Publications by authors named "Philippe Mathurin"

207 Publications

Reply to HEP-21-0216 "Acute Liver Injury due to Therapeutic Doses of Acetaminophen - Confounders must be ruled out!"

Hepatology 2021 Feb 27. Epub 2021 Feb 27.

Hôpital Claude Huriez, Service d'Hépato-gastroentérologie, France.

We disagree with the conclusion of Vojjala et al., which states that clinicians should pay attention to metabolic risk factors, fatty liver and concurrent drug use. The authors questioned the presence of NAFLD in our study. However, the median BMI was normal in the patients admitted with ALITD and was not different from that of patients admitted with acetaminophen overdose: 21.9 vs. 22 kg/m , p=0.5. Therefore, the prevalence of metabolic syndrome was a rare event. Moreover, previous studies have not identified any relationship between BMI and the outcome or pattern of intoxication(1). Obesity was not found to have any impact on acetaminophen toxicity in the study by Radosevich et al.(2).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.31769DOI Listing
February 2021

Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases.

BMC Med 2021 Feb 17;19(1):39. Epub 2021 Feb 17.

Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.

Background: Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4α activity.

Methods: Factors regulating transferrin expression in alcoholic hepatitis (AH) were assessed via transcriptomic/methylomic analysis as well as chromatin immunoprecipitation coupled to DNA sequencing. The findings were corroborated in primary hepatocytes. Serum and liver samples from 40 patients with advanced liver disease of multiple etiologies were also studied.

Results: In patients with advanced liver disease, serum transferrin levels correlated with hepatic transferrin expression (r = 0.51, p = 0.01). Immunohistochemical and biochemical tests confirmed reduced HNF4α and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4α signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGFβ1), tumor necrosis factor α (TNFα), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) negatively associated with transferrin signature. A key regulatory region in transferrin promoter was hypermethylated in patients with AH. In primary hepatocytes, treatment with TGFβ1 or the HNF4α inhibitor BI6015 suppressed transferrin production, while exposure to TNFα, IL-1β, and IL-6 had no effect. The correlation between hepatic HNF4A and transferrin mRNA levels was also seen in advanced liver disease.

Conclusions: Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4α signaling and liver failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12916-021-01917-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887823PMC
February 2021

Early liver transplantation for corticosteroid non-responders with acute severe autoimmune hepatitis: The SURFASA score.

J Hepatol 2021 Jan 24. Epub 2021 Jan 24.

AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Inserm Unité 1193, Université Paris-Saclay, FHU Hépatinov, Centre de Référence Maladies Inflammatoires des Voies Biliaires et Hépatites Auto-immunes, Villejuif, France. Electronic address:

Background & Aims: In acute severe autoimmune hepatitis (AS-AIH), the optimal timing for liver transplantation (LT) remains controversial. The objectives of this study were to determine early predictive factors for a non-response to corticosteroids and to propose a score to identify patients in whom LT is urgently indicated.

Methods: This was a retrospective, multicenter study (2009-2016). A diagnosis of AS-AIH was based on: i) Definite or probable AIH based on the simplified IAIHG score; ii) international normalized ratio (INR) ≥1.5 and/or bilirubin >200 μmol/L; iii) No previous history of AIH; iv) Histologically proven AIH. A treatment response was defined as LT-free survival at 90 days. The evolution of variables from corticosteroid initiation (day-D0) to D3 was estimated from: Δ%3 = (D3-D0)/D0.

Results: A total of 128 patients were included, with a median age of 52 (39-62) years; 72% were female. Overall survival reached 88%. One hundred and fifteen (90%) patients received corticosteroids, with a LT-free survival rate of 66% at 90 days. Under multivariate analysis, D0-INR (odds ratio [OR] 6.85; 95% CI 2.23-21.06; p <0.001), Δ%3-INR ≥0.1% (OR 6.97; 95% CI 1.59-30.46; p <0.01) and Δ%3-bilirubin ≥-8% (OR 5.14; 95% CI 1.09-24.28; p <0.04) were predictive of a non-response. The SURFASA score: -6.80+1.92∗(D0-INR)+1.94∗(Δ%3-INR)+1.64∗(Δ%3-bilirubin), created by combining these variables, was highly predictive of LT or death (AUC = 0.93) (88% specificity; 84% sensitivity) with a cut-off point of <-0.9. Below this cut-off, the chance of responding was 75%. With a score higher than 1.75, the risk of dying or being transplanted was between 85% and 100%.

Conclusion: In patients with AS-AIH, INR at the introduction of corticosteroids and the evolution of INR and bilirubin are predictive of LT or death. Within 3 days of initiating corticosteroids, the SURFASA score can identify non-responders who require a referral for LT. This score needs to be validated in a prospective cohort.

Lay Summary: The management of patients with acute severe autoimmune hepatitis is highly challenging, particularly regarding their early referral for liver transplantation. We found that international normalized ratio at the initiation of corticosteroid therapy and the evolution of international normalized ratio and bilirubin values after 3 days of therapy were highly predictive of liver transplantation or death. We are thus proposing a score that combines these variables and identifies patients in whom liver transplantation is urgently required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2020.12.033DOI Listing
January 2021

Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus.

World J Hepatol 2020 Dec;12(12):1326-1340

U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France.

Background: The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use.

Aim: To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated untreated hepatitis B virus (HBV)-monoinfected patients.

Methods: A prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher's exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors.

Results: Of the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% 30.7%, 0.42 and 50.0% 30.7%, = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group the naïve group (hazard ratio: 2.283, = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo.

Conclusion: The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4254/wjh.v12.i12.1326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772739PMC
December 2020

"Dual aetiology fatty liver disease": A recently proposed term associated with potential pitfalls.

J Hepatol 2021 Apr 16;74(4):979-982. Epub 2020 Dec 16.

CHRU de Lille, Service des maladies de l'appareil digestif, Université Lille 2 and Inserm U995, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2020.11.004DOI Listing
April 2021

Acute Liver Injury With Therapeutic Doses of Acetaminophen: A Prospective Study.

Hepatology 2020 Dec 11. Epub 2020 Dec 11.

Service des Maladies de l'appareil digestif, Hôpital Huriez, CHU de Lille, Lille, France.

Background And Aims: Because of the extensive use of this drug, further evaluation of acute liver injury (ALI) with therapeutic doses of acetaminophen (APAP; ≤6 g/d) is required. We characterize ALI with therapeutic doses of APAP and determine the host factors associated with disease severity and the predictors of outcome.

Approach And Results: All patients admitted with severe APAP-related ALI in our center were included from 2002 to 2019, either attributable to therapeutic doses or overdose. ALI with therapeutic doses (ALITD) was defined as APAP intake <6 g/d. Overall, 311 of 400 patients with APAP-related ALI had overdose and 89 had taken therapeutic doses. The host factors associated with ALITD were fasting ≥1 day (47.5% of ALITD patients vs. 26% in overdose; P = 0.001), excess drinking (93.3% vs. 48.5%; P < 0.0001), and repeated APAP use (4 vs. 1 day; P < 0.0001). Patients with ALITD were older (44 vs. 30.7 years; P < 0.0001) and had more severe liver injury. In the overall population, the independent predictors of disease severity were older age, longer duration of APAP, and excess drinking. Thirty-day survival was lower in ALITD than in overdose (87.2 ± 3.6% vs. 94.6 ± 1.3%; P = 0.02). Age and the presence of at least one of the King's College Hospital criteria were independent predictors of 30-day survival whereas the pattern of drug intoxication, excess drinking, and bilirubin were not.

Conclusions: ALI with therapeutic doses of APAP is associated with more severe liver injury than overdose. It only occurs in patients with excess drinking and/or fasting. A warning should be issued about the repeated use of nontoxic doses of APAP in patients with those risk factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.31678DOI Listing
December 2020

Consequences of TIPSS placement on the body composition of patients with cirrhosis and severe portal hypertension: a large retrospective CT-based surveillance.

Aliment Pharmacol Ther 2020 11 15;52(9):1516-1526. Epub 2020 Sep 15.

Service des maladies de l'appareil digestif, Hôpital Claude Huriez, CHU Lille, Lille, France.

Background: Body composition may be modified after improvement of portal hypertension (PHT) by transjugular intrahepatic portosystemic shunt (TIPSS) insertion.

Aims: To evaluate changes in body composition following TIPSS placement, their relationship with radiological TIPSS patency and function, and the predictive value of these parameters METHODS: We retrospectively included 179 patients with cirrhosis who underwent TIPSS placement in our centre for severe PHT from 2011 to 2017. CT scan-based surveillance was performed at baseline, 1-3 (M1-M3) and 6 months (M6).

Results: The median model for end-stage liver disease (MELD) score was 11.4 (8.8-15.1) and Child-Pugh score 8 (7-9). Only the MELD score (HR 1.14, 95% CI 1.08-1.20) and sarcopenia assessed by transversal right psoas muscle thickness at the umbilical level/height (TPMPT/height) (HR 0.86, 95% CI 0.79-0.96) were independently associated with 6-month mortality on multivariate analysis. After TIPSS insertion, TPMT/height increased from 19 mm/m (baseline) to 19.6 mm/m (M1-M3, P = 0.004) and 21.1 mm/m (M6, P < 0.0001). The improvement and its extent were dependent on the radiological patency and dysfunction of TIPSS. Subcutaneous fat surface (SCFS) increased from 183.4 to 193 cm (P < 0.0001) and 229.8 cm (P < 0.0001), respectively. We observed a decrease in visceral fat surface (VFS) between baseline and M1-M3 (163.5-140.5 cm [P < 0.0001]), but not between M1-M3 and M6 (140.5-141.2 cm [P = 0.9]). SCFS and VFS did not seem to be modified by radiological TIPSS patency and dysfunction.

Conclusions: Sarcopenia is independently associated with 6-month outcome and improves after TIPSS placement, together with an inverse evolution of subcutaneous and visceral fat. TIPSS not only treats PHT but also improves body composition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apt.16080DOI Listing
November 2020

A tool to predict progression of non-alcoholic fatty liver disease in severely obese patients.

Liver Int 2021 01;41(1):91-100

Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France.

Background & Aims: Severely obese patients are a growing population at risk of non-alcoholic fatty liver disease (NAFLD). Considering the increasing burden, a predictive tool of NAFLD progression would be of interest. Our objective was to provide a tool allowing general practitioners to identify and refer the patients most at risk, and specialists to estimate disease progression and adapt the therapeutic strategy.

Methods: This predictive tool is based on a Markov model simulating steatosis, fibrosis and non-alcoholic steatohepatitis (NASH) evolution. This model was developped from data of 1801 severely obese, bariatric surgery candidates, with histological assessment, integrating duration of exposure to risk factors. It is then able to predict current disease severity in the absence of assessment, and future cirrhosis risk based on current stage.

Results: The model quantifies the impact of sex, body-mass index at 20, diabetes, age of overweight onset, on progression. For example, for 40-year-old severely obese patients seen by the general practitioners: (a) non-diabetic woman overweight at 20, and (b) diabetic man overweight at 10, without disease assessment, the model predicts their current risk to have NASH or F3-F4: for (a) 5.7% and 0.6%, for (b) 16.1% and 10.0% respectively. If those patients have been diagnosed F2 by the specialist, the model predicts the 5-year cirrhosis risk: 1.8% in the absence of NASH and 6.0% in its presence for (a), 10.3% and 26.7% respectively, for (b).

Conclusions: This model provides a decision-making tool to predict the risk of liver disease that could help manage severely obese patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.14650DOI Listing
January 2021

Obesity, Diabetes, Coffee, Tea, and Cannabis Use Alter Risk for Alcohol-Related Cirrhosis in 2 Large Cohorts of High-Risk Drinkers.

Am J Gastroenterol 2021 01;116(1):106-115

Drug Health Services, Royal Prince Alfred Hospital, Camperdown, Australia.

Introduction: Sustained high alcohol intake is necessary but not sufficient to produce alcohol-related cirrhosis. Identification of risk factors, apart from lifetime alcohol exposure, would assist in discovery of mechanisms and prediction of risk.

Methods: We conducted a multicenter case-control study (GenomALC) comparing 1,293 cases (with alcohol-related cirrhosis, 75.6% male) and 754 controls (with equivalent alcohol exposure but no evidence of liver disease, 73.6% male). Information confirming or excluding cirrhosis, and on alcohol intake and other potential risk factors, was obtained from clinical records and by interview. Case-control differences in risk factors discovered in the GenomALC participants were validated using similar data from 407 cases and 6,573 controls from UK Biobank.

Results: The GenomALC case and control groups reported similar lifetime alcohol intake (1,374 vs 1,412 kg). Cases had a higher prevalence of diabetes (20.5% (262/1,288) vs 6.5% (48/734), P = 2.27 × 10-18) and higher premorbid body mass index (26.37 ± 0.16 kg/m2) than controls (24.44 ± 0.18 kg/m2, P = 5.77 × 10-15). Controls were significantly more likely to have been wine drinkers, coffee drinkers, smokers, and cannabis users than cases. Cases reported a higher proportion of parents who died of liver disease than controls (odds ratio 2.25 95% confidence interval 1.55-3.26). Data from UK Biobank confirmed these findings for diabetes, body mass index, proportion of alcohol as wine, and coffee consumption.

Discussion: If these relationships are causal, measures such as weight loss, intensive treatment of diabetes or prediabetic states, and coffee consumption should reduce the risk of alcohol-related cirrhosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14309/ajg.0000000000000833DOI Listing
January 2021

Caution With the Use of Lopinavir/Ritonavir in Severely Ill Patients for the Treatment of SARS-CoV-2: A Report of Severe Jaundice.

Am J Gastroenterol 2020 10;115(10):1716-1718

Centre Hospitalier Universitaire Lille, Intensive Care Department, Lille, France.

Introduction: We investigated the potential hepatotoxicity of lopinavir/ritonavir recently used in the treatment of Severe Acute Respiratory Syndrome Coronavirus.

Methods: This is a retrospective cohort of critical patients in a teaching hospital: 12 treated with lopinavir/ritonavir and 30 in the standard-of-care group.

Results: Elevation occurred more frequently in patients treated with lopinavir/ritonavir (33% vs 6.7%).

Discussion: Caution is advised regarding the use of lopinavir/ritonavir in the most severe cases of Severe Acute Respiratory Syndrome Coronavirus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14309/ajg.0000000000000828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473797PMC
October 2020

Genome-wide association study and meta-analysis on alcohol-related liver cirrhosis identifies novel genetic risk factors.

Hepatology 2020 Aug 27. Epub 2020 Aug 27.

Drug Health Services, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, 2050, Australia.

Only a minority of heavy drinkers progress to alcohol-related cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy drinking subjects without known liver disease from Australia, the United States, the United Kingdom and three countries in Europe. Genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, BMI, diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in PNPLA3 (Odds Ratio (OR)=2.19 (G allele), p-value=4.93x10 ) and rs4607179 near HSD17B13 (OR=0.57 (C allele), p-value=1.09x10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a new protective association at rs374702773 in Fas Associated Factor family member 2 (FAF2) (OR=0.61 (del(T) allele), p-value=2.56x10 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR=0.79, p-value=0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the newly identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1, SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a new locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.31535DOI Listing
August 2020

Intestinal Virome in Patients With Alcoholic Hepatitis.

Hepatology 2020 12 10;72(6):2182-2196. Epub 2020 Oct 10.

Department of Medicine, University of California San Diego, La Jolla, CA.

Background And Aims: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD.

Approach And Results: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality.

Conclusions: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.31459DOI Listing
December 2020

Personalized surveillance for hepatocellular carcinoma in cirrhosis - using machine learning adapted to HCV status.

J Hepatol 2020 12 29;73(6):1434-1445. Epub 2020 Jun 29.

AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy; Université Paris 13, Sorbonne Paris Cité, "Equipe labellisée Ligue Contre le Cancer", F-93206 Saint-Denis; Inserm, UMR-1162, "Génomique fonctionnelle des tumeur solides", F-75000, Paris, France. Electronic address:

Background & Aims: Refining hepatocellular carcinoma (HCC) surveillance programs requires improved individual risk prediction. Thus, we aimed to develop algorithms based on machine learning approaches to predict the risk of HCC more accurately in patients with HCV-related cirrhosis, according to their virological status.

Methods: Patients with compensated biopsy-proven HCV-related cirrhosis from the French ANRS CO12 CirVir cohort were included in a semi-annual HCC surveillance program. Three prognostic models for HCC occurrence were built, using (i) Fine-Gray regression as a benchmark, (ii) single decision tree (DT), and (iii) random survival forest for competing risks survival (RSF). Model performance was evaluated from C-indexes validated externally in the ANRS CO22 Hepather cohort (n = 668 enrolled between 08/2012-01/2014).

Results: Out of 836 patients analyzed, 156 (19%) developed HCC and 434 (52%) achieved sustained virological response (SVR) (median follow-up 63 months). Fine-Gray regression models identified 6 independent predictors of HCC occurrence in patients before SVR (past excessive alcohol intake, genotype 1, elevated AFP and GGT, low platelet count and albuminemia) and 3 in patients after SVR (elevated AST, low platelet count and shorter prothrombin time). DT analysis confirmed these associations but revealed more complex interactions, yielding 8 patient groups with varying cancer risks and predictors depending on SVR achievement. On RSF analysis, the most important predictors of HCC varied by SVR status (non-SVR: platelet count, GGT, AFP and albuminemia; SVR: prothrombin time, ALT, age and platelet count). Externally validated C-indexes before/after SVR were 0.64/0.64 [Fine-Gray], 0.60/62 [DT] and 0.71/0.70 [RSF].

Conclusions: Risk factors for hepatocarcinogenesis differ according to SVR status. Machine learning algorithms can refine HCC risk assessment by revealing complex interactions between cancer predictors. Such approaches could be used to develop more cost-effective tailored surveillance programs.

Lay Summary: Patients with HCV-related cirrhosis must be included in liver cancer surveillance programs, which rely on ultrasound examination every 6 months. Hepatocellular carcinoma (HCC) screening is hampered by sensitivity issues, leading to late cancer diagnoses in a substantial number of patients. Refining surveillance periodicity and modality using more sophisticated imaging techniques such as MRI may only be cost-effective in patients with the highest HCC incidence. Herein, we demonstrate how machine learning algorithms (i.e. data-driven mathematical models to make predictions or decisions), can refine individualized risk prediction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2020.05.052DOI Listing
December 2020

Absence of impact of direct acting antivirals for hepatitis C virus on recurrent hepatocellular carcinoma tumor growth in the AFEF/ANRS CO22 Hepather cohort.

Clin Res Hepatol Gastroenterol 2021 Jan 25;45(1):101459. Epub 2020 Jun 25.

Hepatology Unit, Hôpital Cochin, AP-HP, 27, rue du Fg Saint-Jacques, 75014 Paris, France.

Background: Although it has now been excluded that direct-acting antivirals (DAA) are associated with a significant risk of hepatocellular carcinoma (HCC) in HCV-infected patients, a possible effect of DAA on tumor growth is still a subject of debate. We performed a blind comparison of the kinetics of HCC recurrence in patients after HCV treatment with or without DAA to evaluate the potential aggressiveness of HCC after DAA treatment.

Basic Procedures: Thirty-nine HCV-infected patients from the AFEF/ANRS CO22 Hepather cohort who experienced HCC recurrence after so-called curative treatment were evaluated. Contrast-enhanced CT and/or MR images were read blindly 6 months before HCC recurrence and during the follow-up period. Seventeen patients who received DAA (DAA+) before HCC recurrence were compared to the 22 who did not receive (DAA-), according to the LiRads and mRECIST criteria.

Main Findings: There were 28 men and 11 women, median age 62 years old, 37 (95%) with cirrhosis. DAA+ patients had a lower median MELD score (8±2 vs. 10±4, P=0.0286) than DAA- patients. The median time to HCC recurrence (time from the date of curative treatment to the diagnosis of recurrence) was not different (20 vs. 18 months) (P=0.73) between the two groups. There was no difference between the 2 groups in the overall survival and/or transplantation-free survival (P=0.71) and for the mRECIST time to progression (P=0.25).

Conclusion: This blinded analysis of HCC recurrence after HCC treatment does not support any negative impact of DAA therapy on the severity or progression of recurrent HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinre.2020.04.022DOI Listing
January 2021

Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis.

Gastroenterology 2020 10 15;159(4):1290-1301.e5. Epub 2020 Jun 15.

Service des Maladies de l'Appareil Digestif et de la Nutrition, Centre Hospitalier Universitaire de Lille, Lille, France; LIRIC (Lille Inflammation Research International Center) U995, Université de Lille, Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Universitaire de Lille, Lille, France. Electronic address:

Background And Aims: Studies are needed to determine the long-term effects of bariatric surgery for patients with nonalcoholic steatohepatitis (NASH). We evaluated sequential liver samples, collected the time of bariatric surgery and 1 and 5 years later, to assess the long-term effects of bariatric surgery in patients with NASH.

Methods: We performed a prospective study of 180 severely obese patients with biopsy-proven NASH, defined by the NASH clinical research network histologic scores. The patients underwent bariatric surgery at a single center in France and were followed for 5 years. We obtained liver samples from 125 of 169 patients (76%) having reached 1 year and 64 of 94 patients (68%) having reached 5 years after surgery. The primary endpoint was the resolution of NASH without worsening of fibrosis at 5 years. Secondary end points were improvement in fibrosis (reduction of ≥1 stage) at 5 years and regression of fibrosis and NASH at 1 and 5 years.

Results: At 5 years after bariatric surgery, NASH was resolved, without worsening fibrosis, in samples from 84% of patients (n = 64; 95% confidence interval, 73.1%-92.2%). Fibrosis decreased, compared with baseline, in samples from 70.2% of patients (95% CI, 56.6%-81.6%). Fibrosis disappeared from samples from 56% of all patients (95% CI, 42.4%-69.3%) and from samples from 45.5% of patients with baseline bridging fibrosis. Persistence of NASH was associated with no decrease in fibrosis and less weight loss (reduction in body mass index of 6.3 ± 4.1 kg/m in patients with persistent NASH vs reduction of 13.4 ± 7.4 kg/m; P = .017 with resolution of NASH). Resolution of NASH was observed at 1 year after bariatric surgery in biopsies from 84% of patients, with no significant recurrence between 1 and 5 years (P = .17). Fibrosis began to decrease by 1 year after surgery and continued to decrease until 5 years (P < .001).

Conclusions: In a long-term follow-up of patients with NASH who underwent bariatric surgery, we observed resolution of NASH in liver samples from 84% of patients 5 years later. The reduction of fibrosis is progressive, beginning during the first year and continuing through 5 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2020.06.006DOI Listing
October 2020

Real life experience of mycophenolate mofetil monotherapy in liver transplant patients.

Clin Res Hepatol Gastroenterol 2021 Jan 11;45(1):101451. Epub 2020 Jun 11.

Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France. Electronic address:

Background: Mycophenolate mofetil (MMF) monotherapy following liver transplantation (LT) remains controversial due to a risk of acute rejection. The aim of this study was to report the largest multicenter experience of the use a MMF monotherapy guided by therapeutic drug monitoring using pharmacoslope modeling and Bayesian estimations of the MPA inter-dose AUC (AUC) before withdrawing calcineurin inhibitors (CNI) and to evaluate the benefit of MMF monotherapy.

Methods: MMF daily doses were adjusted to reach the AUC target of 45μg.h/mL. Then CNI were withdrawn and patients were followed on liver test and clinical outcomes.

Main Findings: From 2000-2014, in 2 transplantation centers, 94 liver transplant recipients received MMF monotherapy 6.5±4 years after LT. The mean AUC was 45.5±16μg.h/mL. During follow-up, 4 patients experienced acute rejection (4%). During the first year, estimated glomerular filtration rate (eGFR) improved from 46.2±10.5 to 49.1±11.5mL/kg/min (P=0.025). Benefit persisted at year 5. In patients with metabolic syndrome, eGFR did not improve.

Conclusion: MMF monotherapy regimen appears usually safe and beneficial, with low risk of acute rejection and eGFR improvement. Therapeutic drug monitoring strategy seemed useful by identifying 14% of patients with low MMF exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinre.2020.04.017DOI Listing
January 2021

Combined alcoholic and non-alcoholic steatohepatitis.

JHEP Rep 2020 Jun 22;2(3):100101. Epub 2020 May 22.

Service des maladies de l'appareil digestif, Hôpital Huriez, Rue Polonowski, 59037 Lille Cedex, France.

While metabolic syndrome and alcohol consumption are the two main causes of chronic liver disease, one of the two conditions is often predominant, with the other acting as a cofactor of morbimortality. It has been shown that obesity and alcohol act synergistically to increase the risk of fibrosis progression, hepatic carcinogenesis and mortality, while genetic polymorphisms can strongly influence disease progression. Based on common pathogenic pathways, there are several potential targets that could be used to treat both diseases; based on the prevalence and incidence of these diseases, new therapies and clinical trials are needed urgently.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhepr.2020.100101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267467PMC
June 2020

Prevalence and Risk Factors of Nonalcoholic Fatty Liver Disease and Advanced Fibrosis in General Population: the French Nationwide NASH-CO Study.

Gastroenterology 2020 08 4;159(2):791-793.e2. Epub 2020 May 4.

Hepatogastroenterology Service, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2020.04.048DOI Listing
August 2020

Transcatheter aortic valve replacement (TAVR) as bridge therapy restoring eligibility for liver transplantation in cirrhotic patients.

Am J Transplant 2020 09 8;20(9):2567-2570. Epub 2020 Jul 8.

Department of Hepatogastroenterology, CHU Lille, Lille, France.

Severe aortic stenosis is a widespread valve disease, constituting a contraindication to organ transplantation due to cardiovascular morbidity and projected mortality. Mortality after conventional surgical aortic valve replacement in cirrhotic patients depends upon the Child-Pugh class. In the past few years, transcatheter aortic valve replacement has progressively become the treatment of choice for high-risk patients with severe aortic stenosis. Here, we report the cases of 3 cirrhotic patients who became eligible for liver transplantation after successful transcatheter aortic valve replacement as bridge therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajt.15955DOI Listing
September 2020

Liver transplantation in patients with alcohol-related liver disease: current status and future directions.

Lancet Gastroenterol Hepatol 2020 05;5(5):507-514

Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

The survival of patients with alcohol-related liver disease who receive a liver transplant has steadily improved to reach 80-85% at 1 year post-transplantation. The standard requirement for liver transplant-abstinence from alcohol for 6 months before transplantation-has been applied widely, but few data support the use of this rule as the sole criterion for selecting candidates for liver transplantation. When determining the suitability of a patient for transplantation, many liver transplant programmes now try to balance the period of abstinence against the risk of death associated with the severity of liver damage. Data accumulated since 2011 suggest that early liver transplantation (ie, transplantation without a specific period of abstinence) in patients with severe alcoholic hepatitis who do not respond to medical therapy is an effective therapeutic strategy. Further studies are needed to help refine the selection of patients with alcohol-related liver disease who have been abstinent for less than 6 months as suitable liver transplant candidates, and to improve the treatment of alcohol use disorder in those patients who have received a liver transplant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2468-1253(19)30451-0DOI Listing
May 2020

Serum Transferrin Is an Independent Predictor of Mortality in Severe Alcoholic Hepatitis.

Am J Gastroenterol 2020 03;115(3):398-405

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.

Objectives: Severe alcoholic hepatitis (sAH) confers substantial mortality, but the disease course is difficult to predict. As iron parameters are attractive outcome predictors in other liver diseases, we tested their prognostic ability in sAH.

Methods: Serum ferritin, transferrin, iron, transferrin saturation, nontransferrin-bound iron, soluble transferrin receptor, and hepcidin were measured in 828 patients with sAH recruited prospectively through the STOPAH trial. The cohort was randomly divided into exploratory (n = 200) and validation sets (n = 628).

Results: Patients with sAH had diminished serum transferrin but increased transferrin saturation. Among iron parameters, baseline transferrin was the best predictor of 28-day (area under the receiver operated characteristic 0.72 [95% confidence interval 0.67-0.78]) and 90-day survival (area under the receiver operated characteristic 0.65 [0.61-0.70]). Transferrin's predictive ability was comparable with the composite scores, namely model of end-stage liver disease, Glasgow alcoholic hepatitis score, and discriminant function, and was independently associated with survival in multivariable analysis. These results were confirmed in a validation cohort. Transferrin did not correlate with markers of liver synthesis nor with non-transferrin-bound iron or soluble transferrin receptor (as markers of excess unbound iron and functional iron deficiency, respectively).

Discussion: In patients with sAH, serum transferrin predicts mortality with a performance comparable with commonly used composite scoring systems. Hence, this routinely available parameter might be a useful marker alone or as a component of prognostic models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14309/ajg.0000000000000492DOI Listing
March 2020

IL-33/ST2 pathway regulates neutrophil migration and predicts outcome in patients with severe alcoholic hepatitis.

J Hepatol 2020 06 15;72(6):1052-1061. Epub 2020 Jan 15.

Hôpital Claude-Huriez, Service Maladies de l'Appareil Digestif, CHU Lille, Lille, France; Université de Lille/Inserm/CHU de Lille, U995 - LIRIC - Lille Inflammation Research Center, Lille, France. Electronic address:

Background & Aims: Severe alcoholic hepatitis (SAH) is associated with a high risk of infection. The IL-33/ST2 pathway is involved in sepsis control but data regarding its role in alcohol-related liver disease (ALD) are lacking. We aimed to characterize the role of IL-33/ST2 in the polymorphonuclear neutrophils (PMNs) of patients with ALD and SAH.

Methods: Serum and circulating neutrophils were collected from patients with SAH, alcoholic cirrhosis and healthy controls. We quantified IL-33/ST2 pathway activity and CXCR2 at baseline and after exposure to IL-33. We also determined the migration capacity of PMNs.

Results: The decoy receptor of IL-33 (soluble ST2 [sST2]) was increased in SAH vs. cirrhosis and controls, demonstrating the defect in this pathway during ALD. The sST2 level was associated with response to treatment, 2-month survival, infection-free survival and probability of infection in SAH. Endotoxemia was weakly correlated with sST2. GRK2, a negative regulator of CXCR2, was overexpressed in PMNs of patients with SAH and cirrhosis and was decreased by IL-33. CXCR2 levels on PMNs were lower in SAH vs. cirrhosis and controls. Treatment with IL-33 partially restored CXCR2 expression in SAH and cirrhosis. PMN migration upon IL-8 was lower in patients with SAH and cirrhosis vs. controls. Treatment with IL-33 partially restored migration in those with SAH and cirrhosis. Interestingly, the migration capacity of PMNs and the response to IL-33 were enhanced in responders to corticosteroids (Lille <0.45) compared to non-responders.

Conclusion: The IL33/ST2 pathway is defective in SAH and predicts outcome. This defect is associated with decreased CXCR2 expression on the surface of PMNs and lower migration capacity, which can be corrected by IL-33, especially in patients responding to steroids. These results suggest that IL-33 has therapeutic potential for SAH and its infectious complications.

Lay Summary: The neutrophils of patients with severe alcoholic hepatitis are associated with a defect in the IL-33/ST2 pathway. This defect is associated with lower migration capacities in neutrophils and a higher probability of getting infected. Administration of IL-33 to the neutrophils at least partly restores this defect and may be effective at reducing the risk of infection in patients with severe alcoholic hepatitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2019.12.017DOI Listing
June 2020

A Model to Identify Heavy Drinkers at High Risk for Liver Disease Progression.

Clin Gastroenterol Hepatol 2020 Sep 11;18(10):2315-2323.e6. Epub 2020 Jan 11.

Université de Lille, INSERM, Centre Hospitalier Universitaire de Lille, U1286-INFINITE, Lille, France; Université de Paris, IAME, INSERM, Paris, France. Electronic address:

Background & Aims: Alcohol-related liver disease (ALD) causes chronic liver disease. We investigated how information on patients' drinking history and amount, stage of liver disease, and demographic feature can be used to determine risk of disease progression.

Methods: We collected data from 2334 heavy drinkers (50 g/day or more) with persistently abnormal results from liver tests who had been admitted to a hepato-gastroenterology unit in France from January 1982 through December 1997; patients with a recorded duration of alcohol abuse were assigned to the development cohort (n=1599; 75% men) or the validation cohort (n=735; 75% men), based on presence of a liver biopsy. We collected data from both cohorts on patient history and disease stage at the time of hospitalization. For the development cohort, severity of the disease was scored by the METAVIR (due to the availability of liver histology reports); in the validation cohort only the presence of liver complications was assessed. We developed a model of ALD progression and occurrence of liver complications (hepatocellular carcinoma and/or liver decompensation) in association with exposure to alcohol, age at the onset of heavy drinking, amount of alcohol intake, sex and body mass index. The model was fitted to the development cohort and then evaluated in the validation cohort. We then tested the ability of the model to predict disease progression for any patient profile (baseline evaluation). Patients with a 5-y weighted risk of liver complications greater than 5% were considered at high risk for disease progression.

Results: Model results are given for the following patient profiles: men and women, 40 y old, who started drinking at an age of 25 y, drank 150 g/day, and had a body mass index of 22 kg/m according to the disease severity at baseline evaluation. For men with baseline F0-F2 fibrosis, the model estimated the probabilities of normal liver, steatosis, or steatohepatitis at baseline to be 31.8%, 61.5% and 6.7%, respectively. The 5-y weighted risk of liver complications was 1.9%, ranging from 0.2% for men with normal liver at baseline evaluation to 10.3% for patients with steatohepatitis at baseline. For women with baseline F0-F2 fibrosis, probabilities of normal liver, steatosis, or steatohepatitis at baseline were 25.1%, 66.5% and 8.4%, respectively; the 5-y weighted risk of liver complications was 3.2%, ranging from 0.5% for women with normal liver at baseline to 14.7% for patients with steatohepatitis at baseline. Based on the model, men with F3-F4 fibrosis at baseline have a 24.5% 5-y weighted risk of complications (ranging from 20.2% to 34.5%) and women have a 30.1% 5-y weighted risk of complications (ranging from 24.7% to 41.0%).

Conclusions: We developed a Markov model that integrates data on level and duration of alcohol use to identify patients at high risk of liver disease progression. This model might be used to adapt patient care pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cgh.2019.12.041DOI Listing
September 2020

Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting.

Gut 2020 04 26;69(4):764-780. Epub 2019 Dec 26.

Department of Metabolism, Faculty of Medicine, Imperial College, London, UK.

Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area.In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver International Liver Congress in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2019-319720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236084PMC
April 2020

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.

Lancet 2019 12 5;394(10215):2184-2196. Epub 2019 Dec 5.

Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA. Electronic address:

Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH.

Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6.

Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group).

Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.

Funding: Intercept Pharmaceuticals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(19)33041-7DOI Listing
December 2019

Meeting Report: The Dallas Consensus Conference on Liver Transplantation for Alcohol Associated Hepatitis.

Liver Transpl 2020 01;26(1):127-140

Baylor University Medical Center, Dallas, TX.

Liver transplantation (LT) for alcohol associated hepatitis (AH) remains controversial. We convened a consensus conference to examine various aspects of LT for AH. The goal was not to unequivocally endorse LT for AH; instead, it was to propose recommendations for programs that perform or plan to perform LT for AH. Criteria were established to determine candidacy for LT in the setting of AH and included the following: (1) AH patients presenting for the first time with decompensated liver disease that are nonresponders to medical therapy without severe medical or psychiatric comorbidities; (2) a fixed period of abstinence prior to transplantation is not required; and (3) assessment with a multidisciplinary psychosocial team, including a social worker and an addiction specialist/mental health professional with addiction and transplantation expertise. Supporting factors included lack of repeated unsuccessful attempts at addiction rehabilitation, lack of other substance use/dependency, acceptance of diagnosis/insight with a commitment of the patient/family to sobriety, and formalized agreement to adhere to total alcohol abstinence and counseling. LT should be avoided in AH patients who are likely to spontaneously recover. Short-term and longterm survival comparable to other indications for LT must be achieved. There should not be further disparity in LT either by indication, geography, or other sociodemographic factors. Treatment of alcohol-use disorders should be incorporated into pre- and post-LT care. The restrictive and focused evaluation process described in the initial LT experience for AH worldwide may not endure as this indication gains wider acceptance at more LT programs. Transparency in the selection process is crucial and requires the collection of objective data to assess outcomes and minimize center variation in listing. Oversight of program adherence is important to harmonize listing practices and outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lt.25681DOI Listing
January 2020

Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.

Nature 2019 11 13;575(7783):505-511. Epub 2019 Nov 13.

Department of Medicine, University of California San Diego, La Jolla, CA, USA.

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-019-1742-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872939PMC
November 2019

Untreated alcohol use disorder in people who inject drugs (PWID) in France: a major barrier to HCV treatment uptake (the ANRS-FANTASIO study).

Addiction 2020 03 20;115(3):573-582. Epub 2019 Nov 20.

Service Universitaire d'Addictologie de Lyon (SUAL), CH Le Vinatier, Université de Lyon, Bron, France.

Background And Aims: Although people who inject drugs (PWID) are the core at-risk population in the hepatitis C virus (HCV) epidemic in industrialized countries, few initiate treatment. Alcohol use disorder (AUD), common within this population, has been identified as a barrier to HCV treatment uptake in the general population. We investigated whether the arrival of new and well-tolerated HCV treatments (direct-acting antivirals: DAA) has improved HCV treatment uptake in French PWID compared with former treatments (pegylated interferon-based treatments: Peg-IFN).

Design: Using discrete-time Cox proportional hazards models based on exhaustive care delivery data, we tested for associations between AUD (defined by AUD-related long-term illness status, diagnosis coding during hospitalization and/or AUD pharmacological treatment) and first HCV treatment delivery, after adjusting for gender, age, complementary universal health cover, liver disease severity and type of opioid agonist therapy (OAT) received. Separate analyses were performed for 2012-13 (Peg-IFN era) and 2014-16 (DAA era).

Setting: France.

Participants: All French people chronically HCV-infected who received OAT at least once during 2012-16 and were covered by the national health insurance (n = 24 831).

Measurements: Incidence rate of HCV treatment uptake, hazard ratios associated with AUD and other covariates.

Findings: Incidence rate (IR) of HCV treatment uptake per 100 person-years was 6.56, confidence interval (CI) = 6.30-6.84; and IR = 5.70, 95% CI = 5.51-5.89 for Peg-IFN-based treatment (2012-13) and DAA (2014-16), respectively. After multiple adjustment, people with AUD not receiving related medication had 30 and 14% lower Peg-IFN-based treatment and DAA uptake, respectively, than those without AUD [hazard ratio (HR) = 0.70, 95% CI = 0.62-0.80 and HR = 0.86, 95% CI = 0.78-0.94]. No difference was observed between those treated for AUD and those without AUD.

Conclusions: Despite the benefits of direct-acting antiviral treatment, untreated alcohol use disorder appears to remain a major barrier to hepatitis C virus treatment access for people who inject drugs in France.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/add.14820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027887PMC
March 2020

Editorial: when cirrhosis deserves haemodialysis-rethinking strategies. Authors' reply.

Aliment Pharmacol Ther 2019 08;50(4):457-458

Hôpital Claude Huriez, Service Maladies de l'Appareil Digestif and INSERM Unité 995, Lille, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apt.15366DOI Listing
August 2019