Publications by authors named "Jérôme Boursier"

132 Publications

Cannabis Use Is Inversely Associated with Overweight and Obesity in Hepatitis B Virus-Infected Patients (ANRS CO22 Hepather Cohort).

Cannabis Cannabinoid Res 2021 Oct 13. Epub 2021 Oct 13.

Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, ISSPAM, Marseille, France.

Chronic hepatitis B virus (HBV) infection may evolve into cirrhosis and hepatocellular carcinoma, and this progression may be accelerated by specific risk factors, including overweight and obesity. Although evidence for a protective effect of cannabis use on elevated body weight has been found for other populations, no data are available for HBV-infected patients. We aimed to identify risk factors (including cannabis use) for overweight and obesity in patients with HBV chronic infection. Using baseline data from the French ANRS CO22 Hepather cohort, we performed two separate analyses, one using "central obesity" (based on waist circumference) and the other "overweight" and "obesity" (based on body mass index) as outcomes. Logistic and multinomial regressions were used to model central obesity and overweight/obesity, respectively. Among the 3706 patients in the study population, 50.8% had central obesity, 34.7% overweight, and 14.4% obesity. After multivariable adjustment, current cannabis use was associated with a 59% lower risk of central obesity compared with no lifetime use (adjusted odds ratio [95% CI]: 0.41 [0.24 to 0.70]). It was also associated with a 54% and 84% lower risk of overweight (adjusted relative risk ratio [95% CI]: 0.46 [0.27 to 0.76]) and obesity (0.16 [0.04 to 0.67]), respectively. Cannabis use was associated with lower risks of overweight and obesity in patients with HBV chronic infection. Future studies should test whether these potential benefits of cannabis and cannabinoid use translate into reduced liver disease progression in this high-risk population.
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http://dx.doi.org/10.1089/can.2021.0094DOI Listing
October 2021

acNASH index to diagnose nonalcoholic steatohepatitis: a prospective derivation and global validation study.

EClinicalMedicine 2021 Nov 1;41:101145. Epub 2021 Oct 1.

MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Background: There is an unmet need for non-invasive biomarkers for the diagnosis of nonalcoholic steatohepatitis (NASH) in non-specialized settings. We aimed to develop and validate a non-invasive test for diagnosing NASH in individuals with biopsy-proven nonalcoholic fatty liver disease (NAFLD).

Methods: We developed a non-invasive test named the that combines serum creatinine and aspartate aminotransferase levels in a derivation cohort of 390 Chinese NAFLD patients admitted to the hepatology center of the First Affiliated Hospital of Wenzhou Medical University (China) between December 2016 and September 2019 and subsequently validated in five external cohorts of different ethnicities of patients with biopsy-confirmed NAFLD (pooled n=1,089).

Findings: The performance of the acNASH index for identifying NASH (defined as NAFLD activity score ≥5 with score of ≥1 for each steatosis, lobular inflammation and ballooning) was good in the derivation cohort with an area under receiver operating characteristics (AUROC) of 0·818 (95%CI 0·777-0·860). A cutoff of acNASH index <4·15 gave a sensitivity (Se) of 91%, a specificity (Sp) of 48% and a negative predictive value (NPV) of 83% for ruling-out NASH, conversely, a cutoff of acNASH >7·73 gave a Sp of 91%, Se of 53% and a positive predictive value (PPV) of 85% for ruling-in NASH. In the pooled validation cohort (n=1,089), the diagnostic performance of the index was also good with AUROC=0·805 (95%CI 0·780-0·830), NPV of 93% for ruling-out NASH and PPV of 73% for ruling-in NASH. Subgroup analyses showed similar performance in patients with diabetes or subjects with normal serum transaminase levels.

Interpretation: The acNASH index shows promising utility as a simple non-invasive biomarker for diagnosing NASH among adults with biopsy-proven NAFLD of different ethnicities from different countries.

Funding: The National Natural Science Foundation of China (82070588), High Level Creative Talents from Department of Public Health in Zhejiang Province (S2032102600032) and Project of New Century 551 Talent Nurturing in Wenzhou.
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http://dx.doi.org/10.1016/j.eclinm.2021.101145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495106PMC
November 2021

Liver fibrosis staging by computed tomography: prospective randomized multicentric evaluation of image analyses.

Clin Res Hepatol Gastroenterol 2021 Sep 6:101797. Epub 2021 Sep 6.

Hepato-gastroenterology department, Angers University Hospital, Angers, France.

Aim: Liver fibrosis staging is essential. We prospectively evaluated the liver fibrosis staging performance of computed tomography (CT).

Methods: 70 hepato-gastroenterology clinicians were randomized into three stratified groups with different image analyses of radiological semiology, i.e., on raw images (group 1) and on expert-annotated (group 2) and computerized-morphometry-enriched (group 3) images. Radiological fibrosis staging based on seven simple descriptors into four stages equivalent to Metavir stages (F0/1, F2, F3, F4=cirrhosis) was determined at baseline and after image analyses in 10 patients with chronic liver diseases (two per F) concordant for four independent fibrosis stagings including Metavir. 23,800 CT images were analysed, providing 1400 fibrosis stagings.

Results: Fibrosis staging: overall (3 groups) accuracy (correct classification rate) was, baseline: 43%, post-analysis: 60% (p<0.001) without significant progression in group 1 (6%, p=0.207) contrary to groups 2 (34%, p<0.001) and 3 (13%, p=0.007). Cirrhosis diagnosis: overall accuracy was, baseline: 84%, post-analysis: 89% (p<0.001) without significant progression in group 1 (0%, p=1) contrary to groups 2 (8%, p=0.009) and 3 (7%, p=0.015). Baseline AUROCs were good (≥0.83) for marked fibrosis (F≥3 or cirrhosis) in all groups. Post-analysis AUROCs became excellent (≥0.89) in group 2 for all diagnostic targets (≥0.98 for F≥3 and cirrhosis) and in group 3 for cirrhosis. In post-analysis group 2, discrimination between all F was excellent (especially, F1 from F0) with an Obuchowski index at 0.87. Negative and positive predictive values for marked fibrosis were 98% and 95%, respectively.

Conclusion: Simple CT descriptors accurately discriminate all Metavir liver fibrosis stages.
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http://dx.doi.org/10.1016/j.clinre.2021.101797DOI Listing
September 2021

Management of diabetes mellitus in patients with cirrhosis: An overview and joint statement.

Diabetes Metab 2021 09 4;47(5):101272. Epub 2021 Aug 4.

Département d'Endocrinologie, Diabétologie, et Maladies Métaboliques, Hôpital Universitaire de Dijon, France; INSERM LNC UMR1231, Dijon, France.

Type 2 diabetes mellitus (T2DM) is a frequent comorbidity in patients with cirrhosis that is projected to rise in prevalence due to the worldwide burden of obesity, insulin-resistance and non-alcoholic fatty liver disease. The management of T2DM in patients with cirrhosis is complex given the requirement for accurate adaptation according to the level of liver function impairment, with lack of summary of the little evidence available in the literature. Here, we summarise the data available with respect to the epidemiology and the impact of T2DM in patients with cirrhosis, as well as those on the management of T2DM in these patients. We provide guidance for the diagnosis of T2DM and the monitoring of glycaemic control in patients with cirrhosis, and for the management of nutrition and pharmacological treatments in relation to the level of liver dysfunction.
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http://dx.doi.org/10.1016/j.diabet.2021.101272DOI Listing
September 2021

Non-invasive diagnosis and follow-up of non-alcoholic fatty liver disease.

Clin Res Hepatol Gastroenterol 2021 Jul 28;46(1):101769. Epub 2021 Jul 28.

Service d'hépato-gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, Pessac, France; INSERM U1053, Université de Bordeaux, Bordeaux, France.

NAFLD is a frequent disease that affects 25% of the worldwide population. There is no specific diagnostic test for NAFLD, and the diagnosis mainly relies on the elimination of the other causes of chronic liver diseases with liver biopsy kept for unsure diagnoses. Non-invasive tests are now available to assess NAFLD severity and therefore to help physicians decide on the patient management and follow-up. These non-invasive tests can also be used to define pathways that organize referrals from primary care and diabetology clinics to the liver specialist, with the ambition to improve the screening of asymptomatic patients with NAFLD and advanced liver disease. NAFLD being the liver expression of the metabolic syndrome, physicians need also take care to screen for diabetes and to evaluate the cardiovascular risk in those patients. These recommendations from the French Association for the Study of the Liver (AFEF) aim at providing guidance on the following questions: how to diagnose NAFLD; how non-invasive tests should be used to assess NAFLD severity; how to follow patients with NAFLD; when to perform liver biopsy in NAFLD; and how to decide referral to the liver specialist for a patient with NAFLD.
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http://dx.doi.org/10.1016/j.clinre.2021.101769DOI Listing
July 2021

Quality criteria for the measurement of liver stiffness.

Clin Res Hepatol Gastroenterol 2021 Jul 27;46(1):101761. Epub 2021 Jul 27.

Service d'hépato-gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, pessac & INSERM U1053, Université de Bordeaux, Bordeaux, France.

Liver elastography offers the possibility of a quick, non-invasive, and painless evaluation of the liver with immediate results at bedside. Transient elastography is the most validated technology, and many others such as point shear wave elastography, 2D-shear wave elastography, or magnetic resonance elastography have been developed. To ensure the best evaluation, several conditions of examination must be respected for liver stiffness measurement. Indeed, patient, operator and examination characteristics have all been shown to influence the result of liver stiffness measurement. Food intake increases liver stiffness, whereas withdrawal in alcoholics is associated with a decrease in elastography results. Inter-observer reproducibility of the measurement seems suboptimal, and the influence of the operator experience is still being debated. The measurement site and the FibroScan® probe must be correctly chosen. Finally, the intrinsic characteristics and quality criteria of the measurement, especially the interquartile range/median ratio, must be carefully checked to avoid overestimation of liver stiffness. Most of the results come from studies which have evaluated transient elastography, with less data available for the other technologies. Liver stiffness measurement could appear as a simple way to explore the liver, but several conditions must be met before deciding the patient management according to its result.
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http://dx.doi.org/10.1016/j.clinre.2021.101761DOI Listing
July 2021

Anti-diabetic drugs and NASH: from current options to promising perspectives.

Expert Opin Investig Drugs 2021 Aug 12;30(8):813-825. Epub 2021 Jul 12.

Department of Endocrinology, Université De Nantes, CHU Nantes, CNRS, INSERM, L'institut Du Thorax, Nantes, France.

: Accumulating evidence supports a bidirectional association between nonalcoholic steatohepatitis (NASH) and type 2 diabetes (T2D). There is a clinical challenge to consider pharmaceutical strategies targeting the metabolic dysfunction common to NASH and T2D pathogenesis.: By using PubMed, we performed a literature search to review the potential beneficial effect of anti-diabetic and metabolic investigational drugs on NASH.: Since insulin resistance is central in the pathophysiology of both T2D and NASH, there is an urgent need for new insulin sensitizers. Peroxisome proliferator-activated receptor (PPAR) agonists, especially PPARγ and pan-PPARs agonists, have shown some beneficial effects on both NASH and liver fibrosis, but their routine use should be limited by their safety profile. Incretin-based therapies, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and the polyagonists (GLP-1, GIP, glucagon) under development are the most promising anti-diabetic drugs for NASH treatment, mainly due to their action on body weight loss. Preliminary, preclinical and early phase studies suggest that SGLT2 inhibitors and fibroblast growth factor (FGF)19 and FGF21-based therapies are promising targets for NASH and T2D treatment. The common weakness for all of these drugs is their limited effect on liver fibrosis, potentially due to short-term trial design.
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http://dx.doi.org/10.1080/13543784.2021.1951701DOI Listing
August 2021

FibroTest for Evaluating Fibrosis in Non-Alcoholic Fatty Liver Disease Patients: A Systematic Review and Meta-Analysis.

J Clin Med 2021 May 29;10(11). Epub 2021 May 29.

Department of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

(1) Background: FibroTest™ is a multi-marker panel, suggested by guidelines as one of the surrogate markers with acceptable performance for detecting fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). A number of studies evaluating this test have been published after publication of the guidelines. This study aims to produce summary estimates of FibroTest™ diagnostic accuracy. (2) Methods: Five databases were searched for studies that evaluated FibroTest™ against liver biopsy as the reference standard in NAFLD patients. Two authors independently screened the references, extracted data, and assessed the quality of included studies. Meta-analyses of the accuracy in detecting different levels of fibrosis were performed using the bivariate random-effects model and the linear mixed-effects multiple thresholds model. (3) Results: From ten included studies, seven were eligible for inclusion in our meta-analysis. Five studies were included in the meta-analysis of FibroTest™ in detecting advanced fibrosis and five in significant fibrosis, resulting in an AUC of 0.77 for both target conditions. The meta-analysis of three studies resulted in an AUC of 0.69 in detecting any fibrosis, while analysis of three other studies showed higher accuracy in cirrhosis (AUC: 0.92). (4) Conclusions: Our meta-analysis showed acceptable performance (AUC > 0.80) of FibroTest™ only in detecting cirrhosis. We observed more limited performance of the test in detecting significant and advanced fibrosis in NAFLD patients. Further primary studies with high methodological quality are required to validate the reliability of the test for detecting different fibrosis levels and to compare the performance of the test in different settings.
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http://dx.doi.org/10.3390/jcm10112415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198930PMC
May 2021

Comorbidities Are Associated with Fibrosis in NAFLD Subjects: A Nationwide Study (NASH-CO Study).

Dig Dis Sci 2021 May 24. Epub 2021 May 24.

Hepatogastroenterology Service, Hôpital Hautepierre, Hôpitaux Universitaires de Strasbourg, 67000, Strasbourg, France.

Background: The relationship between the severity of NAFLD and extra-hepatic events such as cardiovascular disease (CVD), extra-hepatic cancer (EHC) or chronic kidney diseases (CKD) has not been clearly investigated in the general population.

Aims: The aim of this study was to assess whether the severity of fibrosis in NAFLD subjects was associated with extra-hepatic diseases based on noninvasive markers in a large population-based cohort.

Methods: The study population included a cohort of 118,664 participants from the nationwide CONSTANCES cohort. After excluding individuals with excessive alcohol consumption and other causes of liver disease, 102,344 were included. The noninvasive diagnosis of NAFLD and fibrosis was performed using a combination of the Fatty Liver Index (FLI) and the Forns Index. The history of CVD or EHC was recorded by a physician, and CKD was defined by a glomerular filtration rate < 60 ml/mn.

Results: The prevalence of NAFLD (FLI > 60) was 18.2%, 10% with mild fibrosis (Forns Index < 4.2), 7.7% with intermediate fibrosis (Forns Index 4.2-6.9), and 0.4% with advanced fibrosis (Forns Index > 6.9). The prevalence of CVD, EHC, or CKD increased significantly with the severity of fibrosis (p < 0.0001). When adjusted for demographic, metabolic risk factors, and smoking, NAFLD with intermediate or advanced fibrosis remained associated with CVD (OR 1.36, p < 0.0001 and OR 3.07, p < 0.0001, respectively), EHC (OR 1.24, p = 0.001 and OR 1.64, p = 0.004, respectively), and CKD (OR 1.18, p = 0.03 and OR 2.09, p < 0.0001, respectively).

Conclusions: In a large adult population-based cohort, there is a dose-dependent relationship between the severity of fibrosis and CVD, EHC, or CKD in NAFLD subjects.
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http://dx.doi.org/10.1007/s10620-021-07032-zDOI Listing
May 2021

Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis.

Gut 2021 May 17. Epub 2021 May 17.

Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University Mainz, Mainz, Rhineland-Palatinate, Germany.

Objective: Liver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies.

Design: Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations.

Results: Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (<1.3; ≥2.67) followed by LSM-VCTE cut-offs (<8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63-68) and 86% (84-87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (<1.3; ≥3.48) followed by LSM cut-offs (<8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37-39) and specificity of 90% (89-91) with 19% needing biopsy.

Conclusion: Sequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies.
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http://dx.doi.org/10.1136/gutjnl-2021-324243DOI Listing
May 2021

Carrot Supplementation Improves Blood Pressure and Reduces Aortic Root Lesions in an Atherosclerosis-Prone Genetic Mouse Model.

Nutrients 2021 Apr 2;13(4). Epub 2021 Apr 2.

UMR 1280 Physiopathologie des Adaptations Nutritionnelles (PhAN), INRAE, Université de Nantes, 44 093 Nantes, France.

Epidemiological studies have shown that carrot consumption may be associated with a lower risk of developing several metabolic dysfunctions. Our group previously determined that the Bolero (Bo) carrot variety exhibited vascular and hepatic tropism using cellular models of cardiometabolic diseases. The present study evaluated the potential metabolic and cardiovascular protective effect of Bo, grown under two conditions (standard and biotic stress conditions (BoBS)), in apolipoprotein E-knockout (ApoE) mice fed with high fat diet (HFD). Effects on metabolic/hemodynamic parameters and on atherosclerotic lesions have been assessed. Both Bo and BoBS decreased plasma triglyceride and expression levels of genes implicated in hepatic lipogenesis and lipid oxidation. BoBS supplementation decreased body weight gain, secretion of very-low-density lipoprotein, and increased cecal propionate content. Interestingly, Bo and BoBS supplementation improved hemodynamic parameters by decreasing systolic, diastolic, and mean blood pressure. Moreover, Bo improved cardiac output. Finally, Bo and BoBS substantially reduced the aortic root lesion area. These results showed that Bo and BoBS enriched diets corrected most of the metabolic and cardiovascular disorders in an atherosclerosis-prone genetic mouse model and may therefore represent an interesting nutritional approach for the prevention of cardiovascular diseases.
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http://dx.doi.org/10.3390/nu13041181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065932PMC
April 2021

A predictive score of inadequate bowel preparation based on a self-administered questionnaire: PREPA-CO.

Clin Res Hepatol Gastroenterol 2021 Jul 20;45(4):101693. Epub 2021 Apr 20.

Hepato-Gastroenterology Department, Angers University Hospital, Angers, France; HIFIH Laboratory, UPRES 3859, SFR 4208, Angers University, Angers, France.

Introduction: Inadequate bowel preparation before colonoscopy has a 20-30% rate and impedes on the quality of the procedure. The aim of this study was to develop a predictive score of inadequate bowel preparation, using a patient questionnaire on potential risk factors.

Methods: In this single center study, consecutive patients with colonoscopy indication were enrolled. The primary outcome was inadequate bowel preparation defined by Boston Bowel Preparation Scale (BBPS) score <7 or a score ≤1 in any of the 3 colonic segments.

Results: A total of 561 patients were included. Inadequate bowel preparation was seen in 25.0% of cases. Seven risk factors were selected into the prediction model of inadequate bowel preparation: diabetes or obesity, irregular physical activity, cirrhosis, use of antidepressants or neuroleptics, use of opiate medication, history of surgery and history of inadequate bowel preparation. The risk score, named PREPA-CO, had an AUROC of 0.621, adequately predicted bowel cleanliness in 68.3% of cases, with a specificity of 75.8% and a negative predictive value of 80.8%.

Conclusion: We developed a predictive score named "Prepa-Co", allowing the identification of patients at high risk of inadequate bowel preparation. In clinical practice, this score could help tailor the prescription of the preparation to the patient.
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http://dx.doi.org/10.1016/j.clinre.2021.101693DOI Listing
July 2021

Case-finding strategies in non-alcoholic fatty liver disease.

JHEP Rep 2021 Apr 5;3(2):100219. Epub 2020 Dec 5.

Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK.

Among the large population of patients with non-alcoholic fatty liver disease (NAFLD), identifying those with advanced disease remains challenging. Many patients are diagnosed late, following the development of liver-related complications, leading to poor clinical outcomes. Accumulating evidence suggests that using non-invasive tests for liver fibrosis in patients with metabolic risk factors improves the detection of patients in need of specialised management and is cost-effective. Because of the vast number of patients requiring evaluation, the active participation of general practitioners and physicians who manage patients with metabolic disorders, such as diabetologists, is crucial; this calls for the increased awareness of NAFLD beyond liver clinics. Non-invasive case-finding strategies will need to be further validated and generalised for upcoming drug therapies to have the required impact on the worldwide burden of NAFLD.
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http://dx.doi.org/10.1016/j.jhepr.2020.100219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896150PMC
April 2021

Disease burden and economic impact of diagnosed non-alcoholic steatohepatitis in five European countries in 2018: A cost-of-illness analysis.

Liver Int 2021 06 18;41(6):1227-1242. Epub 2021 Mar 18.

Hôpital de la Pitié-Salpêtrière, Paris, France.

Background And Aims: Non-alcoholic steatohepatitis (NASH) is a chronic disease that can progress to end-stage liver disease (ESLD). A large proportion of early-stage NASH patients remain undiagnosed compared to those with advanced fibrosis, who are more likely to receive disease management interventions. This study estimated the disease burden and economic impact of diagnosed NASH in the adult population of France, Germany, Italy, Spain and the United Kingdom in 2018.

Methods: The socioeconomic burden of diagnosed NASH was estimated using cost-of-illness methodology applying a prevalence approach to estimate the number of adults with NASH and the attributable economic and wellbeing costs. Given undiagnosed patients do not incur costs in the study, the probability of diagnosis is central to cost estimation. The analysis was based on a literature review, databases and consultation with clinical experts, economists and patient groups.

Results: The proportion of adult NASH patients with a diagnosis ranged from 11.9% to 12.7% across countries, which increased to 38.8%-39.1% for advanced fibrosis (F3-F4 compensated cirrhosis). Total economic costs were €8548-19 546M. Of these, health system costs were €619-1292M. Total wellbeing costs were €41 536-90 379M. The majority of the undiagnosed population (87.3%-88.2% of total prevalence) was found to have early-stage NASH, which, left untreated, may progress to more resource consuming ESLD over time.

Conclusions: This study found that the majority of economic and wellbeing costs of NASH are experienced in late disease stages. Earlier diagnosis and care of NASH patients could reduce future healthcare costs.
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http://dx.doi.org/10.1111/liv.14825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252761PMC
June 2021

LPS-enriched small extracellular vesicles from metabolic syndrome patients trigger endothelial dysfunction by activation of TLR4.

Metabolism 2021 05 11;118:154727. Epub 2021 Feb 11.

SOPAM, U1063, INSERM, UNIV Angers, SFR ICAT, Angers, France; Centre Hospitalo-Universitaire d'Angers, France. Electronic address:

Background: Metabolic syndrome (MetS) is characterized by a cluster of interconnected risk factors -hyperglycemia, dyslipidemia, hypertension and obesity- leading to an increased risk of cardiovascular events. Small extracellular vesicles (sEVs) can be considered as new biomarkers of different pathologies, and they are involved in intercellular communication. Here, we hypothesize that sEVs are implicated in MetS-associated endothelial dysfunction.

Methods: Circulating sEVs of non-MetS (nMetS) subjects and MetS patients were isolated from plasma and characterized. Thereafter, sEV effects on endothelial function were analyzed by measuring nitric oxide (NO) and reactive oxygen species (ROS) production, and mitochondrial dynamic proteins on human endothelial aortic cells (HAoECs).

Results: Circulating levels of sEVs positively correlated with anthropometric and biochemical parameters including visceral obesity, glycaemia, insulinemia, and dyslipidemia. Treatment of HAoECs with sEVs from MetS patients decreased NO production through the inhibition of the endothelial NO-synthase activity. Injection of MetS-sEVs into mice impaired endothelium-dependent relaxation induced by acetylcholine. Furthermore, MetS-sEVs increased DHE and MitoSox-associated fluorescence in HAoECs, reflecting enhanced cytosolic and mitochondrial ROS production which was not associated with mitochondrial biogenesis or dynamic changes. MetS patients displayed elevated circulating levels of LPS in plasma, and, at least in part, it was associated to circulating sEVs. Pharmacological inhibition and down-regulation of TLR4, as well as sEV-carried LPS neutralization, results in a substantial decrease of ROS production induced by MetS-sEVs.

Conclusion: These results evidence sEVs from MetS patients as potential new biomarkers for this syndrome, and TLR4 pathway activation by sEVs provides a link between the endothelial dysfunction and metabolic disturbances described in MetS.
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http://dx.doi.org/10.1016/j.metabol.2021.154727DOI Listing
May 2021

Cross-linkage between bacterial taxonomy and gene functions: a study of metagenome-assembled genomes of gut microbiota in adult non-alcoholic fatty liver disease.

Aliment Pharmacol Ther 2021 03 22;53(6):722-732. Epub 2021 Jan 22.

Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France.

Background: The reconstruction of metagenome-assembled genomes (MAGs) has emerged as a powerful approach for combining the taxonomic and functional content of microbial populations.

Aim: To use this new approach to highlight mechanisms linking gut microbiota to NAFLD severity METHODS: Stool samples were collected from 96 NAFLD patients on the day of liver biopsy. Shotgun DNA sequencing of the gut microbiota was performed on an Illumina HiSeq3000 system. Contigs were binned into MAGs according to their co-abundances and tetranucleotide frequencies using Metabat v.0.32.4. Predicted protein-coding genes were clustered in orthologous groups (OGs) with DIAMOND against the EggNOG v4.5 database. Liver biopsies were read in accordance with the NASH CRN classification.

Results: Fifty-four patients had NASH and 44 had significant fibrosis (F ≥ 2). Sequencing of DNA extracted from stools resulted in 13.8 + 3.2 million paired-end reads per sample. Of the 4,000 reconstructed MAGs, 220 in NASH patients, 192 in non-NASH patients, 203 in F ≥ 2 patients and 230 in F0-1 patients had > 70% completeness and < 5% contamination. Within these MAGs, 28 OGs were associated with NASH, 33 with significant fibrosis, and seven with both NASH and significant fibrosis. The study of MAGs showed associations between NAFLD severity and some gut bacteria with microbiota functions related to hydrogen sulfide production, citrate transport, hemicellulose degradation, aldehyde production and vitamin B12 synthesis.

Conclusion: Using new metagenomics methods, our study unveils potential mechanisms by which certain bacteria from the gut microbiota could protect or contribute to the development of NASH and liver fibrosis in NAFLD.
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http://dx.doi.org/10.1111/apt.16262DOI Listing
March 2021

Two-dimensional shear wave elastography predicts survival in advanced chronic liver disease.

Gut 2021 Jan 21. Epub 2021 Jan 21.

Department of Radiology, Beaujon University Hospital, Clichy, France.

Objective: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.

Design: This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.

Results: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM.

Conclusion: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.
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http://dx.doi.org/10.1136/gutjnl-2020-323419DOI Listing
January 2021

Bacterial and eukaryotic extracellular vesicles and nonalcoholic fatty liver disease: new players in the gut-liver axis?

Am J Physiol Gastrointest Liver Physiol 2021 04 20;320(4):G485-G495. Epub 2021 Jan 20.

INSERM UMR1063, Stress Oxydant et Pathologies Métaboliques, Faculté de Santé, Université d'Angers, Université Bretagne Loire, Angers, France.

The liver and intestine communicate in a bidirectional way through the biliary tract, portal vein, and other components of the gut-liver axis. The gut microbiota is one of the major contributors to the production of several proteins and bile acids. Imbalance in the gut bacterial community, called dysbiosis, participates in the development and progression of several chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD). NAFLD is currently considered the main chronic liver disease worldwide. Dysbiosis contributes to NAFLD development and progression, notably by a greater translocation of pathogen-associated molecular patterns (PAMPs) in the blood. Lipopolysaccharide (LPS) is a PAMP that activates Toll-like receptor 4 (TLR4), induces liver inflammation, and participates in the development of fibrogenesis. LPS can be transported by bacterial extracellular vesicles (EVs). EVs are spherical structures produced by eukaryotic and prokaryotic cells that transfer information to distant cells and may represent new players in NAFLD development and progression. The present review summarizes the role of eukaryotic EVs, either circulating or tissue-derived, in NAFLD features, such as liver inflammation, angiogenesis, and fibrosis. Circulating EV levels are dynamic and correlate with disease stage and severity. However, scarce information is available concerning the involvement of bacterial EVs in liver disease. The present review highlights a potential role of bacterial EVs in insulin resistance and liver inflammation, although the mechanism involved has not been elucidated. In addition, because of their distinct signatures, eukaryotic and prokaryotic EVs may also represent a promising NAFLD diagnostic tool as a "liquid biopsy" in the future.
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http://dx.doi.org/10.1152/ajpgi.00362.2020DOI Listing
April 2021

Reliability Criteria of Two-Dimensional Shear Wave Elastography: Analysis of 4277 Measurements in 788 Patients.

Clin Gastroenterol Hepatol 2020 Dec 16. Epub 2020 Dec 16.

Laboratoire HIFIH, UPRES EA3859, SFR 4208, Université d'Angers, Angers, France; Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire d'Angers, Angers, France.

Background & Aims: Two-dimensional shear wave elastography (2D-SWE) is an accurate method for the non-invasive evaluation of liver fibrosis. We aimed to determine the reliability criteria and the number of necessary reliable measurements for 2D-SWE.

Methods: 788 patients with chronic liver disease underwent liver biopsy and 2D-SWE examination in three centers. The 4277 2D-SWE measurements performed were 2:1 randomly divided into derivation (n = 2851) and validation (n = 1426) sets. Reliability criteria for a 2D-SWE measurement were defined in the derivation set from the intrinsic characteristics given by the device (mean liver stiffness, standard deviation, diameter of the region of interest), with further evaluation in the validation set.

Results: In the whole population of 4277 measurements, AUROC for bridging fibrosis was 0.825 ± 0.006 and AUROC for cirrhosis was 0.880 ± 0.006. Mean stiffness and coefficient of variation (CV) were independent predictors of bridging fibrosis or cirrhosis. From these two parameters, new criteria were derived to define a reliable 2D-SWE measurement: stiffness <8.8 kPa, or stiffness between 8.8-11.9 kPa with CV <0.25, or stiffness ≥12.0 kPa with CV <0.10. In the validation set, AUROC for bridging fibrosis was 0.830 ± 0.013 in reliable measurements vs 0.667 ± 0.031 in unreliable measurements (P < .001). AUROC for cirrhosis was 0.918±0.014 vs 0.714 ± 0.027, respectively (P < .001). The best diagnostic accuracy for a 2D-SWE examination was achieved from three reliable measurements.

Conclusions: Reliability of a 2D-SWE measurement relies on the coefficient of variation and the liver stiffness level. A 2D-SWE examination should include three reliable measurements according to our new criteria.
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http://dx.doi.org/10.1016/j.cgh.2020.12.013DOI Listing
December 2020

Microbiota-derived extracellular vesicles and metabolic syndrome.

Acta Physiol (Oxf) 2021 04 22;231(4):e13600. Epub 2021 Jan 22.

INSERM UMR1063, Stress Oxydant et Pathologies Métaboliques, Faculté de Santé, Université d'Angers, Université Bretagne Loire, Angers, France.

Aim: Metabolic syndrome is a major health problem concerning approximately 25% of worldwide population. Metabolic syndrome regroups a cluster of five metabolic abnormalities predisposing to Type 2 Diabetes mellitus. Dysbiotic gut microbiota is accompanied by an increase of both intestinal permeability and pathogen-associated molecular patterns translocation into blood circulation to induce metabolic endotoxemia responsible for the low-grade systemic inflammation and insulin resistance in metabolic syndrome. Among pathogen-associated molecular patterns, bacterial extracellular vesicles are gaining growing attention. The latter are produced by eukaryotic and prokaryotic cells and are vectors of communication between gut microbiota and its host The present review brings evidence to the importance of the control of the balance between the different subsets of gut microbiota in the development of metabolic diseases including metabolic syndrome.

Results: The ability of bacteria, including gut bacteria, to release extracellular vesicles implicated in host metabolic homeostasis is highlighted with their plethora of actions on intestinal barrier, inflammation and insulin resistance.

Conclusion: Bacterial extracellular vesicles can be considered as key players in the pathophysiological of metabolic diseases and may represent an interesting strategy for specific manipulations of microbiome for promoting host health.
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http://dx.doi.org/10.1111/apha.13600DOI Listing
April 2021

Refining the Baveno VI elastography criteria for the definition of compensated advanced chronic liver disease.

J Hepatol 2021 05 9;74(5):1109-1116. Epub 2020 Dec 9.

UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK. Electronic address:

Background: The Baveno VI consensus proposed a dual liver stiffness (LS) by transient elastography threshold of <10 and >15 kPa for excluding and diagnosing compensated advanced chronic liver disease (cACLD) in the absence of other clinical signs. Herein, we aimed to validate these criteria in a real-world multicentre study.

Methods: We included 5,648 patients (mean age 51 ± 13 years, 53% males) from 10 European liver centres who had a liver biopsy and LS measurement within 6 months. We included patients with chronic hepatitis C (n = 2,913, 52%), non-alcoholic fatty liver disease (NAFLD, n = 1,073, 19%), alcohol-related liver disease (ALD, n = 946, 17%) or chronic hepatitis B (n = 716, 13%). cACLD was defined as fibrosis stage ≥F3.

Results: Overall, 3,606 (66%) and 987 (18%) patients had LS <10 and >15 kPa, respectively, while cACLD was histologically confirmed in 1,772 (31%) patients. The cut-offs of <10 and >15 kPa showed 75% sensitivity and 96% specificity to exclude and diagnose cACLD, respectively. Examining the ROC curve, a more optimal dual cut-off at <7 and >12 kPa, with 91% sensitivity and 92% specificity for excluding and diagnosing cACLD (AUC 0.87; 95% CI 0.86-0.88; p <0.001) was derived. Specifically, for ALD and NAFLD, a low cut-off of 8 kPa can be used (sensitivity=93%). For the unclassified patients, we derived a risk model based on common patient characteristics with better discrimination than LS alone (AUC 0.74 vs. 0.69; p <0.001).

Conclusions: Instead of the Baveno VI proposed <10 and >15 kPa dual cut-offs, we found that the <8 kPa (or <7 kPa for viral hepatitis) and >12 kPa dual cut-offs have better diagnostic accuracy in cACLD.

Lay Summary: The term compensated advanced chronic liver disease (cACLD) was introduced in 2015 to describe the spectrum of advanced fibrosis and cirrhosis in asymptomatic patients. It was also suggested that cACLD could be diagnosed or ruled out based on specific liver stiffness values, which can be non-invasively measured by transient elastography. Herein, we assessed the suggested cut-off values and identified alternative values that offered better overall accuracy for diagnosing or ruling out cACLD.
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http://dx.doi.org/10.1016/j.jhep.2020.11.050DOI Listing
May 2021

Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis.

Sci Transl Med 2020 12;12(572)

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of , a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort ( = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of , , and , whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.
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http://dx.doi.org/10.1126/scitranslmed.aba4448DOI Listing
December 2020

Transient Versus Two-Dimensional Shear-Wave Elastography in a Multistep Strategy to Detect Advanced Fibrosis in NAFLD.

Hepatology 2021 Jun 19;73(6):2196-2205. Epub 2021 May 19.

Centre d'Investigation de la Fibrose Hépatique, Hôpital Haut-Lévêque, University Hospital of Bordeaux, Pessac, France.

Background And Aims: The combination of laboratory and elastography tests allows the accurate diagnosis of advanced liver fibrosis in patients with NAFLD. In this study, we compared the diagnostic performances of a two-step strategy (laboratory tests and vibration-controlled transient elastography [VCTE] or two-dimensional shear-wave elastography with SuperSonic Imagine [2D-SWE-SSI]) and the added value of a three-step strategy (laboratory tests and two elastography methods).

Approach And Results: From a prospective registry, we retrospectively selected 577 consecutive patients with suspicion of NAFLD who underwent laboratory tests to calculate the Fibrosis-4 (FIB-4) score, liver stiffness evaluation by VCTE (M and XL probes) and 2D-SWE-SSI, and liver biopsy. The diagnostic performances and need for liver biopsy in unclassified patients for the diagnosis of advanced fibrosis (F ≥ 3) in multistep strategies were compared. The area under the curve of FIB-4, VCTE, and 2D-SWE-SSI was 0.74, 0.82, and 0.88, respectively. Using the same thresholds, the FIB-4/2D-SWE-SSI and FIB-4/VCTE diagnostic performances were comparable (sensitivity, 71.4% and 66%; specificity, 91.4% and 91.5%; and accuracy, 83.7% and 81.4%; all P = not significant). Conversely, more patients required liver biopsy after 2D-SWE-SSI (24.6% versus 15.3%, P < 0.001). Performing a second elastography technique in patients with unreliable or gray zone (between 8 and 10 kPa) results greatly decreased the need for liver biopsy (42/577, 7.3%). The diagnostic performances (accuracy, sensitivity, and specificity) of FIB-4/2D-SWE-SSI/VCTE and FIB-4/VCTE/2D-SWE-SSI were comparable (81.1%, 71.5%, and 87.9% versus 81.3%, 69.7%, and 89.5%, respectively; all P = not significant).

Conclusions: Using the same cutoff values, 2D-SWE-SSI is as accurate as VCTE for advanced liver fibrosis diagnosis in NAFLD. The three-step strategy in selected patients strongly decreased the need for liver biopsy while maintaining excellent accuracy.
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http://dx.doi.org/10.1002/hep.31655DOI Listing
June 2021

Apple Supplementation Improves Hemodynamic Parameter and Attenuates Atherosclerosis in High-Fat Diet-Fed Apolipoprotein E-Knockout Mice.

Biomedicines 2020 Nov 12;8(11). Epub 2020 Nov 12.

SOPAM, U1063, INSERM, UNIV Angers, SFR ICAT, 49 800 Angers, France.

Epidemiological studies describe the association between apple consumption and improved cardiovascular and metabolic dysfunction. Our recent multiparametric screening on cellular model studies has shown that apples exhibit vascular tropism including Granny Smith (GS) variety independently of the storage condition. The present study aimed to evaluate the cardiovascular and metabolic protection of supplementation of GS variety after storage in classic cold (GSCC) and extreme ultra-low oxygen conditions (GSXO) in the apolipoprotein E-deficient 8-week-old mice fed with high fat diet for 14 weeks. Supplementation with GSCC and GXO decreases circulating triglycerides, the expression of genes involved in lipogenesis, without change in cholesterol and glucose concentrations and HOMA-IR. Only GSXO supplementation ameliorates body weight gain, insulin level, and HDL/LDL ratio. GSXO supplementation does not modify cardiac parameters; while supplementation with GSCC decreases heart rate and improves cardiac output. Interestingly, GSCC and GSXO reduce systolic and diastolic blood pressure with a differential time course of action. These effects are associated with substantial decrease of atherosclerotic lesions. These data reinforce the knowledge about the vascular tropism of apple supplementation and underscore their ability to improve both cardiovascular and metabolic alterations in a mouse model of atherosclerosis.
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http://dx.doi.org/10.3390/biomedicines8110495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697153PMC
November 2020

The European NAFLD Registry: A real-world longitudinal cohort study of nonalcoholic fatty liver disease.

Contemp Clin Trials 2020 11 9;98:106175. Epub 2020 Oct 9.

Sorbonne Université, Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France.

Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS 'Liver Investigation: Testing Marker Utility in Steatohepatitis' consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace.
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http://dx.doi.org/10.1016/j.cct.2020.106175DOI Listing
November 2020

Evaluation of the Hepatorenal B-Mode Ratio and the "Controlled Attenuation Parameter" for the Detection and Grading of Steatosis.

Ultraschall Med 2020 Sep 29. Epub 2020 Sep 29.

Department of Radiology, University Hospital Centre Angers, France.

Purpose:  The aim of this study was to evaluate the hepatorenal index ratio of Supersonic Imagine (B-mode ratio) and the controlled attenuation parameter (CAP) of FibroScan for the noninvasive diagnosis and grading of steatosis.

Materials And Methods:  Two centers prospectively included patients who underwent liver biopsy, B-mode ratio and CAP evaluation all on the same day between June 2017 and July 2019. MRI and histological morphometry were also performed in center 1. Histology (classic semiquantitative score and morphometry) was used as the reference.

Results:  Concerning the B-mode ratio, the AUROCs for ≥ S1, ≥ S2 and ≥ S3 were respectively 0.896 ± 0.20, 0.775 ± 0.30 and 0.729 ± 0.39 with the best cut-off values being 1.22 for ≥ S1 (Se = 76.4 %, Sp = 93.2 %), 1.42 for ≥ S2 (Se = 70.2 %, Sp = 71.2 %) and 1.54 for ≥ S3 (Se = 68.4 %, Sp = 69.8 %). The correlation between the B-mode ratio and morphometry was moderate (Rs = 0.575, p < 0.001) and the correlation between the B-mode ratio and MRI was good (Rs = 0.613, p < 0.001). Concerning the CAP, the AUROCs for ≥  S1, ≥ S2 and ≥ S3 were 0.926 ± 0.18, 0.760 ± 0.30 and 0.701 ± 0.40, respectively, with the best cut-off values being 271 dB/m for ≥ S1 (Se = 84 %, Sp = 88.2 %), 331 dB/m for ≥ S2 (Se = 64.5 %, Sp = 74.7 %) and 355 dB/m for ≥ S3 (Se = 55.3 %, Sp = 75.1 %). The correlation between the CAP and morphometry and between the CAP and MRI was moderate in both cases (Rs = 0.526, p < 0.001 and Rs = 0.397, p < 0.001, respectively). The B-mode ratio was better at ruling in and the CAP was better at ruling out the disease.

Conclusion:  B-mode ratio and CAP show similar and good performance for the diagnosis of steatosis (≥ S1). However, both techniques are limited with respect to differentiating mild to moderate (≥ S2) or severe (≥ S3) steatosis.
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http://dx.doi.org/10.1055/a-1233-2290DOI Listing
September 2020

Non-selective beta-blockers increase overall and liver mortality in alcoholic cirrhosis with MELD ≥ 12 over 5 years of follow-up.

Liver Int 2021 01;41(1):168-179

Liver-Gastroenterology Department, University Hospital, HIFIH Laboratory, Angers University, Angers, France.

Background & Aims: Non-cardioselective beta-blocker (NSBB) effects on mortality in cirrhosis are controversial. We evaluated the impact of NSBBs on mortality according to liver severity and mortality cause.

Methods: Two hundred and fifty-eight patients with alcoholic cirrhosis were included in a retroprospective cohort: 129 NSBB-treated and 129 controls. The NSBB group had the following significant baseline differences: higher MELD, more frequent previous gastrointestinal bleeding, large oesophageal varices (OV) and lower heart rate. Propranolol dose was 160 mg/d in 81% of NSBB patients.

Results: (i) Liver function: during 5.3 ± 2.6 years of follow-up, MELD progression was higher in NSBB patients: 1 (-1-4) than in controls: 0 (-1-1) (P = .017). (ii) Overall survival: no significant differences were observed between NSBBs and controls (Kaplan-Meier curves: P = .291). In multivariate Cox analysis, baseline MELD interacted with NSBB (P = .011). Thus, the NSBB hazard ratio (HR) was 0.99 (0.50-1.98) in MELD < 12 vs 3.17 (1.19-8.42) in MELD ≥ 12. (iii) Liver survival: NSBB decreased liver survival (Kaplan-Meier: P = .031). In multivariate Cox analysis, baseline MELD interacted with NSBB (P < .001). The NSBB HR was 0.81 (0.30-2.19) in MELD < 12 vs 6.23 (1.94-20.0) in MELD ≥ 12. In competing risk multivariate analysis for liver mortality, the MELD-NSBB interaction was significant (P < .001): the NSBB HR was 1.02 (0.36-2.91) in MELD < 12 vs 9.24 (3.18-26.9) in MELD ≥ 12. 4) Non-liver survival: contrastingly, non-liver survival was increased by NSBBs, especially in MELD ≥ 12 (competing Kaplan-Meier: P = .044). These results were confirmed in propensity risk score (PRS)-matched patients.

Conclusion: In alcoholic cirrhosis with rather high propranolol doses, overall and liver survival are significantly aggravated when MELD is ≥12.
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http://dx.doi.org/10.1111/liv.14674DOI Listing
January 2021

Prognostic accuracy of FIB-4, NAFLD fibrosis score and APRI for NAFLD-related events: A systematic review.

Liver Int 2021 02;41(2):261-270

Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background & Aims: Fibrosis is the strongest predictor for long-term clinical outcomes among patients with non-alcoholic fatty liver disease (NAFLD). There is growing interest in employing non-invasive methods for risk stratification based on prognosis. FIB-4, NFS and APRI are models commonly used for detecting fibrosis among NAFLD patients. We aimed to synthesize existing literature on the ability of these models in prognosticating NAFLD-related events.

Methods: A sensitive search was conducted in two medical databases to retrieve studies evaluating the prognostic accuracy of FIB-4, NFS and APRI among NAFLD patients. Target events were change in fibrosis, liver-related event and mortality. Two reviewers independently performed reference screening, data extraction and quality assessment (QUAPAS tool).

Results: A total of 13 studies (FIB-4:12, NFS: 11, APRI: 10), published between 2013 and 2019, were retrieved. All studies were conducted in a secondary or tertiary care setting, with follow-up ranging from 1 to 20 years. All three markers showed consistently good prognostication of liver-related events (AUC from 0.69 to 0.92). For mortality, FIB-4 (AUC of 0.67-0.82) and NFS (AUC of 0.70-0.83) outperformed APRI (AUC of 0.52-0.73) in all studies. All markers had inconsistent performance for predicting change in fibrosis stage.

Conclusions: FIB-4, NFS, and APRI have demonstrated ability to risk stratify patients for liver-related morbidity and mortality, with comparable performance to a liver biopsy, although more head-to-head studies are needed to validate this. More refined models to prognosticate NAFLD-events may further enhance performance and clinical utility of non-invasive markers.
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http://dx.doi.org/10.1111/liv.14669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898346PMC
February 2021

Accuracy of cytokeratin 18 (M30 and M65) in detecting non-alcoholic steatohepatitis and fibrosis: A systematic review and meta-analysis.

PLoS One 2020 11;15(9):e0238717. Epub 2020 Sep 11.

Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Introduction: Association between elevated cytokeratin 18 (CK-18) levels and hepatocyte death has made circulating CK-18 a candidate biomarker to differentiate non-alcoholic fatty liver from non-alcoholic steatohepatitis (NASH). Yet studies produced variable diagnostic performance. We aimed to provide summary estimates with increased precision for the accuracy of CK-18 (M30, M65) in detecting NASH and fibrosis among non-alcoholic fatty liver disease (NAFLD) adults.

Methods: We searched five databases to retrieve studies evaluating CK-18 against a liver biopsy in NAFLD adults. Reference screening, data extraction and quality assessment (QUADAS-2) were independently conducted by two authors. Meta-analyses were performed for five groups based on the CK-18 antigens and target conditions, using one of two methods: linear mixed-effects multiple thresholds model or bivariate logit-normal random-effects model.

Results: We included 41 studies, with data on 5,815 participants. A wide range of disease prevalence was observed. No study reported a pre-defined cut-off. Thirty of 41 studies provided sufficient data for inclusion in any of the meta-analyses. Summary AUC [95% CI] were: 0.75 [0.69-0.82] (M30) and 0.82 [0.69-0.91] (M65) for NASH; 0.73 [0.57-0.85] (M30) for fibrotic NASH; 0.68 (M30) for significant (F2-4) fibrosis; and 0.75 (M30) for advanced (F3-4) fibrosis. Thirteen studies used CK-18 as a component of a multimarker model.

Conclusions: For M30 we found lower diagnostic accuracy to detect NASH compared to previous meta-analyses, indicating a limited ability to act as a stand-alone test, with better performance for M65. Additional external validation studies are needed to obtain credible estimates of the diagnostic accuracy of multimarker models.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238717PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485872PMC
October 2020

Obstructive sleep apnea, chronic obstructive pulmonary disease and NAFLD: an individual participant data meta-analysis.

Sleep Med 2021 01 22;77:357-364. Epub 2020 Apr 22.

HP2 Laboratory, INSERM U1042, Grenoble Alpes University, Grenoble, France; EFCR Laboratory, Pole Thorax et Vaisseaux, Grenoble Alps University Hospital, Grenoble, France. Electronic address:

Rationale: Chronic intermittent hypoxia occurring in obstructive sleep apnea (OSA) is independently associated with nonalcoholic fatty liver disease (NAFLD). Chronic obstructive pulmonary disease (COPD) has also been suggested to be linked with liver disease.

Objective: In this individual participant data meta-analysis, we investigated the association between liver damage and OSA and COPD severity.

Methods And Measurements: Patients suspected of OSA underwent polysomnography (PSG) or home sleep apnea testing (HSAT). Non-invasive tests were used to evaluate liver steatosis (Hepatic Steatosis Index) and fibrosis (Fibrotest or FibroMeter). An individual participant data meta-analysis approach was used to determine if the severity of OSA/COPD affects the type and severity of liver disease. Results were confirmed by multivariate and causal mediation analysis. Sub-group analyses were performed to investigate specific populations.

Main Results: Among 2120 patients, 1584 had steatosis (75%). In multivariable analysis, risk factors for steatosis were an apnea-hypopnea index (AHI) > 5/h, body mass index (BMI) > 26 kg/m, age, type 2 diabetes (all p-values <0.01) and male gender (p = 0.02). Concerning fibrosis, among 2218 patients 397 had fibrosis (18%). Risk factors associated with fibrosis were BMI>26 kg/m, age, male gender, and type 2 diabetes (all p-values <0.01). AHI severity was not associated with fibrosis. A combination of AHI >30/h and COPD stage 1 was associated with an increased risk of steatosis.

Conclusion: This meta-analysis confirms the strong association between steatosis and the severity of OSA. The relation between OSA and fibrosis is mainly due to BMI as shown by causal mediation analysis.
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http://dx.doi.org/10.1016/j.sleep.2020.04.004DOI Listing
January 2021
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