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Adult human liver slice cultures:Modelling of liver fibrosis and evaluation of new anti-fibrotic drugs

World Journal of Hepatology 2021年第2期13卷 187-217页

作者： Daria Kartasheva-Ebertz Jesintha Gaston Loriane Lair-Mehiri Pierre-Philippe Massault Olivier Scatton Jean-Christophe Vaillant Vladimir Alexei Morozov Stanislas Pol Sylvie Lagaye Institut Pasteur Immunobiologie des Cellules DendritiquesINSERM U1223Paris 75015France BioSPC Universitéde ParisParis 75005France Service de Chirurgie digestive Hépato-biliaire et EndocrinienneAPHPGroupe Hospitalier CochinParis 75014France Service de Chirurgie digestive et Hépato bilio pancréatique AP-HPGroupe Hospitalier La Pitié-SalpétrièreMedecine Sorbonne UniversitéParis 75013France Center for HIV and Retrovirology Department of Infectious DiseasesRobert Koch InstituteBerlin 13353Germany Département d'Hépatologie AP-HPGroupe Hospitalier CochinUniversitéde ParisParis 75014France

BACKGROUND Liver fibrosis can result in end-stage liver failure and death.AIM To examine human liver fibrogenesis and anti-fibrotic therapies,we evaluated the three dimensional ex vivo liver slice(LS)model.METHODS Fibrotic liver samples(F0 to F4 fibrosis stage according to the METAVIR score)were collected from patients after liver resection.Human liver slices(HLS)were cultivated for up to 21 days.Hepatitis C virus(HCV)infection,alcohol(ethanol stimulation)and steatosis(palmitate stimulation)were examined in fibrotic(F2 to F4)liver slices infected(or not)with HCV.F0-F1 HLS were used as controls.At day 0,either ursodeoxycholic acid(choleretic and hepatoprotective properties)and/or α-tocopherol(antioxidant properties)were added to standard of care on HLS and fibrotic liver slices,infected(or not)with HCV.Expression of the biomarkers of fibrosis and the triglyceride production were checked by quantitative reverse transcription polymerase chain reaction and/or enzymelinked immunosorbent assay.RESULTS The cultures were viable in vitro for 21 days allowing to study fibrosis inducers and to estimate the effect of anti-fibrotic drugs.Expression of the biomarkers of fibrosis and the progression to steatosis(estimated by triglycerides production)was increased with the addition of HCV and/or ethanol or palmitate.From day 15 of the follow-up studies,a significant decrease of both transforming growth factorβ-1 and Procol1A1 expression and triglycerides production was observed when a combined anti-fibrotic treatment was applied on HCV infected F2-F4 LS cultures.CONCLUSION These results show that the human three dimensional ex vivo model effectively reflects the in vivo processes in damaged human liver(viral,alcoholic,nonalcoholic steatohepatitis liver diseases)and provides the proof of concept that the LS examined model permits a rapid evaluation of new anti-fibrotic therapies when used alone or in combination.

关键词： Human liver fibrosis Hepatitis C virus Alcoholic liver disease nonalcoholic steatohepatitis Ex vivo model Drugs

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Non-alcoholic fatty liver disease in diabetes:When to refer to the hepatologist?

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World Journal of Diabetes 2021年第9期12卷 1479-1493页

作者： Reshu Khandelwal Anuradha S Dassanayake Hari S Conjeevaram Shivaram P Singh Department of Gastroenterology Srirama Chandra Bhanja(SCB)Medical College and HospitalCuttack 753007OdishaIndia Department of Medicine Colombo North Centre for Liver DiseaseUniversity of KelaniyaKelaniya 11600Sri Lanka Division of Gastroenterology and Hepatology University of Michigan Medical SchoolAnn ArborMI 48109United States

Non-alcoholic fatty liver disease(NAFLD)has become one of the most common chronic liver diseases worldwide.A strong relationship exists between NAFLD and diabetes mellitus.There is growing evidence of a mechanistically complex and strong association between the two diseases.Current data also shows that one disease actually leads to worsening of the other and vice versa.Understanding of the various pathophysiological mechanisms involved,natural history and spectrum of these two diseases is essential not only for early diagnosis and management but also for prevention of severe disease forms.Despite the tremendous progress made in recent times in acquiring knowledge about these highly prevalent diseases,the guidelines and recommendations for screening and management of diabetics with NAFLD remain ambiguous.An interdisciplinary approach is required to not only raise awareness of the prevalence of NAFLD in diabetics but also for better patient management.This can help attenuate the development of significant complications,such as cirrhosis,decompensation and hepatocellular carcinoma in these patients,thereby halting NAFLD in its tracks.This review focuses on the pivotal role of primary care physicians and endocrinologists in identification of NAFLD in diabetics in early stages and the role of proactive screening for prompt referral to hepatologist.

关键词： Fibrosis Diabetes Insulin resistance Non-alcoholic fatty liver disease nonalcoholic steatohepatitis Steatosis

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Role of betaine in liver disease-worth revisiting or has the die been cast?

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World Journal of Gastroenterology 2020年第38期26卷 5745-5748页

作者： Sandeep Mukherjee Department of Medicine Creighton University Medical CenterDivision of GastroenterologyOmahaNE 68124United States

nonalcoholic steatohepatitis(NASH)is an important indication for liver transplantation in many Western countries due to the epidemic of obesity and insulin resistance.Unfortunately,no medication is approved for NASH and risk factor modification is often advised.Over the last decade,several clinical trials on NASH have been conducted with several ongoing and the future looks promising.Although betaine(trimethyl glycine)was evaluated for NASH,results were mixed in the clinical trials in large part due to the quality of the studies.It seems reasonable to re-evaluate betaine in clinical trials for NASH and alcoholic liver disease due to its low cost,tolerability and mechanism of action.

关键词： Betaine Obesity Insulin resistance nonalcoholic steatohepatitis Cirrhosis S-adenosyl homocysteine S-adenosyl methionine

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Non-alcoholic Fatty Liver Disease:A Clinical Update

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Journal of Clinical and Translational Hepatology 2017年第4期5卷 384-393页

作者： Joseph M Pappachan Shithu Babu Babu Krishnan Nishal C Ravindran Department of Endocrinology Diabetes&MetabolismRoyal Lancaster InfirmaryUniversity Hospitals of Morecambe Bay NHS TrustLancasterUK Department of Medicine Dorset County HospitalDorchesterUK Department of Gastroenterology&Hepatology Royal Bournemouth HospitalBournemouthUK Department of Gastroenterology&Hepatology Hinchingbrooke HospitalHinchingbrookeHuntingdonUK

Non-alcoholic fatty liver disease(NAFLD)is currently the most common chronic liver disease in developed countries because of the obesity epidemic.The disease increases liverrelated morbidity and mortality,and often increases the risk for other comorbidities,such as type 2 diabetes and cardiovascular disease.Insulin resistance related to metabolic syndrome is the main pathogenic trigger that,in association with adverse genetic,humoral,hormonal and lifestyle factors,precipitates development of NAFLD.Biochemical markers and radiological imaging,along with liver biopsy in selected cases,help in diagnosis and prognostication.Intense lifestyle changes aiming at weight loss are the main therapeutic intervention to manage cases.Insulin sensitizers,antioxidants,lipid lowering agents,incretin-based drugs,weight loss medications,bariatric surgery and liver transplantation may be necessary for management in some cases along with lifestyle measures.This review summarizes the latest evidence on the epidemiology,natural history,pathogenesis,diagnosis and management of NAFLD.

关键词： nonalcoholic fatty liver disease(NAFLD) nonalcoholic steatohepatitis NASH Insulin resistance Metabolic syndrome Lifestyle interventions Bariatric surgery

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Abnormal liver enzymes: A review for clinicians

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World Journal of Hepatology 2021年第11期13卷 1688-1698页

作者： M Ammar Kalas Luis Chavez Monica Leon Pahnwat Tonya Taweesedt Salim Surani Department of Internal Medicine Texas Tech University Health Science CenterEl PasoTX 79905United States Department of General Surgery University of MexicoCiudad de Mexico 01120Mexico Department of Medicine Corpus Christi Medical CenterCorpus ChristiTX 78412United States Department of Medicine Texas A&M UniversityCollege StationTX 77843United States Department of Anesthesiology Mayo ClinicRochesterMN 55905United States

Liver biochemical tests are some of the most commonly ordered routine tests in the inpatient and outpatient setting,especially with the automatization of testing in this technological era.These tests include aminotransferases,alkaline phosphatase,gamma-glutamyl transferase,bilirubin,albumin,prothrombin time and international normalized ratio(INR).Abnormal liver biochemical tests can be categorized based on the pattern and the magnitude of aminotransferases elevation.Generally,abnormalities in aminotransferases can be classified into a hepatocellular pattern or cholestatic pattern and can be further sub-classified based on the magnitude of aminotransferase elevation to mild[5-15×ULN).Hepatocellular pattern causes include but are not limited to;non-alcoholic fatty liver disease/non-alcoholic steatohepatitis,alcohol use,chronic viral hepatitis,liver cirrhosis(variable),autoimmune hepatitis,hemochromatosis,Wilson’s disease,alpha-1 antitrypsin deficiency,celiac disease,medication-induced and ischemic hepatitis.Cholestatic pattern causes include but is not limited to;biliary pathology(obstruction,autoimmune),other conditions with hyperbilirubinemia(conjugated and unconjugated).It is crucial to interpret these commonly ordered tests accurately as appropriate further workup,treatment and referral can greatly benefit the patient due to prompt treatment which can improve the natural history of several of the diseases mentioned and possibly reduce the risk of progression to the liver cirrhosis.

关键词： Liver function test Liver enzymes Hepatitis Liver biochemical studies nonalcoholic steatohepatitis Hyperbilirubenemia

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Association of nonalcoholic fatty liver disease and liver cancer

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World Journal of Gastroenterology 2015年第3期21卷 913-918页

作者： Perla Oliveira Schulz Fabio Goncalves Ferreira Maria de Fátima Araújo Nascimento Andrea Vieira Mauricio Alves Ribeiro André Ibrahim David Luiz Arnaldo Szutan Gastroenterology Service Internal Medicine DepartmentSanta Casa School of Medical SciencesSao Paulo 01277-900Brazil Department of Surgery Liver and Portal Hypertension GroupSanta Casa School of Medical SciencesSao Paulo 01277-900Brazil Pathology Department Santa Casa School of Medical SciencesSao Paulo 01277-900Brazil GI Transplant Service Gastroenterology DepartmentUniversity of Sao PauloSao Paulo 01246-903Brazil

AIM:To investigate the association between nonalcoholic fatty liver disease(NAFLD) and liver cancer,and NAFLD prevalence in different liver tumors.METHODS:This is a retrospective study of the clinical,laboratory and histological data of 120 patients diagnosed with primary or secondary hepatic neoplasms and treated at a tertiary center where they underwent hepatic resection and/or liver transplantation,with subsequent evaluation of the explant or liver biopsy.The following criteria were used to exclude patients from the study:a history of alcohol abuse,hepatitis B or C infection,no tumor detected in the liver tissue examined by histological analysis,and the presence of chronic autoimmune hepatitis,hemochromatosis,Wilson's disease,or hepatoblastoma.The occurrence of NAFLD and the association with its known risk factors were studied.The risk factors considered were diabetes mellitus,impaired glucose tolerance,impaired fasting glucose,body mass index,dyslipidemia,and arterial hypertension.Presence of reticulin fibers in the hepatic neoplasms was assessed by histological analysis using slide-mounted specimens stained with either hematoxylin and eosin or Masson's trichrome and silver impregnation.Analysis of tumor-free liver parenchyma was carried out to determine the association between NAFLD and its histological grade.RESULTS:No difference was found in the association of NAFLD with the general population(34.2% and 30.0% respectively,95%CI:25.8-43.4).Evaluation by cancer type showed that NAFLD was more prevalent in patients with liver metastasis of colorectal cancer than in patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma(OR = 3.99,95%CI:1.78-8.94,P nonalcoholic steatohepatitis,and liver fibrosis,and their r

关键词： Hepatocellular carcinoma Colorectal liver metastases Intrahepatic cholangiocarcinoma Liver fibrosis nonalcoholic fatty liver disease nonalcoholic steatohepatitis

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Diabetes Mellitus Predicts Occurrence of Cirrhosis and Hepatocellular Cancer in Alcoholic Liver and Non-alcoholic Fatty Liver Diseases

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Journal of Clinical and Translational Hepatology 2015年第1期3卷 9-16页

作者： Evan J.Raff Donny Kakati Joseph R.Bloomer Mohamed Shoreibah Khalid Rasheed Ashwani K.Singal Department of Internal Medicine UAB Birmingham AL USA Division of Gastroenterology and Hepatology UAB BirminghamAL USA Department of Internal Medicine UAB Montgomery Program Huntsville AL USA

Background and Aims:Alcohol abuse and nonalcoholic fatty liver disease (NAFLD) are common causes of liver disease.Diabetes mellitus (DM) is a common comorbidity among NAFLD patients.We performed this study with the specific aim to examine the impact of DM on progression of alcoholic liver disease (ALD) liver and NAFLD.Methods:Medical charts of 480 patients with ALD or NAFLD (2004-2011) managed at a tertiary center were retrospectively reviewed.NAFLD was diagnosed based on exclusion of other causes of liver disease and alcohol use of 40 g/d in women or >60 g/d in men for >5years.Results:Of 480 patients (307 NAFLD),200 diabetics differed from nondiabetics for:age (52±11 vs.49±11 years;p=0.004);male gender (48% vs.57%;p=0.03);metabolic syndrome (49% vs.30%;p=0.0002);NAFLD (80% vs.56%;p<0.0001);cirrhosis (70% vs.59%;p=0.005);and hepatocellular carcinoma (HCC;8% vs.3%;p=0.009).Over a 3 year median follow-up period,diabetics relative to nondiabetics had a higher probability to develop cirrhosis (60% vs.41%;p=0.022) and HCC (27% vs.10%;p=0.045).There was a trend for increased development of hepatic encephalopathy in diabetics compared to nondiabetics (55% vs.39%;p=0.053),and there was no difference between the two groups in survival or other liver disease complications.Conclusions:DM increased risk for cirrhosis and HCC among patients with ALD and NAFLD.Prospective studies with longer follow-up periods are needed to examine the impact of DM on survival and the role of aggressive HCC screening in diabetic cirrhotics.

关键词： Diabetes mellitus steatohepatitis nonalcoholic steatohepatitis Alcoholic cirrhosis

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Association of non-alcoholic fatty liver disease and COVID-19: A literature review of current evidence

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World Journal of Hepatology 2021年第8期13卷 916-925页

作者： Prajna Anirvan Shivaram P Singh Alexa Giammarino Sanjaya K Satapathy Department of Gastroenterology Sriram Chandra Bhanj Medical College and HospitalCuttack 753007OdishaIndia Department of Internal Medicine Donald and Barbara Zucker School of Medicine at HofstraManhassetNY 11030United States Division of Hepatology at Sandra Atlas Bass Center for Liver Diseases and Transplantation Donald and Barbara Zucker School of Medicine at HofstraManhassetNY 11030United States

The coronavirus disease 2019(COVID-19)pandemic has swept through nations,crippled economies and caused millions of deaths worldwide.Many people diagnosed with COVID-19 infections are often found to develop liver injury,which,in a small portion of patients,progresses to severe liver disease.Liver injury in the form of elevated transaminases,hyperbilirubinemia and alterations in serum albumin has been observed to be higher in patients with severe forms of the disease.Those who already have insult to the liver from chronic disease,such as nonalcoholic fatty liver disease(NAFLD)may be at the greatest disadvantage.The severity of COVID-19 also seems to be driven by the presence of NAFLD and other co-morbidities.About 25%of the global population has NAFLD.With such a widespread prevalence of NAFLD,understanding the disease progression of COVID-19 and the occurrence of liver injury in this vulnerable population assumes great significance.In this review,we present an overview of COVID-19 infection in patients with NAFLD.

关键词： SARS-CoV-2 Fatty liver Mitochondria Nitrosative stress Oxidative stress COVID-19 Metabolic associated fatty liver disease nonalcoholic fatty liver disease Progressive liver disease nonalcoholic steatohepatitis

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Non-alcoholic steatohepatitis in liver transplant recipients diagnosed by serum cytokeratin 18 and transient elastography:A prospective study

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World Journal of Hepatology 2021年第12期13卷 2179-2191页

作者： Alshaima Alhinai Afsheen Qayyum-Khan Xun Zhang Patrick Samaha Peter Metrakos Marc Deschenes Philip Wong Peter Ghali Tian-Yan Chen Giada Sebastiani Experimental Medicine McGill UniversityMontreal H4A3J1Canada Medicine McGill University Health CentreMontreal H4A3J1Canada Departments of Pediatrics and Epidemiology McGill UniversityMontreal H4A3J1Canada Cancer Research Program The Research Institute of McGill University and The Research Institute of McGill University Health CenterMontreal H4A3J1Canada Medicine University of FloridaJacksonvilleFlorida 32218United States

BACKGROUND nonalcoholic fatty liver disease(NAFLD)and nonalcoholic steatohepatitis(NASH)seem common after liver transplantation.AIM To investigate incidence and predictors of NAFLD and NASH by employing noninvasive testing in liver transplant recipients,namely controlled attenuation parameter(CAP)and the serum biomarker cytokeratin 18(CK-18).We also evaluated the diagnostic accuracy of CK-18 and CAP compared to liver histology.METHODS We prospectively recruited consecutive adult patients who received liver transplant at the McGill University Health Centre between 2015-2018.Serial measurements of CK-18 and CAP were recorded.NAFLD and NASH were diagnosed by CAP≥270 dB/m,and a combination of CAP≥270 dB/m with CK-18>130.5 U/L,respectively.Incidences and predictors of NAFLD and NASH were investigated using survival analysis and Cox proportional hazards.RESULTS Overall,40 liver transplant recipients(mean age 57 years;70%males)were included.During a median follow-up of 16.8 mo(interquartile range 15.6-18.0),63.0%and 48.5%of patients developed NAFLD and NASH,respectively.On multivariable analysis,after adjusting for sex and alanine aminotransferase,body mass index was an independent predictor of development of NAFLD[adjusted hazard ratio(aHR):1.21,95%confidence interval(CI):1.04-1.41;P=0.01]and NASH(aHR:1.26,95%CI:1.06-1.49;P<0.01).Compared to liver histology,CAP had a 76%accuracy to diagnose NAFLD,while the accuracy of CAP plus CK-18 to diagnose NASH was 82%.CONCLUSION NAFLD and NASH diagnosed non-invasively are frequent in liver transplant recipients within the first 18 mo.Close follow-up and nutritional counselling should be planned in overweight patients.

关键词： nonalcoholic steatohepatitis nonalcoholic fatty liver disease Controlled attenuation parameter Cytokeratin 18 Overweight Accuracy

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Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

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World Journal of Hepatology 2015年第2期7卷 177-188页

作者： Elmar Aigner Gunter Weiss Christian Datz Obesity Research Unit Paracelsus Medical University Salzburg5020 Salzburg Austria First Department of Medicine Paracelsus Medical University Salzburg5020 Salzburg Austria Department of Internal Medicine VI Medical University Innsbruck6020 Innsbruck Austria Department of Internal Medicine General Hospital Oberndorf5111 Oberndorf Austria

Elevated iron stores as indicated by hyperferritinemiawith normal or mildly elevated transferrin saturation a n d m o s t l y m i l d h e p a t i c i r o n d e p o s i t i o n a r e a characteristic finding in subjects with non-alcoholic fatty liver disease(NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the "dysmetabolic iron overload syndrome". Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxylradicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications.

关键词： Dysmetabolic iron overload syndrome Hepcidin Iron overload Metabolic syndrome nonalcoholic fatty liver disease nonalcoholic steatohepatitis

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