicatella, while resistant dextrin increased the abundance of Parabacteroides, Blautia, and Dubosiella. Major changes in fecal metabolites were confirmed for HFID-fed mice, including those related to entero-hepatic circulation (i.e., bile acids), tryptophan metabolism (e.g., indole derivatives), and lipid metabolism (e.g., lipoic acid), as well as increased antioxidants including isorhapontigenin. Furthermore, resistant dextrin decreased inflammatory cytokine levels and intestinal permeability and ameliorated intestinal damage. Together, these findings augmented current knowledge on prebiotic treatment for NAFLD.
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Affiliation(s)
- Zheng Zhang
- State Key Laboratory of Biobased Material and Green Papermaking, School of Food Science and Engineering, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250353, China.
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25
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Fatouh AM, Elshafeey AH, Abdelbary A. Liver targeting of ledipasvir via galactosylated chitosan-coated spanlastics: chemical synthesis, statistical optimization, in vitro, and pharmacokinetic evaluation. Drug Deliv Transl Res 2021; 12:1161-1174. [PMID: 33948896 DOI: 10.1007/s13346-021-00993-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2021] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Ledipasvir is an effective direct acting antiviral agent used in the treatment of hepatitis C virus. The high price of ledipasvir was a reason for its limited provision to wide population of HCV patients. OBJECTIVES Our objective is the formulation of liver targeted drug delivery system that can increase the amount of ledipasvir delivered to liver and prolong its liver residence in an attempt to reduce its recommended dose and its costing in the treatment of HCV. METHODS Different ledipasvir-loaded spanlastic formulations were prepared using the ethanol injection method and evaluated with respect to the particle size, zeta potential, polydispersity index, and entrapment efficiency %. Using Design-Expert ® software, the optimum spanlastics formulation was selected; then, it was coated by synthesized galactosylated chitosan. A pharmacokinetic study was carried out to evaluate the ability of the prepared galactosylated chitosan-coated spanlastics formulation to enhance ledipasvir liver bioavailability when it was administrated via the oral route. RESULTS The pharmacokinetic study revealed that the optimized galactosylated chitosan-coated spanlastics exhibited significantly higher liver peak concentration (Cmax) and area under liver concentration versus time curve (AUC0-72 h) and significant prolongation in the liver terminal half life (t½) and mean residence time (MRT) compared to the free ledipasvir dispersion with values of 6270 ng/g, 61,706.3 ng.h/g, 15.85 h, and 24.66 h, respectively. CONCLUSIONS Enhanced liver bioavailability of ledipasvir has been accomplished using the developed galactosylated chitosan-coated spanlastics which can be a base for probable reduction in the required dose of ledipasvir in HCV treatment.
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Affiliation(s)
- Ahmed M Fatouh
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini St, Cairo, 11562, Egypt.
| | - Ahmed H Elshafeey
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini St, Cairo, 11562, Egypt
| | - Ahmed Abdelbary
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini St, Cairo, 11562, Egypt
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26
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BC B, Jaiswal RK, Gupta PK, Paudel R, Subedi RK. Carotid Intima-media Thickness in Patients with Non-alcoholic Fatty Liver Disease Attending a Tertiary Care Center: A Descriptive Cross-sectional Study. JNMA J Nepal Med Assoc 2021; 59. [PMID: 34508436 PMCID: PMC8673453 DOI: 10.31729/jnma.5179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease is fatty infiltration of the liver in the absence of other causes of steatosis. It is strongly associated with central adiposity, high body mass index, insulin resistance states, hypertension, hyperlipidemia which are features of metabolic syndrome. The objective of study is to find out the carotid intima-media thickness of non alcoholic fatty liver disease patients attending a tertiary care center. METHODS This was a descriptive cross sectional study conducted at National Academy of Medical Sciences, Bir Hospital from July 2018 to June 2019 among 70 diagnosed cases of non alcoholic fatty liver disease based on ultrasound findings. Data collection was started after receiving ethical approval from Institutional Review Board of the Institute. Convenience sampling method was used. Data were entered using Microsoft Excel. The carotid intima-media thickness of both sides were measured by ultrasound. Statistical Package for Social Sciences version 20 was used for analysis. RESULTS Out of 70 cases, the mean carotid intima-media thickness was 0.7140±0.1796mm on right and 0.7161±0.1828mm on left side. Among 70 cases 45 (64.3%) were Grade II non alcoholic fatty liver disease and 25 (35.7%) were Grade I. It was 0.5720±0.1275mm and 0.7929±0.1546mm in Grade I and II non alcoholic fatty liver disease cases respectively on right side whereas it was 0.5676±0.1259mm and 0.7987±0.1557mm respectively on left side. CONCLUSIONS This study showed increased carotid intima-media thickness in non alcoholic fatty liver disease cases.
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Affiliation(s)
- Bom BC
- Department of Radiology, Rapti Academy of Health Sciences, Dang, Nepal
| | | | | | - Rajan Paudel
- Central Department of Public Health, Institute of Medicine, Tribhuwan University, Kathmandu, Nepal
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Ramadan MS, Russo V, Nigro G, Durante-Mangoni E, Zampino R. Interplay between Heart Disease and Metabolic Steatosis: A Contemporary Perspective. J Clin Med 2021; 10:jcm10081569. [PMID: 33917867 PMCID: PMC8068259 DOI: 10.3390/jcm10081569] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 03/26/2021] [Accepted: 04/03/2021] [Indexed: 12/12/2022] Open
Abstract
The liver-heart axis is a growing field of interest owing to rising evidence of complex bidirectional interplay between the two organs. Recent data suggest non-alcoholic fatty liver disease (NAFLD) has a significant, independent association with a wide spectrum of structural and functional cardiac diseases, and seems to worsen cardiovascular disease (CVD) prognosis. Conversely, the effect of cardiac disease on NAFLD is not well studied and data are mostly limited to cardiogenic liver disease. We believe it is important to further investigate the heart-liver relationship because of the tremendous global health and economic burden the two diseases pose, and the impact of such investigations on clinical decision making and management guidelines for both diseases. In this review, we summarize the current knowledge on NAFLD diagnosis, its systemic manifestations, and associations with CVD. More specifically, we review the pathophysiological mechanisms that govern the interplay between NAFLD and CVD and evaluate the relationship between different CVD treatments and NAFLD progression.
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Affiliation(s)
- Mohammad Said Ramadan
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Vincenzo Russo
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Gerardo Nigro
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Emanuele Durante-Mangoni
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
- Correspondence:
| | - Rosa Zampino
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
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Fatouh AM, Elshafeey AH, Abdelbary A. Galactosylated Chitosan Coated Liposomes of Ledipasvir for Liver Targeting: Chemical Synthesis, Statistical Optimization, In-vitro and In-vivo evaluation. J Pharm Sci 2020; 110:1148-1159. [PMID: 33039437 DOI: 10.1016/j.xphs.2020.10.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/29/2020] [Accepted: 10/02/2020] [Indexed: 01/27/2023]
Abstract
Ledipasvir is a novel antiviral agent used in the treatment of hepatitis C. We aim in our study to increase its delivery to hepatocytes and prolong its retention within liver. Several formulae of ledipasvir loaded liposomes were prepared and the best formula regarding particle size, zeta potential, polydispersity index and entrapment efficiency was selected. On the other hand, galactosylated chitosan was synthesized in a chemical reaction. Then the best liposomes formula was coated with the galactosylated chitosan. Having galactose residues on their surface, the coated liposomes can bind to the asialoglycoprotein receptors on the targeted hepatocytes enhancing ledipasvir uptake into them. The galactosylated chitosan coated liposomes had particle size of 218.2 nm ± 7.21, zeta potential of 27.15 mV ± 1.76, polydispersity index of 0.278 ± 0.055 and entrapment efficiency % of 54.63% ± 0.05 respectively. The pharmacokinetic study revealed a significant increase in the liver peak concentration (Cmax) and the area under liver concentration versus time curve AUC(0-72 h) and significant prolongation in the liver terminal half life (t½) and mean residence time (MRT) in comparison to the oral dispersion of ledipasvir with values of 11,400 ng/g, 88,855 ng∗h/g, 32.00 h and 18.11 h respectively.
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Affiliation(s)
- Ahmed M Fatouh
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Ahmed H Elshafeey
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Ahmed Abdelbary
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Hosain MZ, Hyodo F, Mori T, Takahashi K, Nagao Y, Eto H, Murata M, Akahoshi T, Matsuo M, Katayama Y. Development of a novel molecular probe for the detection of liver mitochondrial redox metabolism. Sci Rep 2020; 10:16489. [PMID: 33020535 PMCID: PMC7536409 DOI: 10.1038/s41598-020-73336-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 09/15/2020] [Indexed: 11/10/2022] Open
Abstract
Redox status influences the course of the inflammatory, metabolic, and proliferative liver diseases. Oxidative stress is thought to play a crucial and sustained role in the pathological progression of early steatosis to severe hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Oxidative stress induced by reactive oxygen species which are generated in the mitochondria can lead to chronic organelle damage in hepatocytes. Currently, the diagnosis of liver disease requires liver biopsy, which is invasive and associated with complications. The present report describes the development of a novel molecular probe, EDA-PROXYL, with higher reactivity and mitochondrial selectivity than standard carboxyl-PROXYL and carbamoyl-PROXYL probes. The membrane permeability of our probe improved in aqueous environments which led to increased accumulation in the liver and interaction of EDA-PROXYL with the carnitine transporter via the amine (NH3+) group further increased accumulation. This increased mitochondrial sensitivity and enhanced accumulation highlight the potential of EDA-PROXYL as a molecular probe for determining metabolic reactions of the mitochondria. Thus, this novel probe could be a tool for the evaluation of redox status of the mitochondria to assess the degree of liver injury and, ultimately, the response to pharmacological therapy.
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Affiliation(s)
- Md Zahangir Hosain
- Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Fuminori Hyodo
- Department of Radiology, School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan.
- Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
- Department of Frontier Science for Imaging, School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan.
| | - Takeshi Mori
- Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
- Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
- Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
| | - Koyo Takahashi
- Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Yusuke Nagao
- Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Hinako Eto
- Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Center for Advanced Medical Innovation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masaharu Murata
- Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Center for Advanced Medical Innovation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Tomohiko Akahoshi
- Center for Advanced Medical Innovation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masayuki Matsuo
- Department of Radiology, School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Yoshiki Katayama
- Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
- Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
- Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
- International Research Center for Molecular Systems, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
- Center for Advanced Medical Innovation, Kyushu University, 744 Motooka, Nishi-Ku, Fukuoka, 819-0395, Japan
- Department of Biomedical Engineering, Chung Yuan Christian University, 200 Chung Pei Rd., Chung Li, 32023, Taiwan, ROC
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Oancea CN, Butaru AE, Streba CT, Pirici D, Rogoveanu I, Diculescu MM, Gheonea DI. Global hepatitis C elimination: history, evolution, revolutionary changes and barriers to overcome. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2020; 61:643-653. [PMID: 33817705 PMCID: PMC8112794 DOI: 10.47162/rjme.61.3.02] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/25/2021] [Indexed: 02/05/2023]
Abstract
The fundamental discovery of the hepatitis C virus (HCV) in 1989 has led to winning this year's Nobel Prize in Medicine. This achievement guided all the steps in identifying the elements of the virus, in order to develop the treatment and to increase the screening solutions, which have slowed the exposure to the virus. The management of infection started with interferon-alpha (IFN-α), which has later enhanced by adding Ribavirin. Nowadays, HCV treatment is based on direct-acting antiviral agents (DAAs). Currently, HCV infection benefits of curative treatment, with which most patients can be cured. When speaking about hepatitis C future, we can say it is looking bright, considering all the progress that has been made in recent years and all the options that we have for curing all genotypes of HCV infection. The aim of this review is to sum up the historical characteristics of HCV discovery, the evolution of treatment and screening actions, gaps, and stages for achieving the international elimination target of the World Health Organization.
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Affiliation(s)
- Carmen Nicoleta Oancea
- Department of Scientific Research Methodology and Department of Pulmonology, University of Medicine and Pharmacy of Craiova, Romania;
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Kim A, Yang HR, Cho JM, Chang JY, Moon JS, Ko JS. A Nomogram for Predicting Non-Alcoholic Fatty Liver Disease in Obese Children. Pediatr Gastroenterol Hepatol Nutr 2020; 23:276-285. [PMID: 32483549 PMCID: PMC7231740 DOI: 10.5223/pghn.2020.23.3.276] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 01/15/2020] [Accepted: 02/11/2020] [Indexed: 12/11/2022] Open
Abstract
PURPOSE Non-alcoholic fatty liver disease (NAFLD) ranges in severity from simple steatosis to steatohepatitis. Early detection of NAFLD is important for preventing the disease from progressing to become an irreversible end-stage liver disease. We developed a nomogram that allows for non-invasive screening for NAFLD in obese children. METHODS Anthropometric and laboratory data of 180 patients from our pediatric obesity clinic were collected. Diagnoses of NAFLD were based on abdominal ultrasonographic findings. The nomogram was constructed using predictors from a multivariate analysis of NAFLD risk factors. RESULTS The subjects were divided into non-NAFLD (n=67) and NAFLD groups (n=113). Factors, including sex, body mass index, abdominal circumference, blood pressure, insulin resistance, and levels of aspartate aminotransferase, alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γGT), uric acid, triglycerides, and insulin, were significantly different between the two groups (all p<0.05) as determined using homeostatis model assessment of insulin resistance (HOMA-IR). In our multivariate logistic regression analysis, elevated serum ALT, γGT, and triglyceride levels were significantly related to NAFLD development. The nomogram was established using γGT, uric acid, triglycerides, HOMA-IR, and ALT as predictors of NAFLD probability. CONCLUSION The newly developed nomogram may help predict NAFLD risk in obese children. The nomogram may also allow for early NAFLD diagnosis without the need for invasive liver biopsy or expensive liver imaging, and may also allow clinicians to intervene early to prevent the progression of NAFLD to become a more advanced liver disease.
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Affiliation(s)
- Ahlee Kim
- Department of Pediatrics, Bundang Jasaeng General Hospital, Seongnam, Korea
| | - Hye Ran Yang
- Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Min Cho
- Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ju Young Chang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
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da Silva LDCM, de Oliveira JT, Tochetto S, de Oliveira CPMS, Sigrist R, Chammas MC. Ultrasound elastography in patients with fatty liver disease. Radiol Bras 2020; 53:47-55. [PMID: 32313337 PMCID: PMC7159044 DOI: 10.1590/0100-3984.2019.0028] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatic steatosis, or fatty liver disease, occurs due to the accumulation of lipids in hepatocytes. When it becomes chronic, lobular inflammation develops and the disease can evolve to hepatic fibrosis, liver cirrhosis, or hepatocellular carcinoma. Early diagnosis is desirable because patients diagnosed in the early stage of the disease respond better to treatment. In the early stages of fatty liver disease, the physical examination is often unremarkable. Fatty liver disease and hepatic fibrosis can be diagnosed and monitored through laboratory tests, imaging, and biopsy. Among the imaging methods, ultrasound stands out as an effective means of diagnosing and following patients with liver disease. Ultrasound used in conjunction with elastography (ultrasound elastography) has recently shown great utility in the follow-up of such patients. Ultrasound elastography studies the degree of deformation (stiffness) of an organ or lesion, so that when there is hardening, fibrosis, or cirrhosis of the liver, those alterations are well demonstrated. In this review article, we discuss the application of the different types of ultrasound elastography for liver studies: transient elastography, point shear wave elastography, and two-dimensional shear wave elastography. Although magnetic resonance elastography may also be used in the analysis of liver fibrosis, it will not be addressed in this article.
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Affiliation(s)
| | | | - Sandra Tochetto
- Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil
| | | | - Rosa Sigrist
- Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil
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Lu Y, Wang Q, Yu L, Yin X, Yang H, Xu X, Xia Y, Luo Y, Peng Y, Yu Q, Chen Z, Yu J, Lai M, Wu N, Pan XB, Zheng X. Revision of serum ALT upper limits of normal facilitates assessment of mild liver injury in obese children with non-alcoholic fatty liver disease. J Clin Lab Anal 2020; 34:e23285. [PMID: 32267017 PMCID: PMC7370732 DOI: 10.1002/jcla.23285] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 02/14/2020] [Accepted: 02/21/2020] [Indexed: 01/04/2023] Open
Abstract
Background The serum alanine aminotransferase (ALT) level is a critical parameter for evaluating liver injury in non‐alcoholic fatty liver disease (NAFLD). However, the currently accepted upper limits of normal (ULN) for serum ALT (ULN‐ALT) are debated, as they may be excessively high. Methods A total of 1638 children aged 6‐16 years, comprising 507 children with normal BMI (500 healthy children and 7 children with NAFLD), 199 overweight children, and 932 obese children, were included in the analysis. We re‐evaluated the ULN‐ALT in 500 healthy Chinese children using the 95th percentiles of serum ALT levels as revised ULN‐ALT. Fatty liver was identified by ultrasound examination. Results Significant positive correlations between serum ALT levels and body mass index (BMI) were detected in overweight boys (r = .399, P < .001), obese boys (r = .398, P < .001), and obese girls (r = .392, P < .001). The prevalence percentages of NAFLD were 93.6%, 75.8%, and 37.9% in obese boys with serum ALT levels of >50, 25‐50, and ≤25 U/L and were 81.6%, 67.9%, and 20.6% in obese girls with serum ALT levels of >40, 20‐40, and ≤20 U/L, respectively. Conclusion Serum ALT levels significantly correlated with abnormal BMI values in children, suggesting a rigorous BMI threshold is needed to establish the cutoffs for serum ULN‐ALT in children. Besides, the revised serum ULN‐ALT can uncover mild liver injury in obese children with NAFLD.
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Affiliation(s)
- Yutian Lu
- Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou, Zhejiang, China
| | - Qiongdan Wang
- Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou, Zhejiang, China
| | - Lisha Yu
- Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou, Zhejiang, China
| | - XueRui Yin
- Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou, Zhejiang, China
| | - Huijie Yang
- Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou, Zhejiang, China
| | - Xi Xu
- Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou, Zhejiang, China
| | - Ying Xia
- Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou, Zhejiang, China
| | - Yue Luo
- Department of Pediatric Endocrinology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ying Peng
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou, Zhejiang, China
| | - Qigui Yu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Zhanguo Chen
- Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jian Yu
- Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Meimei Lai
- Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Nan Wu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Xiao-Ben Pan
- School of Medicine, Department of Basic Medical Science, Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Key Laboratory of Inflammation and Immunoregulation of Hangzhou, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xiaoqun Zheng
- Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou, Zhejiang, China
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Chen X, Zhang Z, Cui B, Jiang A, Tao H, Cheng S, Liu Y. Combination of Chronic Alcohol Consumption and High-Salt Intake Elicits Gut Microbial Alterations and Liver Steatosis in Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:1750-1759. [PMID: 31971384 DOI: 10.1021/acs.jafc.9b07368] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Alcohol is a globally well-established cause of fatty liver disease (FLD). Increased salt consumption is associated with an increased prevalence of adipocyte hypertrophy and liver injury. In this study, high dietary salt potentiated chronic alcohol-induced hepatic damage. We explored the physiological mechanism of alcoholic FLD in the gastrointestinal tract. Male C57BL/6J mice (8-week-old) were fed a high-salt diet (HSD; 4% NaCl) with or without chronic ethanol (CE) for 1 month. The fecal microbiota, serum biochemical indices, intestinal permeability, level of liver damage, and liver mitochondria were evaluated. The HSD, CE, and their combination (HSDE) significantly changed the gut microbiota's structure, and the HSDE mice contained more probiotic species (e.g., Bifidobacterium and Lactobacillus). The serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels were increased, and the lipid was accumulated in the liver tissues in the CE, HSD, and HSDE groups, which indicated liver damage, especially in the HSDE group. The increased intestinal permeability and mitochondrial dysfunction in the liver cells caused greater injury in the HSDE group than in the other groups. Thus, consuming HSD with alcohol contributes to FLD development and progression.
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Affiliation(s)
- Xiao Chen
- College of Food Science , South China Agricultural University , Guangzhou 510642 , China
| | - Zheng Zhang
- State Key Laboratory of Biobased Material and Green Papermaking , Qilu University of Technology, Shandong Academy of Sciences , Jinan 250000 , China
| | - Bo Cui
- State Key Laboratory of Biobased Material and Green Papermaking , Qilu University of Technology, Shandong Academy of Sciences , Jinan 250000 , China
| | - Aimin Jiang
- College of Food Science , South China Agricultural University , Guangzhou 510642 , China
| | - Haiteng Tao
- State Key Laboratory of Biobased Material and Green Papermaking , Qilu University of Technology, Shandong Academy of Sciences , Jinan 250000 , China
| | | | - Yong Liu
- Yucheng Maternal and Child Health Hospital , Dezhou 251200 , China
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Effect of high-intensity interval training and omega-3 supplementation on liver enzymes and lipid profile of young men. Sci Sports 2020. [DOI: 10.1016/j.scispo.2019.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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David-Silva A, Esteves JV, Morais MRPT, Freitas HS, Zorn TM, Correa-Giannella ML, Machado UF. Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice. Diabetes Metab Syndr Obes 2020; 13:739-751. [PMID: 32231437 PMCID: PMC7085338 DOI: 10.2147/dmso.s242282] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 02/29/2020] [Indexed: 12/11/2022] Open
Abstract
PURPOSE NAFLD is a hepatic component of type 2 diabetes mellitus (T2D), in which impaired hepatic glucose production plays an important role. Inhibitors of sodium glucose transporter 2 (SGLT2) reduce glycemia and exert beneficial effects on diabetic complications. Recently, dual SGLT1/2 inhibition has been proposed to be more effective in reducing glycemia. We hypothesized that improving hepatic glucose metabolism induced by SGLT1/2 inhibition could be accompanied by beneficial effects on NAFLD progression. METHODS Glycemic homeostasis, hepatic glucose production and NAFLD features were investigated in obese T2D mice, treated with SGLT1/2 inhibitor phlorizin for 1 week. RESULTS T2D increased glycemia; insulinemia; hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and glucose transporter 2 (Slc2a2 gene); hepatocyte nuclear factors 1A/4A/3B-binding activity in Slc2a2; endogenous glucose production; liver weight, plasma transaminase concentration as well as hepatic inflammation markers, and induced histological signals of non-alcoholic steatohepatitis (NASH, according to NASH-CRN Pathology Committee System). Phlorizin treatment restored all these parameters (mean NASH score reduced from 5.25 to 2.75 P<0.001); however, plasma transaminase concentration was partially reverted and some hepatic inflammation markers remained unaltered. CONCLUSION NAFLD accompanies altered hepatic glucose metabolism in T2D mice and that greatly ameliorated through short-term treatment with the dual SGLT1/2 inhibitor. This suggests that altered hepatic glucose metabolism participates in T2D-related NAFLD and highlights the pharmacological inhibition of SGLTs as a useful approach not only for controlling glycemia but also for mitigating development and/or progression of NAFLD.
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Affiliation(s)
- Aline David-Silva
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - João Victor Esteves
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Mychel Raony P T Morais
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Helayne Soares Freitas
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Telma Maria Zorn
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Maria Lucia Correa-Giannella
- Laboratório de Carboidratos e Radioimunoensaio, LIM-18, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Ubiratan Fabres Machado
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Correspondence: Ubiratan Fabres Machado Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, São Paulo, SP05508-900, BrazilTel +55 11 30917494 Email
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Sherif FM, Elmogy SA, EL-wahab RMA, Wahab MA. Utility of magnetic resonance proton density fat fraction technique in quantification of liver fat in living donors for liver transplantation. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2019. [DOI: 10.1186/s43055-019-0061-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hepatic steatosis in living donors for liver transplantation causes morbidity of both donor and recipient. This study aims at evaluating magnetic resonance proton density fat fraction technique (MR PDFF) in quantitative evaluation of living donor’s hepatic steatosis compared to histopathology.
Results
The examined potential living liver donors’ liver biopsies revealed hepatic steatosis < 5% (grade 0) in 40 donors and 5–10% (grade 1) in 7 donors. MR PDFF technique with IDEAL sequence showed excellent results for prediction and quantitative evaluation of liver fat with sensitivity, specificity, and accuracy of 85.7%, 97.5%, and 95.7%, respectively, compared to histopathology (95% confidence interval 0.98–1.01). There was an excellent inter-reader agreement between both readers in estimation of MR liver fat fraction (r = 0.969 at 95% confidence interval 0.946–0.983).
Conclusion
Noninvasive hepatic MR PDFF technique with IDEAL sequence is a precise reliable technique for pre-operative quantitative assessment of hepatic steatosis in potential living liver donors.
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Jensen VS, Tveden-Nyborg P, Zacho-Rasmussen C, Quaade ML, Ipsen DH, Hvid H, Fledelius C, Wulff EM, Lykkesfeldt J. Variation in diagnostic NAFLD/NASH read-outs in paired liver samples from rodent models. J Pharmacol Toxicol Methods 2019; 101:106651. [PMID: 31733366 DOI: 10.1016/j.vascn.2019.106651] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 08/26/2019] [Accepted: 11/05/2019] [Indexed: 02/06/2023]
Abstract
INTRODUCTION In animal models of non-alcoholic fatty liver disease (NAFLD), assessment of disease severity and treatment effects of drugs rely on histopathological scoring of liver biopsies. However, little is known about the sampling variation in liver samples from animal models of NAFLD, even though several histopathological hallmarks of the disease are known to be affected by sampling variation in patients. The aim of this study was to assess the sampling variation in multiple paired liver biopsies from three commonly used diet-induced rodent models of NAFLD. METHODS Eight male C57BL/6 mice, 8 male Sprague Dawley rats and 16 female Hartley guinea pigs were fed a NAFLD-inducing high-fat diet for 16 weeks (mice and rats), 20 or 24 weeks (guinea pigs). After the initial diet period, liver sections were sampled and subsequently assessed by histopathological scoring and biochemical analyses. RESULTS Fibrosis was heterogeneously distributed throughout the liver in mice, manifesting as both intra- and interlobular statistically significant differences. Hepatic triglyceride content showed interlobular differences in mice, and both intra- and interlobular differences in guinea pigs (24-week time point) all of which were statistically significant. Also, hepatic cholesterol content was subject to significant intra-lobular sampling variation in mice, and hepatic glycogen content differed significantly between lobes in mice and guinea pigs. DISCUSSION Dependent on animal model, both histopathological and biochemical end-points differed between sampling sites in the liver. Based on these findings, we recommend that sample site location is highly standardized and properly reported in order to minimize potential sampling variation and to optimize reproducibility and meaningful comparisons of preclinical studies of NAFLD.
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Affiliation(s)
- Victoria S Jensen
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, DK-1870 Frederiksberg, Denmark; Global Research, Novo Nordisk A/S, Novo Nordisk Park 1, DK-2760 Maaloev, Denmark.
| | - Pernille Tveden-Nyborg
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, DK-1870 Frederiksberg, Denmark.
| | - Christina Zacho-Rasmussen
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, DK-1870 Frederiksberg, Denmark.
| | - Michelle L Quaade
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, DK-1870 Frederiksberg, Denmark.
| | - David H Ipsen
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, DK-1870 Frederiksberg, Denmark.
| | - Henning Hvid
- Global Research, Novo Nordisk A/S, Novo Nordisk Park 1, DK-2760 Maaloev, Denmark.
| | - Christian Fledelius
- Global Research, Novo Nordisk A/S, Novo Nordisk Park 1, DK-2760 Maaloev, Denmark.
| | - Erik M Wulff
- Global Research, Novo Nordisk A/S, Novo Nordisk Park 1, DK-2760 Maaloev, Denmark.
| | - Jens Lykkesfeldt
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, DK-1870 Frederiksberg, Denmark.
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Yamada K, Mizukoshi E, Seike T, Horii R, Terashima T, Iida N, Kitahara M, Sunagozaka H, Arai K, Yamashita T, Honda M, Takamura T, Harada K, Kaneko S. Serum C16:1n7/C16:0 ratio as a diagnostic marker for non-alcoholic steatohepatitis. J Gastroenterol Hepatol 2019; 34:1829-1835. [PMID: 30864239 DOI: 10.1111/jgh.14654] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 02/28/2019] [Accepted: 03/04/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Accurate diagnosis of non-alcoholic steatohepatitis (NASH) from non-alcoholic fatty liver disease (NAFLD) is clinically important. Therefore, there is a need for easier ways of diagnosing NASH. In this study, we investigated the serum fatty acid composition and evaluated the possibility of using the serum fatty acid composition as a diagnostic marker of NASH. METHODS The subjects were 78 NAFLD patients (non-alcoholic fatty liver [NAFL]: 30, NASH: 48) and 24 healthy individuals. Fatty acids extracted from the liver tissue and serum were identified and quantified by gas chromatography. In addition, we evaluated the relationship between serum and liver tissue fatty acid composition, patient background, and liver histology. The diagnostic performance of NASH was evaluated by calculating the area under the receiver operating characteristic (AUROC). RESULTS The results of the fatty acid analysis showed the C16:1n7/C16:0 ratio to have the strongest correlation between serum and liver tissue (r = 0.865, P < 0.0001). The serum C16:1n7/C16:0 ratio in the NASH group was higher compared with that in the NAFL group (P = 0.0007). Evaluation of the association of the serum C16:1n7/C16:0 ratio with liver histology revealed significant correlation with lobular inflammation score, ballooning score, and fibrosis score. The AUROC for predicting NASH in all NAFLD patients was 0.7097. The AUROC was nearly equivalent even when the study subjects were restricted to patients with a fibrosis score ≤ 2 only (AUROC 0.6917). CONCLUSION Measuring the serum C16:1n7/C16:0 ratio may be an effective non-invasive method for diagnosing NASH, particularly in its early stages.
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Affiliation(s)
- Kazutoshi Yamada
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Takuya Seike
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Rika Horii
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Takeshi Terashima
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Noriho Iida
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Masaaki Kitahara
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Hajime Sunagozaka
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
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Di Mauro S, Scamporrino A, Petta S, Urbano F, Filippello A, Ragusa M, Di Martino MT, Scionti F, Grimaudo S, Pipitone RM, Privitera G, Di Pino A, Scicali R, Valenti L, Dongiovanni P, Fracanzani A, Rabuazzo AM, Craxì A, Purrello M, Purrello F, Piro S. Serum coding and non-coding RNAs as biomarkers of NAFLD and fibrosis severity. Liver Int 2019; 39:1742-1754. [PMID: 31169972 PMCID: PMC6771597 DOI: 10.1111/liv.14167] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 05/28/2019] [Accepted: 05/31/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS In patients with non-alcoholic fatty liver disease (NAFLD), liver biopsy is the gold standard to detect non-alcoholic steatohepatitis (NASH) and stage liver fibrosis. We aimed to identify differentially expressed mRNAs and non-coding RNAs in serum samples of biopsy-diagnosed mild and severe NAFLD patients with respect to controls and to each other. METHODS We first performed a whole transcriptome analysis through microarray (n = 12: four Control: CTRL; four mild NAFLD: NAS ≤ 4 F0; four severe NAFLD NAS ≥ 5 F3), followed by validation of selected transcripts through real-time PCRs in an independent internal cohort of 88 subjects (63 NAFLD, 25 CTRL) and in an external cohort of 50 NAFLD patients. A similar analysis was also performed on liver biopsies and HepG2 cells exposed to oleate:palmitate or only palmitate (cellular model of NAFL/NASH) at intracellular/extracellular levels. Transcript correlation with histological/clinical data was also analysed. RESULTS We identified several differentially expressed coding/non-coding RNAs in each group of the study cohort. We validated the up-regulation of UBE2V1, BNIP3L mRNAs, RP11-128N14.5 lncRNA, TGFB2/TGFB2-OT1 coding/lncRNA in patients with NAS ≥ 5 (vs NAS ≤ 4) and the up-regulation of HBA2 mRNA, TGFB2/TGFB2-OT1 coding/lncRNA in patients with Fibrosis stages = 3-4 (vs F = 0-2). In in vitro models: UBE2V1, RP11-128N14.5 and TGFB2/TGFB2-OT1 had an increasing expression trend ranging from CTRL to oleate:palmitate or only palmitate-treated cells both at intracellular and extracellular level, while BNIP3L was up-regulated only at extracellular level. UBE2V1, RP11-128N14.5, TGFB2/TGFB2-OT1 and HBA2 up-regulation was also observed at histological level. UBE2V1, RP11-128N14.5, BNIP3L and TGFB2/TGFB2-OT1 correlated with histological/biochemical data. Combinations of TGFB2/TGFB2-OT1 + Fibrosis Index based on the four factors (FIB-4) showed an Area Under the Curve (AUC) of 0.891 (P = 3.00E-06) or TGFB2/TGFB2-OT1 + Fibroscan (AUC = 0.892, P = 2.00E-06) improved the detection of F = 3-4 with respect to F = 0-2 fibrosis stages. CONCLUSIONS We identified specific serum coding/non-coding RNA profiles in severe and mild NAFLD patients that possibly mirror the molecular mechanisms underlying NAFLD progression towards NASH/fibrosis. TGFB2/TGFB2-OT1 detection improves FIB-4/Fibroscan diagnostic performance for advanced fibrosis discrimination.
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Affiliation(s)
- Stefania Di Mauro
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi‐Nesima HospitalUniversity of CataniaCataniaItaly
| | - Alessandra Scamporrino
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi‐Nesima HospitalUniversity of CataniaCataniaItaly
| | - Salvatore Petta
- Section of Gastroenterology, Di.Bi.M.I.SUniversity of PalermoPalermoItaly
| | - Francesca Urbano
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi‐Nesima HospitalUniversity of CataniaCataniaItaly
| | - Agnese Filippello
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi‐Nesima HospitalUniversity of CataniaCataniaItaly
| | - Marco Ragusa
- Department of BioMedical Sciences and BioTechnologySection of Biology and Genetics Giovanni Sichel, Unit of Molecular, Genome and Complex Systems BioMedicineCataniaItaly,Oasi Research Institute - IRCCSTroina94018Italy
| | - Maria T. Di Martino
- Department of Experimental and Clinical MedicineMagna Graecia UniversityCatanzaroItaly
| | - Francesca Scionti
- Department of Experimental and Clinical MedicineMagna Graecia UniversityCatanzaroItaly
| | - Stefania Grimaudo
- Section of Gastroenterology, Di.Bi.M.I.SUniversity of PalermoPalermoItaly
| | | | - Graziella Privitera
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi‐Nesima HospitalUniversity of CataniaCataniaItaly
| | - Antonino Di Pino
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi‐Nesima HospitalUniversity of CataniaCataniaItaly
| | - Roberto Scicali
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi‐Nesima HospitalUniversity of CataniaCataniaItaly
| | - Luca Valenti
- Translational MedicineUniversity of Milan, Fondazione IRCCS Ca' Granda Pad MarangoniMilanItaly
| | - Paola Dongiovanni
- Department of Pathophysiology and Transplantation, Section of Internal MedicineUniversity of Milan, Fondazione Ca' Granda IRCCS Ospedale Maggiore PoliclinicoMilanItaly
| | - Anna Fracanzani
- Department of Pathophysiology and Transplantation, Section of Internal MedicineUniversity of Milan, Fondazione Ca' Granda IRCCS Ospedale Maggiore PoliclinicoMilanItaly
| | - Agata M. Rabuazzo
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi‐Nesima HospitalUniversity of CataniaCataniaItaly
| | - Antonio Craxì
- Section of Gastroenterology, Di.Bi.M.I.SUniversity of PalermoPalermoItaly
| | - Michele Purrello
- Department of BioMedical Sciences and BioTechnologySection of Biology and Genetics Giovanni Sichel, Unit of Molecular, Genome and Complex Systems BioMedicineCataniaItaly
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi‐Nesima HospitalUniversity of CataniaCataniaItaly
| | - Salvatore Piro
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi‐Nesima HospitalUniversity of CataniaCataniaItaly
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Serum cytokeratin-18 and its relation to liver fibrosis and steatosis diagnosed by FibroScan and controlled attenuation parameter in nonalcoholic fatty liver disease and hepatitis C virus patients. Eur J Gastroenterol Hepatol 2019; 31:633-641. [PMID: 30839434 DOI: 10.1097/meg.0000000000001385] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common cause of chronic liver disease worldwide. Multiple diagnostic noninvasive methods for NAFLD were studied (both serological and imaging), either single or combined. Attention has been focused on cytokeratin-18 (CK18) as a novel serological marker for the diagnosis of steatosis/fibrosis in NAFLD and hepatitis C virus (HCV) patients. AIM The aim of this study was to evaluate serum CK18 in NAFLD and HCV fibrosis/steatosis and also to correlate its performance with the diagnostic accuracy of transient elastography (TE) and controlled attenuation parameter (CAP) in the diagnosis of fibrosis/steatosis in these patients. PATIENTS AND METHODS Three equal groups of participants were enrolled (n=135): group I included patients with chronic HCV, group II included NAFLD patients, and group III included control participants. For all groups, TE/CAP and labs including serum CK18 were performed. Liver biopsy was performed for the NAFLD group. RESULTS Serum CK18 was significantly higher in the NAFLD group (19.01±3.49 ng/ml) versus the HCV group (8.95±1.06 ng/ml) and the control group (4.83±1.6 ng/ml) (P<0.001). The CK18 levels in biopsy stages (steatosis, ballooning, inflammation, and fibrosis) and FibroScan/CAP degrees showed that CK18 increased significantly with steatosis and fibrosis stages (biopsy or FibroScan/CAP), but did not reach significance with ballooning or inflammation grades. CK18 was significantly different in nonalcoholic steatohepatitis versus non-nonalcoholic steatohepatitis patients (P=0.041). The best CK18 cutoff to detect steatosis (S≥2) in NAFLD and HCV was 11.65 and 6.84 ng/ml, respectively with an overall sensitivity and specificity over 97%. The CK18 cutoff for significant fibrosis (F≥2) by FibroScan in the NAFLD/HCV groups was 9.115 ng/ml, with 62.5%/69.2% sensitivity/specificity (P=0.031). However, inflammation had a cutoff with a marginal P value (P=0.080), and a reliable cutoff for ballooning was not attained (P=0.386). There was a positive correlation between CK18 and fibrosis (by FibroScan) in the NAFLD and HCV groups (P<0.05). The correlation between CK18 and steatosis in CAP and the nonalcoholic fatty liver disease activity score was very good (P<0.001). CONCLUSION Serum CK18 is related strongly to the development/progression of NAFLD and HCV-related fibrosis/steatosis. TE was correlated highly with liver biopsy results. The combination of CK18 with other noninvasive modalities increases the diagnostic yield of these tests.
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Lefere S, Van de Velde F, Hoorens A, Raevens S, Van Campenhout S, Vandierendonck A, Neyt S, Vandeghinste B, Vanhove C, Debbaut C, Verhelst X, Van Dorpe J, Van Steenkiste C, Casteleyn C, Lapauw B, Van Vlierberghe H, Geerts A, Devisscher L. Angiopoietin-2 Promotes Pathological Angiogenesis and Is a Therapeutic Target in Murine Nonalcoholic Fatty Liver Disease. Hepatology 2019; 69:1087-1104. [PMID: 30259536 DOI: 10.1002/hep.30294] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/20/2018] [Indexed: 12/21/2022]
Abstract
Angiogenesis contributes to the development of nonalcoholic steatohepatitis (NASH) and promotes inflammation, fibrosis, and progression to hepatocellular carcinoma (HCC). Angiopoietin-2 (Ang-2) is a key regulator of angiogenesis. We aimed to investigate the role of Ang-2 and its potential as a therapeutic target in NASH using human samples, in vivo mouse models, and in vitro assays. Serum Ang-2 levels were determined in 104 obese patients undergoing bariatric surgery and concomitant liver biopsy. The effect of the Ang-2/Tie2 receptor inhibiting peptibody L1-10 was evaluated in the methionine-choline deficient (MCD) and streptozotocin-western diet nonalcoholic fatty liver disease mouse models, and in vitro on endothelial cells and bone marrow-derived macrophages. The hepatic vasculature was visualized with µCT scans and scanning electron microscopy of vascular casts. Serum Ang-2 levels were increased in patients with histological NASH compared with patients with simple steatosis and correlated with hepatic CD34 immunoreactivity as a marker of hepatic angiogenesis. Serum and hepatic Ang-2 levels were similarly increased in mice with steatohepatitis. Both preventive and therapeutic L1-10 treatment reduced hepatocyte ballooning and fibrosis in MCD diet-fed mice and was associated with reduced hepatic angiogenesis and normalization of the vascular micro-architecture. Liver-isolated endothelial cells and monocytes from MCD-fed L1-10-treated mice showed reduced expression of leukocyte adhesion and inflammatory markers, respectively, compared with cells from untreated MCD diet-fed mice. In the streptozotocin-western diet model, therapeutic Ang-2 inhibition was able to reverse NASH and attenuate HCC progression. In vitro, L1-10 treatment mitigated increased cytokine production in lipopolysaccharide-stimulated endothelial cells but not in macrophages. Conclusion: Our findings provide evidence for Ang-2 inhibition as a therapeutic strategy to target pathological angiogenesis in NASH.
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Affiliation(s)
- Sander Lefere
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium
| | | | - Anne Hoorens
- Department of Pathology, Ghent University, Ghent, Belgium
| | - Sarah Raevens
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium
| | - Sanne Van Campenhout
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium
| | - Astrid Vandierendonck
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium
| | | | | | - Christian Vanhove
- Department of Electronics and Information Systems, Ghent University, Ghent, Belgium
| | - Charlotte Debbaut
- Department of Electronics and Information Systems, Ghent University, Ghent, Belgium
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium
| | - Jo Van Dorpe
- Department of Pathology, Ghent University, Ghent, Belgium
| | - Christophe Van Steenkiste
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium
| | - Christophe Casteleyn
- Department of Morphology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.,Applied Veterinary Morphology, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Belgium
| | - Bruno Lapauw
- Department of Endocrinology, Ghent University, Ghent, Belgium
| | - Hans Van Vlierberghe
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium
| | - Anja Geerts
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium
| | - Lindsey Devisscher
- Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium
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Handzlik G, Holecki M, Kozaczka J, Kukla M, Wyskida K, Kędzierski L, Pawlicki K, Duława J. Evaluation of metformin therapy using controlled attenuation parameter and transient elastography in patients with non-alcoholic fatty liver disease. Pharmacol Rep 2018; 71:183-188. [PMID: 30780126 DOI: 10.1016/j.pharep.2018.10.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 10/11/2018] [Accepted: 10/25/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is among the most common causes of liver disease worldwide. There is growing evidence on pathogenesis and pathophysiology of NAFLD. However, there is still no universally accepted pharmacotherapy protocol. METHODS The study was conducted on 42 patients with NAFLD. They were randomized to dietary treatment alone (n = 21) or to diet and metformin therapy (n = 21). Liver ultrasonography, controlled attenuation parameter (CAP), liver stiffness (LS), complete blood count, anthropometric and biochemical parameters were obtained before treatment (baseline), and after 3 and 5 months of the therapy. RESULTS Patients treated with diet and metformin exhibited significantly decreased CAP values at 3 and 5 months of the therapy compared to baseline (319 dB/m vs. 285 dB/m; p < 0.05; 319 dB/m vs. 295 dB/m; p < 0.05 respectively). Five months of diet and the metformin therapy resulted in significant reduction of LS value (6.2 kPa vs. 5.2 kPa; p < 0.05), while patients treated with diet alone had no significant changes in liver CAP and LS measurements. CONCLUSIONS Metformin therapy combined with dietary treatment seems to be effective for the reduction of hepatic steatosis and fibrosis. However, considering limitations of the study and inconsistent results of previous investigations in this area, there is a need for further research on metformin efficacy in this group of patients.
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Affiliation(s)
- Gabriela Handzlik
- Department of Internal Medicine and Metabolic Diseases, School of Health Sciences, Medical University of Silesia, Katowice, Poland.
| | - Michał Holecki
- Department of Internal Medicine, Autoimmune and Metabolic Diseases, School of Medicine, Medical University of Silesia, Katowice, Poland
| | - Joanna Kozaczka
- Department of Internal Medicine and Metabolic Diseases, School of Health Sciences, Medical University of Silesia, Katowice, Poland
| | - Michał Kukla
- Department of Gastroenterology and Hepatology, School of Medicine, Medical University of Silesia, Katowice, Poland
| | - Katarzyna Wyskida
- Health Promotion and Obesity Management Unit, Department of Pathophysiology, School of Medicine, Medical University of Silesia, Katowice, Poland
| | - Leszek Kędzierski
- Department of Internal Medicine and Metabolic Diseases, School of Health Sciences, Medical University of Silesia, Katowice, Poland
| | - Krzysztof Pawlicki
- Department of Biophysics, School of Medicine, Medical University of Silesia, Katowice, Poland
| | - Jan Duława
- Department of Internal Medicine and Metabolic Diseases, School of Health Sciences, Medical University of Silesia, Katowice, Poland
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Yuan F, Song B, Huang Z, Xia C, Liu X. Quantification of pancreatic fat with dual-echo imaging at 3.0-T MR in clinical application: how do the corrections for T1 and T2* relaxation effect work and simplified correction strategy. Acta Radiol 2018; 59:1021-1028. [PMID: 29260576 DOI: 10.1177/0284185117745908] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Background Dual-echo imaging is a routine clinical magnetic resonance (MR) sequence affected by T1 and T2* relaxation effect in fat quantification. The separate impacts of T1 and T2* relaxation effect in pancreatic fat quantification using dual-echo imaging at 3.0-T MR have not been reported in detail. Purpose To demonstrate the separate T1 and T2* relaxation effect on pancreatic fat quantification by dual-echo imaging at 3.0-T MR and the simplified correction strategy is discussed for convenient clinical application. Material and Methods Twenty-one non-alcoholic fatty liver disease (NAFLD) participants with high risk of pancreatic steatosis were included. Pancreatic fat fractions (FF) by dual-echo imaging with different corrections were compared to that of proton magnetic resonance spectroscopy (1H-MRS). Correlation analysis and Bland-Altman analysis were applied. Results The FF by 1H-MRS was 5.9 ± 1.7%. Significant positive correlation (all P < 0.01) was found between FF by 1H-MRS and each dual-echo imaging, in which T1 and T2* correction showed the best correlation (r = 0.95, FF = 6.2 ± 1.7%) and no correction showed the worst correlation (r = 0.86, FF = 5.2 ± 2.0%), and the simplified T1 and T2* correction manifested as r = 0.93 and FF = 6.3 ± 1.8%. FF by T1 and T2* correction showed the best agreement, while T1 correction showed the worst agreement as compared to that of 1H-MRS. Conclusion T1 and T2* correction shows the best performance while no correction dual-echo imaging remains clinical available which may benefit from prior OP echo. Simplified correction using single T2* (32.6 ms) of water and fat is recommended for convenient clinical application in absence of obvious pancreatic iron overload.
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Affiliation(s)
- Fang Yuan
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, PR China
| | - Bin Song
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, PR China
| | - Zixing Huang
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, PR China
| | - Chunchao Xia
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, PR China
| | - Xijiao Liu
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, PR China
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Fang J, Zhou Z, Chang NF, Wan YL, Tsui PH. Ultrasound parametric imaging of hepatic steatosis using the homodyned-K distribution: An animal study. ULTRASONICS 2018; 87:91-102. [PMID: 29476945 DOI: 10.1016/j.ultras.2018.02.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 01/12/2018] [Accepted: 02/14/2018] [Indexed: 06/08/2023]
Abstract
Hepatic steatosis is an abnormal state where excess lipid mass is accumulated in hepatocyte vesicles. Backscattered ultrasound signals received from the liver contain useful information regarding the degree of steatosis in the liver. The homodyned-K (HK) distribution has been demonstrated as a general model for ultrasound backscattering. The estimator based on the first three integer moments (denoted as "FTM") of the intensity has potential for practical applications because of its simplicity and low computational complexity. This study explored the diagnostic performance of HK parametric imaging based on the FTM method in the assessment of hepatic steatosis. Phantom experiments were initially conducted using the sliding window technique to determine an appropriate window size length (WSL) for HK parametric imaging. Subsequently, hepatic steatosis was induced in male Wistar rats fed a methionine- and choline-deficient (MCD) diet for 0 (i.e., normal control), 1, 2, 4, 6, and 8 weeks (n = 36; six rats in each group). After completing the scheduled MCD diet, ultrasound B-mode and HK imaging of the rat livers were performed in vivo and histopathological examinations were conducted to score the degree of hepatic steatosis. HK parameters μ (related to scatterer number density) and k (related to scatterer periodicity) were expressed as functions of the steatosis stage in terms of the median and interquartile range (IQR). Receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic performance levels of the μ and k parameters. The results showed that an appropriate WSL for HK parametric imaging is seven times the pulse length of the transducer. The median value of the μ parameter increased monotonically from 0.194 (IQR: 0.18-0.23) to 0.893 (IQR: 0.64-1.04) as the steatosis stage increased. Concurrently, the median value of the k parameter increased from 0.279 (IQR: 0.26-0.31) to 0.5 (IQR: 0.41-0.54) in the early stages (normal to mild) and decreased to 0.39 (IQR: 0.29-0.45) in the advanced stages (moderate to severe). The areas under the ROC curves obtained using (μ, k) were (0.947, 0.804), (0.914, 0.575), and (0.813, 0.604) for the steatosis stages of ≥mild, ≥moderate, and ≥severe, respectively. The current findings suggest that ultrasound HK parametric imaging based on FTM estimation has great potential for future clinical diagnoses of hepatic steatosis.
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Affiliation(s)
- Jui Fang
- Ph. D. Program in Biomedical Engineering, College of Engineering, Chang Gung University, Taoyuan, Taiwan
| | - Zhuhuang Zhou
- College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China; Faculty of Information Technology, Beijing University of Technology, Beijing, China
| | - Ning-Fang Chang
- Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yung-Liang Wan
- Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Medical Imaging Research Center, Institute for Radiological Research, Chang Gung University and Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
| | - Po-Hsiang Tsui
- Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Medical Imaging Research Center, Institute for Radiological Research, Chang Gung University and Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
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Zhou YY, Zhou XD, Wu SJ, Hu XQ, Tang B, Poucke SV, Pan XY, Wu WJ, Gu XM, Fu SW, Zheng MH. Synergistic increase in cardiovascular risk in diabetes mellitus with nonalcoholic fatty liver disease: a meta-analysis. Eur J Gastroenterol Hepatol 2018; 30:631-636. [PMID: 29351115 DOI: 10.1097/meg.0000000000001075] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) has been linked to an increased risk of cardiovascular disease (CVD). To explore the impact of diabetes mellitus (DM) as a cardiovascular risk factor, this meta-analysis quantitatively assessed the association of NAFLD and CVD in diabetic patients. METHODS PubMed, EMBASE, and the Cochrane Library database were analyzed until the end of March 2017. Original studies analyzing the association between NAFLD and cardiovascular risk factors in the diabetic population were included. The available data related to outcome were extracted for the effect estimate using a random-effects model. The quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. RESULTS Of the 770 initially identified studies, 11 studies involving 8346 patients were finally included. The Newcastle-Ottawa Quality Assessment Scale scores suggested that the studies included were of high quality. The pooled effects estimate showed that diabetic patients with NAFLD showed a two times increased risk for CVD compared with patients without NAFLD (odds ratio=2.20, 95% confidence interval: 1.67-2.90). Subgroup analysis also yielded a markedly increased risk, with odds ratio (95% confidence interval) values of 2.28 (1.61-3.23) and 1.90 (1.48-2.45) in cross-sectional and cohort studies, respectively. CONCLUSION This is the first meta-analysis investigating the relationship between NAFLD and CVD independent of the impact of DM. Our findings suggested that NAFLD increases the risk of CVD in populations with comparable DM profiles. Diabetic patients diagnosed with NAFLD might benefit from a more early cardiovascular risk assessment, thereby reducing CVD morbidity and mortality.
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Affiliation(s)
- Yao-Yao Zhou
- Department of Cardiology, Jinhua Municipal Hospital, Jinhua
| | | | - Sheng-Jie Wu
- Department of Cardiovascular Medicine, the Heart Center
| | - Xian-Qing Hu
- Department of Cardiology, Jinhua Municipal Hospital, Jinhua
| | - Biao Tang
- Department of Cardiology, Jinhua Municipal Hospital, Jinhua
| | - Sven van Poucke
- Department of Anesthesiology, Intensive Care, Emergency Medicine and Pain Therapy, Ziekenhuis Oost-Limburg, Genk, Belgium
| | | | | | | | - Shen-Wen Fu
- Department of Cardiology, Jinhua Municipal Hospital, Jinhua
| | - Ming-Hua Zheng
- Department of Hepatology, NAFLD Research Center, the First Affiliated Hospital of Wenzhou Medical University
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
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Borrelli A, Bonelli P, Tuccillo FM, Goldfine ID, Evans JL, Buonaguro FM, Mancini A. Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches. Redox Biol 2018; 15:467-479. [PMID: 29413959 PMCID: PMC5975181 DOI: 10.1016/j.redox.2018.01.009] [Citation(s) in RCA: 187] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 01/10/2018] [Accepted: 01/17/2018] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC). Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the "Two Hit Theory" to the "Multiple Hit Theory". However, the general consensus is that the gut microbiota, oxidative stress, and mitochondrial damage play key roles in the pathogenesis of NASH. The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of reactive oxygen species (ROS). The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis. This problem represents the first "Achilles' heel" of the new molecules being evaluated in most ongoing clinical trials. The second is the inability of these molecules to reach the mitochondria, the primary sites of energy production and ROS generation. Recently, a variety of non-pharmacological and pharmacological treatment approaches for NASH have been evaluated including vitamin E, the thiazolidinediones, and novel molecules related to NASH pathogenesis (including obeticholic acid and elafibranor). Recently, a new isoform of human manganese superoxide dismutase (MnSOD) was isolated and obtained in a synthetic recombinant form designated rMnSOD. This protein has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis. Based on these distinctive characteristics, it can be hypothesized that this novel recombinant protein (rMnSOD) potentially represents a new and highly efficient adjuvant therapy to counteract the progression from NASH to HCC.
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Affiliation(s)
- Antonella Borrelli
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G Pascale", 80131 Napoli, Italy.
| | - Patrizia Bonelli
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G Pascale", 80131 Napoli, Italy
| | - Franca Maria Tuccillo
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G Pascale", 80131 Napoli, Italy
| | | | | | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G Pascale", 80131 Napoli, Italy
| | - Aldo Mancini
- Leadhexa Biotechnologies Inc., Belvedere, CA, USA
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Elalfy H, Besheer T, Elhammady D, Mohamed MA, El-Hussiny MAB, Elkashef W, El-Deek BS, Mohamed Alsayed SA. Model for Non-Invasive Diagnosis of NAFLD Incorporating Caspase 3-Cleaved Cytokeratin-18: A Clinical, Serological, and Immunohistochemical Analysis. HEPATITIS MONTHLY 2018; 18. [DOI: 10.5812/hepatmon.60168] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
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Lee MM, Kim HG, Lee SB, Lee JS, Kim WY, Choi SH, Lee SK, Byun CK, Hyun PM, Son CG. CGplus, a standardized herbal composition ameliorates non-alcoholic steatohepatitis in a tunicamycin-induced mouse model. PHYTOMEDICINE 2018; 41:24-32. [PMID: 29519316 DOI: 10.1016/j.phymed.2018.01.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
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Zhou YY, Zhou XD, Wu SJ, Fan DH, Van Poucke S, Chen YP, Fu SW, Zheng MH. Nonalcoholic fatty liver disease contributes to subclinical atherosclerosis: A systematic review and meta-analysis. Hepatol Commun 2018; 2:376-392. [PMID: 29619417 PMCID: PMC5880194 DOI: 10.1002/hep4.1155] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 01/09/2018] [Accepted: 01/11/2018] [Indexed: 12/21/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of atherosclerotic cardiovascular disease. In our meta‐analysis, we aimed to assess the correlation of NAFLD and four surrogate markers of subclinical atherosclerosis. PubMed, Embase, and the Cochrane Library were searched up until April 2017. Original studies investigating the association between NAFLD and subclinical atherosclerosis were included. The outcome data were extracted and pooled for the effect estimate by using a random‐effects model. We used the Newcastle‐Ottawa Quality Assessment Scale to assess the quality of the included studies. Of the 434 initially retrieved studies, 26 studies involving a total of 85,395 participants (including 29,493 patients with NAFLD) were included in this meta‐analysis. The Newcastle‐Ottawa Quality Assessment Scale scores suggested the included studies were of high quality. The pooled effects estimate showed that subjects with NAFLD exhibited a significant independent association with subclinical atherosclerosis compared to the non‐NAFLD group (odds ratio, 1.60; 95% confidence interval, 1.45‐1.78). Subgroup analysis suggested that the presence of NAFLD yielded a remarkable higher risk of increased carotid artery intima‐media thickness/plaques, arterial stiffness, coronary artery calcification, and endothelial dysfunction with odds ratios (95% confidence interval) of 1.74 (1.47‐2.06), 1.56 (1.24‐1.96), 1.40 (1.22‐1.60), and 3.73 (0.99‐14.09), respectively. Conclusion: Our meta‐analysis revealed a close link between NAFLD and subclinical atherosclerosis in light of four different indices. Patients with NAFLD might benefit from screening and surveillance of early atherosclerosis, which would facilitate the prediction of potential cardiovascular disease burden, risk stratification, and appropriate intervention in the long term. (Hepatology Communications 2018;2:376‐392)
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Affiliation(s)
- Yao-Yao Zhou
- Department of Cardiology Jinhua Municipal Hospital Jinhua China
| | - Xiao-Dong Zhou
- Department of Cardiovascular Medicine, Heart Center First Affiliated Hospital of Wenzhou Medical University Wenzhou China
| | - Sheng-Jie Wu
- Department of Cardiovascular Medicine, Heart Center First Affiliated Hospital of Wenzhou Medical University Wenzhou China
| | - Dan-Hong Fan
- Department of Cardiovascular Medicine, Heart Center First Affiliated Hospital of Wenzhou Medical University Wenzhou China
| | - Sven Van Poucke
- Department of Anesthesiology, Intensive Care, Emergency Medicine and Pain Therapy Ziekenhuis Oost-Limburg Genk Belgium
| | - Yong-Ping Chen
- Department of Hepatology, NAFLD Research Center First Affiliated Hospital of Wenzhou Medical University Wenzhou China.,Institute of Hepatology Wenzhou Medical University Wenzhou China
| | - Shen-Wen Fu
- Department of Cardiology Jinhua Municipal Hospital Jinhua China
| | - Ming-Hua Zheng
- Department of Hepatology, NAFLD Research Center First Affiliated Hospital of Wenzhou Medical University Wenzhou China.,Institute of Hepatology Wenzhou Medical University Wenzhou China
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