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A combined nanotherapeutic approach targeting farnesoid X receptor,ferroptosis,and fibrosis for nonalcoholic steatohepatitis treatment

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2228-2246页

作者： Jiangtao Fu Pingping Zhang Zhiguo Sun Guodong Lu Qi Cao Yiting Chen Wenbin Wu Jiabao Zhang Chunlin Zhuang Chunquan Sheng Jiajun Xu Ying Lu Pei Wang The Center for Basic Research and Innovation of Medicine and Pharmacy(MOE) School of PharmacyNaval Medical UniversityShanghai 200433China National Demonstration Center for Experimental Pharmaceutical Education Naval Medical University/Second Military Medical UniversityShanghai 200433China Department of Diving and Hyperbaric Medicine Naval Special Medical CenterNaval Medical UniversityShanghai 200433China

Obeticholic acid(OCA),a farnesoid X receptor(FXR)agonist with favorable effects on fatty and glucose metabolism,has been considered the leading candidate drug for nonalcoholic steatohepatitis(NASH)***,its limited effectiveness in resolving liver fibrosis and lipotoxicity-induced cell death remains a major ***,a newly recognized form of cell death characterized by uncontrolled lipid peroxidation,is involved in the progression of *** oxide(NO)is a versatile biological molecule that can degrade extracellular *** this study,we developed a PEGylated thiolated hollow mesoporous silica nanoparticles(MSN)loaded with OCA,as well as a ferroptosis inhibitor liproxsatin-1 and a NO donor S-nitrosothiol(ONL@MSN).Biochemical analyses,histology,multiplexed flow cytometry,bulk-tissue RNA sequencing,and fecal 16S ribosomal RNA sequencing were utilized to evaluate the effects of the combined nanoparticle(ONL@MSN)in a mouse NASH *** with the OCA-loaded nanoparticles(O@MSN),ONL@MSN not only protected against hepatic steatosis but also greatly ameliorated fibrosis and ***@MSN also displayed enhanced therapeutic actions on the maintenance of intrahepatic macrophages/monocytes homeostasis,inhibition of immune response/lipid peroxidation,and correction of microbiota *** findings present a promising synergistic nanotherapeutic strategy for the treatment of NASH by simultaneously targeting FXR,ferroptosis,and fibrosis.

关键词： nonalcoholic steatohepatitis Nanotherapy Farnesoid X receptor Ferroptosis Fibrosis Obeticholic acid S-Nitrosothiol Liproxstatin-1

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nonalcoholic steatohepatitis-associated hepatocellular carcinoma:Our case series and literature review

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World Journal of Gastroenterology 2010年第12期16卷 1436-1441页

作者： Yoshitaka Takuma Kazuhiro Nouso Department of Gastroenterology Kurashiki Central Hospital Department of Internal Medicine National Hospital Organization Iwakuni Clinical Center Department of Molecular Hepatology Okayama University Graduate School of MedicineDentistryand Pharmaceutical Sciences

Recently,nonalcoholic steatohepatitis(NASH) has been considered to be another cause of liver cirrhosis and hepatocellular carcinoma(HCC).The natural history and prognosis of NASH are ***,we assessed the clinicopathological features of NASH-associated HCC in our experience and reviewed the literature of NASH-associated *** experienced 11 patients with NASH-associated HCC(6 male,5 female;mean age 73.8 ± 4.9 years) who received curative ***(91%) patients had been diagnosed with obesity,diabetes,hypertension,or *** patients(64%) also had a non-cirrhotic *** recurrence-free survival rates at 1,3 and 5 years were 72%,60%,and 60%.We also summarized and reviewed 94 cases of NASH-associated HCC which were reported in the literature(64 male;mean age 66 years).The majority of patients(68%) were obese,66% of patients had diabetes,and 24% had ***,26% of the HCCs arose from the non-cirrhotic *** conclusion,patients with non-cirrhotic NASH may be a high-risk group for HCC,and regular surveillance for HCC is necessary in non-cirrhotic NASH patients as well as cirrhotic patients.

关键词： nonalcoholic steatohepatitis Hepatocellular carcinoma nonalcoholic fatty liver disease Cryptogenic cirrhosis

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Immunotherapy for nonalcoholic steatohepatitis using the multiple cytokine production modulator Y-40138

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World Journal of Gastroenterology 2009年第44期15卷 5533-5540页

作者： Tatsuhiro Tsujimoto Hideto Kawaratani Toshiyuki Kitazawa Hitoshi Yoshiji Masao Fujimoto Masahito Uemura Hiroshi Fukui Third Department of Internal Medicine Nara Medical University840 Shijo-choKashiharaNara 634-8522Japan

AIM:To investigate the possible use of the multiple cytokine production modulator,Y-40138,as a novel immunotherapy in the rat nonalcoholic steatohepatitis (NASH) model. METHODS:We allocated 6-wk-old male F344 rats to choline-supplemented,L-amino acid-defined (CSAA) diet (control group),CSAA diet + Y-40138 (control + Y-40138 group),choline-def icient,L-amino acid-def ined (CDAA) diet (NASH group),or CDAA diet + Y-40138 (NASH + Y-40138 group). In each group,we measured the plasma alanine aminotransferase (ALT) levels,and the plasma and liver levels of tumor necrosis factor-α (TNF-α),interferon-γ (IFN-γ),and interleukin-10 (IL-10). Tissue specimens of phosphate buffered saline-perfused liver were subjected to hematoxylin and eosin staining,Azan staining,Sirius red staining,and immunohistochemical staining (for Kupffer cells and TNF-α). We then extracted Kupffer cells from the collagenase-perfused livers using the Percoll gradient centrifugation method,and measured the TNF-α levels in the supernatant (in vitro TNF-α production by Kupffer cells) using an enzyme-linked immunosorbent assay ***:In comparison to the NASH group,serumALT elevation was mild,production of serum and liver TNF-α and IFN-γ was inhibited,and IL-10 production was increased in the NASH + Y-40138 group. Amelioration of liver histology was also noted in the NASH + Y-40138 group. Kupffer cell immunohistochemical staining revealed no differences between groups,whereas TNF-α immunohistochemical staining showed fewer stained cells in the NASH + Y-40138 group than in the NASH group. The TNF-α levels in the in-vitro Kupffer cell culture supernatant were lower in the NASH + Y-40138 group than in the NASH ***:Administration of Y-40138 to NASH model rats reduced hepatic inflammation and suppressed fibrosis. These results indicate that the multiple cytokine production modulator,Y-40138,is promising as a novel treatment for NASH.

关键词： nonalcoholic steatohepatitis Y-40138 Tumor necrosis factor α Interferon γ Interleukin-10 Kupffer cell Innate immunity

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Effect of Total Flavone of Haw Leaves on Nuclear Factor Erythroid-2 Related Factor and Other Related Factors in nonalcoholic steatohepatitis Rats

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Chinese Journal of Integrative Medicine 2018年第4期24卷 265-271页

作者： WANG De-jun CAI Yue-qin PAN Shui-zhen ZHANG Li-zong CHEN Yun-xiang CHEN Fang-ming JIN Ming YAN Mao-xiang LI Xiao-dong CHEN Zhi-yun Laboratory Animal Research Center Zhejiang Chinese Medical University Hangzhou 310053 China Drug Safety Evaluation Center Zhejing Academy of Medical Sciences Hangzhou 310053 China The First Affiliated Hospital of Zhejiang Chinese Medical University Hangzhou 310053 China

Objective： To investigate the effect of total flavone of haw leaves（TFHL） on the expression of nuclear factor erythroid-2 related factor（Nrf2） and other related factors in nonalcoholic steatohepatitis（NASH） rats induced by high-fat diet and then to further discuss the mechanism of TFHL＇s prevention against NASH. Methods： High-fat diet was fed to 40 rats to establish the NASH model. Then model rats were intragastrically administrated with 40, 80, 160 mg/（kg·day） TFHL, respectively. The pathological changes of liver tissues in NASH rats were detected by oil red O and hematoxylin-eosin（HE） stainings. The expression of Nrf2 in rat liver was examined through immunohistochemistry. The level of 8-iso-prostaglandin F2α in serum was detected through enzyme linked immunosorbent assay（ELISA）. The mR NA and protein levels of Nrf2 and other related factors in liver tissue were measured by real-time reverse transcriptionpolymerase chain reaction and western blot. Results： Lipid deposition, hepatic steatosis, focal necrosis in lobular inflammation and ballooning degeneration were emerged in livers of NASH rats. The 8-iso-prostaglandin F2α in the serum of NASH rats increased significantly compared with the control group（P〈0.05）. The mR NA of Nrf2, hemeoxyenase1（HO-1） and the mR NA and protein levels of quinine oxidoreductase（NQO1） in NASH rats liver tissue showed a striking increase, while the mR NA levels of Keap1, r-glutamylcysteine synthethase（rG CS） and glutathione S-transferase（GST） were significantly decreased compared with the control group（P〈0.05）. After TFHL treatment, 8-iso-prostaglandin F2α level in serum significantly decreased, and Nrf2 mR NA and protein levels in hepatocytes nucleus enhanced compared with the model group（P〈0.05 or 0.01）. Meanwhile the Keap1 mR NA, the mR NA and protein levels of HO-1, NQO1 antibody, rG CS antibody, GST increased after TFHL treatment（P〈0.05 or 0.01）. Conclusions： Nrf2 and other related factors were involved in development of NASH, and

关键词： nonalcoholic steatohepatitis total flavone of Haw leaves nuclear factor erythroid-2 related factor

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Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3869-3878页

作者： Joseph L.Jilek Kayla L.Frost Kevyn A.Jacobus Wenxi He Erica L.Toth Michael Goedken Nathan J.Cherrington Department of Pharmacology&Toxicology College of PharmacyUniversity of ArizonaTucsonAZ 85724USA Rutgers Translational Sciences Rutgers UniversityPiscatawayNJ 08901USA

Disease-mediated alterations to drug disposition constitute a significant source of adverse drug ***(CDDP)elicits nephrotoxicity due to exposure in proximal tubule cells during renal *** to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis(NASH),however,associated changes to substrate toxicity is *** test this,a methionine-and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics,transporter expression,and *** rats administered CDDP(6 mg/kg,i.p.)displayed 20%less nephrotoxicity than healthy ***,CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min,renal secretion decreased from 6.23 to 2.80 mL/min,and renal CDDP accumulation decreased by 15%,relative to healthy *** copper transporter-1 expression decreased,and organic cation transporter-2 and ATPase copper transporting protein-7 b increased slightly,reducing CDDP *** CDDP accumulation increased 250%in NASH rats relative to healthy *** organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats,although no drug-related toxicity was *** data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance,which may alter nephrotoxicity.

关键词： nonalcoholic steatohepatitis NASH Cisplatin Drug transporter Nephrotoxicity

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LC-MS-based lipidomic analysis in distinguishing patients with nonalcoholic steatohepatitis from nonalcoholic fatty liver

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Hepatobiliary & Pancreatic Diseases International 2021年第5期20卷 452-459页

作者： Zhong-Hua Wang Kenneth I Zheng Xiao-Dong Wang Jin Qiao Yang-Yang Li Li Zhang Ming-Hua Zheng Jian Wu Department of Medical Microbiology and Parasitology MOE/NHC/CAMS Key Laboratory of Medical Molecular VirologySchool of Basic Medical SciencesFudan University Shanghai Medical CollegeShanghai 200032China NAFLD Research Center Department of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000China Institute of Hepatology Wenzhou Medical UniversityWenzhou 325000China The Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province Wenzhou 325000China Department of General Practice Huaihai Middle Road Community Health Service Center of Huangpu DistrictShanghai 200025China Department of Pathology The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000China Department of Gastroenterology and Hepatology Zhongshan Hospital of Fudan UniversityShanghai 200032China Laboratory of Fatty Liver and Metabolic Diseases Shanghai Institute of Liver DiseasesFudan University Shanghai Medical CollegeShanghai 200032China

Background: nonalcoholic fatty liver disease(NAFLD) is one of the main liver diseases, and its pathologic profile includes nonalcoholic fatty liver(NAFL) and nonalcoholic steatohepatitis(NASH). However, there is no reliable non-invasive parameter in distinguishing NASH from NAFL in clinical practice. The present study was to find a non-invasive way to differentiate these two categories of NAFLD via lipidomic analysis. Methods: Lipidomic analysis was used to determine the changes of lipid moieties in blood from 20 NAFL and 10 NASH patients with liver biopsy. Liver histology was evaluated after hematoxylin and eosin staining and Masson’s trichrome staining. The profile of lipid metabolites in correlation with steatosis, inflammation, hepatocellular necroptosis, fibrosis, and NAFLD activity score(NAS) was analyzed. Results: Compared with NAFL patients, NASH patients had higher degree of steatosis, ballooning degeneration, lobular inflammation. A total of 434 different lipid molecules were identified, which were mainly composed of various phospholipids and triacylglycerols. Many lipids, such as phosphatidylcholine(PC)(P-22:0/18:1), sphingomyelin(SM)(d14:0/18:0), SM(d14:0/24:0), SM(d14:0/22:0), phosphatidylethanolamine(PE)(18:0/22:5), PC(O-22:2/12:0), and PC(26:1/11:0) were elevated in the NASH group compared to those in the NAFL group. Specific analysis revealed an overall lipidomic profile shift from NAFL to NASH, and identified valuable lipid moieties, such as PCs [PC(14:0/18:2), PE(18:0/22:5) and PC(26:1/11:0)] or plasmalogens [PC(O-22:0/0:0), PC(O-18:0/0:0), PC(O-16:0/0:0)], which were significantly altered in NASH patients. In addition, PC(14:0/18:2), phosphatidic acid(18:2/24:4) were positively correlated with NAS;whereas PC(18:0/0:0) was correlated positively with fibrosis score. Conclusions: The present study revealed overall lipidomic profile shift from NAFL to NASH, identified valuable lipid moieties which may be non-invasive biomarkers in the categorization o

关键词： Lipidomics nonalcoholic steatohepatitis nonalcoholic fatty liver disease Biomarker nonalcoholic activity score Hepatic fibrosis

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Key factors and potential drug combinations of nonalcoholic steatohepatitis:Bioinformatic analysis and experimental validation-based study

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Hepatobiliary & Pancreatic Diseases International 2021年第5期20卷 433-451页

作者： Guang-Han Fan Rong-Li Wei Xu-Yong Wei Chen-Zhi Zhang Zhe-Tuo Qi Hai-Yang Xie Shu-Sen Zheng Xiao Xu Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhou 310006China Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China NHC Key Laboratory of Combined Multi-organ Transplantation Hangzhou 310003China Department of Hepatobiliary and Pancreatic Surgery Shulan(Hangzhou)HospitalHangzhou 310000China

Background:nonalcoholic fatty liver disease and its advanced stage,nonalcoholic steatohepatitis(NASH),are the major cause of hepatocellular carcinoma(HCC)and other end-stage liver ***,the potential mechanism and therapeutic strategies have not been *** study aimed to identify potential roles of mi RNA/m RNA axis in the pathogenesis and drug combinations in the treatment of ***:Microarray GSE59045 and GSE48452 were downloaded from the Gene Expression Omnibus and analyzed using *** we obtained differentially expressed genes(DE-genes).DAVID database was used for Gene Ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment pathway ***-protein interaction(PPI)networks were used for the identification of hub *** found upstream regulators of hub genes using mi RTar *** expression and correlation of key mi RNA and its targets were detected by q *** Pair Seeker was employed to predict drug combinations against *** expression of mi RNA and hub genes in HCC was identified in the Cancer Genome Atlas database and Human Protein Atlas ***:Ninety-four DE-genes were *** and KEGG analysis showed that these predicted genes were linked to lipid *** genes were identified as hub genes in PPI networks,and they were highly expressed in cells with vigorous lipid ***-mi R-335-5 p was the upstream regulator of 9 genes in the 11 hub genes,and it was identified as a key mi *** hub genes were highly expressed in NASH models,while hsa-mi R-335-5 p was lowly *** correlation of mi RNA-m RNA was established by q *** verification indicated that hsa-mi R-335-5 p had inhibitory effect on the development of ***,drug combinations were predicted and the expression of mi RNA and hub genes in HCC was ***:In the study,potential mi RNA-m RNA pathways related to NASH were *** these pathways may be novel s

关键词： nonalcoholic steatohepatitis Hepatocellular carcinoma microRNA Bioinformatic analysis Drug combination

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Schisandra lignans ameliorate nonalcoholic steatohepatitis by regulating aberrant metabolism of phosphatidylethanolamines

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Acta Pharmaceutica Sinica B 2023年第8期13卷 3545-3560页

作者： Lijuan Xue Keanqi Liu Caixia Yan Junling Dun Yexin Xu Linlin Wu Huizhu Yang Huafang Liu Lin Xie Guangji Wang Yan Liang Key Lab of Drug Metabolism&Pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research Department of Clinical Pharmacythe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Analytical Applications Center Shimadzu(China)Co.Ltd.Shanghai 200233China

nonalcoholic steatohepatitis(NASH)is a spectrum of chronic liver disease characterized by hepatic lipid metabolism *** reports emphasized the contribution of triglyceride and diglyceride accumulation to NASH,while the other lipids associated with the NASH pathogenesis remained *** specific purpose of our study was to explore a novel pathogenesis and treatment strategy of NASH via profiling the metabolic characteristics of ***,multi-omics techniques based on LC—Q-TOF/MS,LC—MS/MS and MS imaging were developed and used to screen the action targets related to NASH progress and treatment.A methionine and choline deficient(MCD)diet-induced mouse model of NASH was then constructed,and Schisandra lignans extract(SLE)was applied to alleviate hepatic damage by regulating the lipid metabolism-related enzymes CES2A and *** lipidomics indicated that MCD-diet led to aberrant accumulation of phosphatidylethanolamines(PEs),and SLE could significantly reduce the accumulation of intrahepatic ***,exogenous PE(18:0/18:1)was proved to significantly aggravate the mitochondrial damage and hepatocyte *** PE(18:0/18:1)also deteriorated the NASH progress by up regulating intrahepatic proinflammatory and fibrotic factors,while PE synthase inhibitor exerted a prominent hepatoprotective *** current work provides new insights into the relationship between PE metabolism and the pathogenesis of NASH.

关键词： nonalcoholic steatohepatitis Multi-omics Schisandra lignans extract Phosphatidyle thanolamine PE(18:0/18:1)

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nonalcoholic steatohepatitis in Asian Indians is neither associated with iron overload nor with HFE gene mutations

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World Journal of Gastroenterology 2005年第3期11卷 393-395页

作者： Ajay Duseja Reena Das Mohit Nanda Ashim Das Gurjeewan Garewal Yogesh Chawla Department of Hepatology Department of Hematology Department of Histopathology

AIM: The pathogenesis of occurrence of liver inflammation and fibrosis in patients with nonalcoholic steatohepatitis (NASH) is not completely understood. Other than insulin resistance, iron abnormalities have been thought to be one of the triggering factors. Therefore, our aim was to study the role of iron abnormalities and HFE gene mutations in patients with NASH. METHODS: Thirty-one patients of NASH diagnosed on the basis of clinical examination biochemistry, ultrasonography and liver biopsy (n = 14) were included in the study. Serum iron parameters (n = 23) (iron, ferritin, total iron-binding capacity and transferrin saturation), Perls' iron staining on liver biopsies (n = 14) and HFE gene mutations (C282Y and H63D) (n = 16) were studied in these patients. The association between iron staining, necroinflammatory activity and fibrosis stage on liver biopsies was also determined. RESULTS: Elevated serum iron, ferritin and transferrin saturation above 55% were observed in 4.3% of patients. On histology, 71% of the patients had negative iron staining, 21.4% had 1+ staining, 7.2% had 2+ staining and none had 3+ or 4+ staining. There was no association between the degree of iron staining and necroinflammatory activity (P=0.55) and fibrosis stage (P= 0.09) on histology. None of the patients had C282Y HFE gene mutation and four patients (25%) were found to be heterozygotes for H63D gene mutation. CONCLUSION: Our study does not favor iron overload and HFE gene mutations as major factors in the pathogenesis of NASH in Asian Indians.

关键词： nonalcoholic steatohepatitis Iron overload HFE gene Mutation

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Shear wave velocity is a useful marker for managing nonalcoholic steatohepatitis

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World Journal of Gastroenterology 2010年第23期16卷 2918-2925页

作者： Akihiko Osaki Tomoyuki Kubota Takeshi Suda Masato Igarashi Keisuke Nagasaki Atsunori Tsuchiya Masahiko Yano Yasushi Tamura Masaaki Takamura Hirokazu Kawai Satoshi Yamagiwa Toru Kikuchi Minoru Nomoto Yutaka Aoyagi Department of Gastroenterology and Hepatology Graduate School of Medical and Dental SciencesNiigata University Department of Homeostatic Regulation and Development Graduate School of Medical and Dental SciencesNiigata University Department of Laboratory Medicine Niigata University Medical and Dental Hospital

AIM:To investigate whether a noninvasive measurement of tissue strain has a potential usefulness for management of nonalcoholic steatohepatitis(NASH).METHODS:In total 26 patients,23 NASHs and 3 normal controls were enrolled in this *** was staged based on Brunt *** a region of interest(ROI),a shear wave was evoked by implementing an acoustic radiation force impulse(ARFI),and the propagation velocity was quantif ***:Shear wave velocity(SWV) could be reproducibly quantified at all ROIs in all subjects except for 4 NASH cases,in which a reliable SWV value was not calculated at several *** average SWV of 1.34 ± 0.26 m/s in fibrous stage 0-1 was significantly slower than 2.20 ± 0.74 m/s and 2.90 ± 1.01 m/s in stages 3 and 4,respectively,but was not significantly different from 1.79 ± 0.78 m/s in stage *** a cutoff value was set at 1.47 m/s,receiver operating characteristic analysis showed significance to dissociate stages 3 and 4 from stage 0-1(P=0.0092) with sensitivity,specificity and area under curve of 100%,75% and 94.2%,*** addition,the correlation between SWV and hyaluronic acid was significant(P<0.0001),while a tendency toward negative correlation was observed with serum albumin(P=0.053).CONCLUSION:The clinical implementation of ARFI provides noninvasive repeated evaluations of liver stiffness at an arbitrary position,which has the potential to shed new light on NASH management.

关键词： nonalcoholic steatohepatitis Ultrasound Liver stiffness measurement Shear wave velocity Acoustic radiation force impulse

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