Early prediction of the impact of public health policies on obesity and lifetime risk of type 2 diabetes: A modelling approach.

OBJECTIVE: Help public health decision-making requires a better understanding of the dynamics of obesity and type 2 diabetes and an assessement of different strategies to decrease their burdens. METHODS: Based on 97,848 individual data, collected in the French Health, Health Care and Insurance Survey over 1998-2014, a Markov model was developed to describe the progression of being overweight to obesity, and the onset of type 2 diabetes. This model traces and predicts 2022-2027 burdens of obesity and type 2 diabetes, and lifetime risk of diabetes, according to different scenarios aiming at minimum to stabilize obesity at 5 years. RESULTS: Estimated risks of type 2 diabetes increase from 0.09% (normal weight) to 1.56% (obesity II-III). Compared to the before 1995 period, progression risks are estimated to have nearly doubled for obesity and tripled for type 2 diabetes. Consequently, over 2022-2027, the prevalence of obesity and type 2 diabetes will continue to increase from 17.3% to 18.2% and from 7.3% to 8.1%, respectively. Scenarios statibilizing obesity would require a 22%-decrease in the probability of move up (scenario 1) or a 33%-increase in the probability of move down (scenario 2) one BMI class. However, this stabilization will not affect the increase of diabetes prevalence whereas lifetime risk of diabetes would decrease (30.9% to 27.0%). Combining both scenarios would decrease obesity by 9.9%. Only the prevalence of obesity III shows early change able to predict the outcome of a strategy: for example, 6.7%-decrease at one year, 13.3%-decrease at two years with scenario 1 stabilizing obesity at 5 years. CONCLUSIONS: Prevalences of obesity and type 2 diabetes will still increase over the next 5 years. Stabilizing obesity may decrease lifetime risks of type 2 diabetes without affecting its short-term prevalence. Our study highlights that, to early assess the effectiveness of their program, public health policy makers should rely on the change in prevalence of obesity III.

Performance of non-invasive tests for liver fibrosis resolution after bariatric surgery.

BACKGROUND & AIMS: The value of non-invasive tests for monitoring the resolution of significant liver fibrosis after treatment is poorly investigated. We compared the performances of six non-invasive tests to predict the resolution of significant fibrosis after bariatric surgery. METHODS: Participants were individuals with obesity submitted to needle liver biopsy at the time of bariatric surgery, and 12 and/or 60 months after surgery. We calculated the fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), AST to platelet ratio index (APRI), Hepatic fibrosis score (HFS), Fibrotic NASH index (FNI), and Liver risk score (LRS) at each time point, and compared their performances for predicting significant fibrosis (F ≥ 2) and its resolution following surgery. RESULTS: At baseline, 2436 patients had liver biopsy, including 261 (10.7 %) with significant fibrosis. Overall, 672 patients had pre- and post-operative biopsies (564 at M12 and 328 at M60). The fibrosis stage decreased at M12 and M60 (p < 0.001 vs M0). Resolution of significant fibrosis occurred in 58/121 (47.9 %) at M12 and 32/50 (64 %) at M60. The mean value of all tests decreased after surgery, except for FIB-4. Performances for predicting fibrosis resolution was higher at M60 than at M12 for all tests, and maximal at M60 for FNI and LRS: area under the curve 0.843 (95%CI 0.71-0.95) and 0.92 (95%CI 0.84-1.00); positive likelihood ratio 3.75 (95 % CI 1.33-10.59) and 4.58 (95 % CI 1.65-12.70), respectively. CONCLUSIONS: Results showed the value and limits of non-invasive tests for monitoring the evolution of liver fibrosis after an intervention. Following bariatric surgery, the best performances to predict the resolution of significant fibrosis were observed at M60 with tests combining liver and metabolic traits, namely FNI and LRS.

The ubiquitin-like modifier FAT10 is induced in MASLD and impairs the lipid-regulatory activity of PPARα.

BACKGROUND AND AIMS: Peroxisome Proliferator-Activated Receptor α (PPARα) is a key regulator of hepatic lipid metabolism and therefore a promising therapeutic target against Metabolic-dysfunction Associated Steatotic Liver Diseases (MASLD). However, its expression and activity decrease during disease progression and several of its agonists did not achieve sufficient efficiency in clinical trials with, surprisingly, a lack of steatosis improvement. Here, we identified the Human leukocyte antigen-F Adjacent Transcript 10 (FAT10) as an inhibitor of PPARα lipid metabolic activity during MASLD progression. APPROACH AND RESULTS: In vivo, the expression of FAT10 is upregulated in human and murine MASLD livers upon disease progression and correlates negatively with PPARα expression. The increase of FAT10 occurs in hepatocytes in which both proteins interact. FAT10 silencing in vitro in hepatocytes increases PPARα target gene expression, promotes fatty acid oxidation and decreases intra-cellular lipid droplet content. In line, FAT10 overexpression in hepatocytes in vivo inhibits the lipid regulatory activity of PPARα in response to fasting and agonist treatment in conditions of physiological and pathological hepatic lipid overload. CONCLUSIONS: FAT10 is induced during MASLD development and interacts with PPARα resulting in a decreased lipid metabolic response of PPARα to fasting or agonist treatment. Inhibition of the FAT10-PPARα interaction may provide a means to design potential therapeutic strategies against MASLD.

Conventional cytotoxic chemotherapy for gastrointestinal cancer in patients with cirrhosis: A multicentre case-control study.

BACKGROUND & AIMS: Progresses in management make a higher proportion of cirrhotic patients with gastrointestinal (GI) cancer candidates to chemotherapy. Data are needed on the safety and liver-related events associated with the use of chemotherapy in these patients. METHODS: Forty-nine patients with cirrhosis receiving chemotherapy against GI cancer from 2013 to 2018 were identified in the French Health Insurance Database using ICD-10 codes K70-K74, and matched 1:2 to non-cirrhotic controls (n = 98) on age, tumour type and type of treatment. Adverse events (AE), dose tapering, discontinuation rate, liver-related events and survival rate were compared. RESULTS: Patients with cirrhosis (Child-Pugh A 91%) more often received lower doses (38.8% vs 7.1%, p < .001), without significant differences in terms of grade 3/4 AE or dose tapering rates (29.6% vs. 36.7%; 22.3% vs 24.4%, respectively). Treatment discontinuation rate was higher in patients with cirrhosis (23.3% vs. 11.3%, p = .005). Child-Pugh (p = .007) and MELD (p = .025) scores increased under chemotherapy. Five patients with cirrhosis (10.2%) had liver decompensation within 12 months, and 17.2% of deaths in the cirrhosis group were liver-related versus 0% in matched controls. WHO-PS stage > 1 (HR 3.74, CI95%: 2.13-6.57, p < .001), TNM-stage M1 (HR 3.61, CI 95%: 1.82-7.16, p < .001), non-colorectal cancer (HR 1.73, CI 95%: 1.05-2.86, p = .032) and bilirubin higher than 5 mg/dL (HR 2.26, CI 95%: 1.39-3.70, p < .001) were independent prognostic factors of 2-year mortality, whereas cirrhosis was not. CONCLUSIONS: Chemotherapy should be proposed only in patients with compensated cirrhosis with close monitoring of liver function. Dose management remains challenging. Multidisciplinary management is warranted to improve these patients' outcomes.

Exploring the links between types 2 diabetes and liver-related complications: A comprehensive review.

In recent decades, the prevalence of type 2 diabetes has been steadily increasing, presenting a significant global public health challenge. These epidemiological trends can be attributed to significant lifestyle changes in modern societies, characterized by sedentary behavior and the consumption of hypercaloric, highly processed foods, along with the aging of the human population. As a result, it has become crucial for both public healthcare systems and healthcare providers to prioritize the management of diabetes and identify its systemic consequences. Emerging research has shed light on the links and risks between diabetes and liver events. This comprehensive review aims to explore the complex interplay between type 2 diabetes mellitus and liver-related outcomes, especially hepatocellular carcinoma and cirrhosis, offering insights into effective methods for detecting liver risk in individuals with diabetes. Additionally, the review will assess the various treatments that could hold the potential for positive outcomes in managing both diabetes and metabolic dysfunction-associated steatotic liver disease and liver fibrosis.

Time-of-day-dependent variation of the human liver transcriptome and metabolome is disrupted in MASLD.

Background & Aims: Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), and clock disruption increases susceptibility to MASLD progression in rodent models. We therefore investigated whether the time-of-day-dependent transcriptome and metabolome are significantly altered in human steatotic and MASH livers. Methods: Liver biopsies, collected within an 8 h-window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, steatotic or MASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, steatotic and MASH livers. Results: Herein, we provide a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in MASLD. Transcriptomic analysis showed a robustness of core molecular clock components in steatotic and MASH livers. It also revealed stage-specific, time-of-day-dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intracellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFα and PPARγ signaling were predicted as important contributors to altered rhythmicity. Conclusion: MASLD progression to MASH perturbs time-of-day-dependent processes in human livers, while the differential expression of core molecular clock components is maintained. Impact and implications: This work characterizes the rhythmic patterns of the transcriptome and metabolome in the human liver. Using a cohort of well-phenotyped patients (n = 290) for whom the time-of-day at biopsy collection was known, we show that time-of-day variations observed in histologically normal livers are gradually perturbed in liver steatosis and metabolic dysfunction-associated steatohepatitis. Importantly, these observations, albeit obtained across a restricted time window, provide further support for preclinical studies demonstrating alterations of rhythmic patterns in diseased livers. On a practical note, this study indicates the importance of considering time-of-day as a critical biological variable which may significantly affect data interpretation in animal and human studies of liver diseases.

Bariatric surgery and liver transplantation, here we are now: A French nationwide retrospective study.

At the time of the growing obesity epidemic worldwide, liver transplantation (LT) and metabolic syndrome are closely linked: non-alcohol-related fatty liver disease (NAFLD) is one of the leading indications for liver transplantation, and metabolic syndrome can also appear after liver transplantation, in relation to immunosuppressive medications and weight gain, whatever was the initial liver disease leading to the indication of LT. Therefore, the role of bariatric surgery (BS) is important due to its longer-lasting effect and efficacy. We performed a retrospective review of all 50 adult French liver transplant recipients who had a history of bariatric surgery, including 37 procedures before transplantation, and 14 after. There were three significantly different characteristics when comparing pre-and post-LT BS: patients were older (at the time of BS), presented more frequently arterial hypertension (at the time of LT), and the proportion of NAFLD as initial liver disease leading to LT was lower, in the post-LT group. Regarding pre-LT BS, in one case BS was complicated by liver failure leading to the rapid indication of LT; it was the single patient for whom the delay between BS and LT was less than 1 year; there was no patient who specifically underwent BS for the purpose of LT listing.

Inevitability of disease recurrence after liver transplantation for NAFLD cirrhosis.

Background & Aims: Liver transplantation (LT) is the only available treatment for end-stage non-alcoholic fatty liver disease (NAFLD) (related decompensated cirrhosis and/or hepatocellular carcinoma). The aim of our study was to evaluate the risk of disease recurrence after LT and the factors influencing it. Method: This retrospective multicenter study included adults transplanted for NAFLD cirrhosis between 2000 and 2019 in 20 participating French-speaking centers. Disease recurrence (steatosis, steatohepatitis and fibrosis) was diagnosed from liver graft biopsies. Results: We analyzed 150 patients with at least one graft liver biopsy available ≥6 months after transplantation, among 361 patients transplanted for NAFLD. The median (IQR) age at LT was 61.3 (54.4-64.6) years. The median follow-up after LT was 4.7 (2.8-8.1) years. The cumulative recurrence rates of steatosis and steatohepatitis at 5 years were 80.0% and 60.3%, respectively. Significant risk factors for steatohepatitis recurrence in multivariate analysis were recipient age at LT <65 years (odds ratio [OR] 4.214; p = 0.044), high-density lipoprotein-cholesterol <1.15 mmol/L after LT (OR 3.463; p = 0.013) and grade ≥2 steatosis on the graft at 1 year after LT (OR 10.196; p = 0.001). The cumulative incidence of advanced fibrosis (F3-F4) was 20.0% at 5 years after LT and significant risk factors from multivariate analysis were metabolic syndrome before LT (OR 8.550; p = 0.038), long-term use of cyclosporine (OR 11.388; p = 0.031) and grade ≥2 steatosis at 1 year after LT (OR 10.720; p = 0.049). No re-LT was performed for NAFLD cirrhosis recurrence. Conclusion: Our results strongly suggest that recurrence of initial disease after LT for NAFLD is inevitable and progressive in a large proportion of patients; the means to prevent it remain to be further evaluated. Impact and implications: Non-alcoholic fatty liver disease (NAFLD) is a growing indication for liver transplantation, but the analysis of disease recurrence, based on graft liver biopsies, has been poorly studied. Cumulative incidences of steatosis, steatohepatitis and NAFLD-related significant fibrosis recurrence at 5 years were 85.0%, 60.3% and 48.0%, respectively. Grade ≥2 steatosis on graft biopsy at 1 year (present in 25% of patients) is highly predictive of recurrence of steatohepatitis and advanced fibrosis: bariatric surgery should be discussed in these patients specifically.

Liver Transplantation in Alcohol-related Liver Disease and Alcohol-related Hepatitis.

Alcohol-related liver disease (ARLD) remains one of the leading causes of chronic liver disease and the prevalence of alcohol-related cirrhosis is still increasing worldwide. Thus, ARLD is one of the leading indications for liver transplantation (LT) worldwide especially after the arrival of direct-acting antivirals for chronic hepatitis C infection. Despite the risk of alcohol relapse, the outcomes of LT for ARLD are as good as for other indications such as hepatocellular carcinoma (HCC), with 1-, 5-, and 10- year survival rates of 85%, 74%, and 59%, respectively. Despite these good results, certain questions concerning LT for ARLD remain unanswered, in particular because of persistent organ shortages. As a result, too many transplantation centers continue to require 6 months of abstinence from alcohol for patients with ARLD before LT to reduce the risk of alcohol relapse even though compelling data show the poor prognostic value of this criterion. A recent pilot study even observed a lower alcohol relapse rate in patients receiving LT after less than 6 months of abstinence as long as addictological follow-up is reinforced. Thus, the question should not be whether LT should be offered to patients with ARLD but how to select patients who will benefit from this treatment.

Neo-Adjuvant Use of Sorafenib for Hepatocellular Carcinoma Awaiting Liver Transplantation.

Data on efficacy and safety of sorafenib in a neoadjuvant setting for HCC awaiting liver transplantation (LT) are heterogeneous and scarce. We aimed to investigate the trajectory of patients treated with sorafenib while awaiting LT. All patients listed for HCC and treated with sorafenib were included in a monocentric observational study. A clinical and biological evaluation was performed every month. Radiological tumor response evaluation was realized every 3 months on the waiting list and every 6 months after LT. Among 327 patients listed for HCC, 62 (19%) were treated with Sorafenib. Sorafenib was initiated for HCC progression after loco-regional therapy (LRT) in 50% of cases and for impossibility of LRT in 50% of cases. The mean duration of treatment was 6 months. Thirty six patients (58%) dropped-out for tumor progression and 26 (42%) patients were transplanted. The 5-year overall and recurrent-free survival after LT was 77% and 48% respectively. Patients treated for impossibility of LRT had acceptable 5-year intention-to-treat overall and post-LT survivals. Conversely, patients treated for HCC progression presented high dropout rate and low intention-to-treat survival. Our results suggest that it is very questionable in terms of utility that patients treated for HCC progression should even be kept listed once the tumor progression has been observed.

Are Cirrhotic Patients Receiving Invasive Mechanical Ventilation at Risk of Abundant Microaspiration.

Previous studies have identified cirrhosis as a risk factor for ventilator-associated pneumonia (VAP). The aim of our study was to determine the relationship between cirrhosis and abundant gastric-content microaspiration in intubated critically ill patients. We performed a matched cohort study using data from three randomized controlled trials on abundant microaspiration in patients under mechanical ventilation. Each cirrhotic patient was matched with three to four controls for gender, age ± 5 years and simplified acute physiology score II (SAPS II) ± 5 points. Abundant microaspiration was defined by significant levels of pepsin and alpha-amylase in >30% of tracheal aspirates. All tracheal aspirates were collected for the first 48 h of the study period. The percentage of patients with abundant gastric-content microaspiration was the primary outcome. The abundant microaspiration of oropharyngeal secretions, VAP incidence, the duration of mechanical ventilation, length of intensive care unit (ICU) stay and mortality were the secondary outcomes. A. total of 39 cirrhotic patients were matched to 138 controls. The percentage of patients with abundant gastric-content microaspiration did not differ between the two groups (relative risk: 0.91 (95% CI: 0.75 to 1.10)). There was no significant difference between the two groups in terms of the abundant microaspiration of oropharyngeal secretions, VAP, the duration of mechanical ventilation, the length of ICU stay and mortality. Our results suggest that cirrhosis is not associated with abundant gastric-content microaspiration.

Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis.

Tissue injury triggers activation of mesenchymal lineage cells into wound-repairing myofibroblasts, whose unrestrained activity leads to fibrosis. Although this process is largely controlled at the transcriptional level, whether the main transcription factors involved have all been identified has remained elusive. Here, we report multi-omics analyses unraveling Basonuclin 2 (BNC2) as a myofibroblast identity transcription factor. Using liver fibrosis as a model for in-depth investigations, we first show that BNC2 expression is induced in both mouse and human fibrotic livers from different etiologies and decreases upon human liver fibrosis regression. Importantly, we found that BNC2 transcriptional induction is a specific feature of myofibroblastic activation in fibrotic tissues. Mechanistically, BNC2 expression and activities allow to integrate pro-fibrotic stimuli, including TGFß and Hippo/YAP1 signaling, towards induction of matrisome genes such as those encoding type I collagen. As a consequence, Bnc2 deficiency blunts collagen deposition in livers of mice fed a fibrogenic diet. Additionally, our work establishes BNC2 as potentially druggable since we identified the thalidomide derivative CC-885 as a BNC2 inhibitor. Altogether, we propose that BNC2 is a transcription factor involved in canonical pathways driving myofibroblastic activation in fibrosis.

Benefits of tailored hepatocellular carcinoma screening in patients with cirrhosis on cancer-specific and overall mortality: A modeling approach.

To validate cancer screening programs, experts recommend estimating effects on case fatality rates (CFRs) and cancer-specific mortality. This study evaluates hepatocellular carcinoma (HCC) screening in patients with cirrhosis for those outcomes using a modeling approach. We designed a Markov model to assess 10-year HCC-CFR, HCC-related, and overall mortality per 100,000 screened patients with compensated cirrhosis. The model evaluates different HCC surveillance intervals (none, annual [12 months], semiannual [6 months], or quarterly [3 months]) and imaging modalities (ultrasound [US] or magnetic resonance imaging [MRI]) in various annual incidences (0.2%, 0.4%, or 1.5%). Compared to no surveillance, 6-month US reduced the 10-year HCC-CFR from 77% to 46%. With annual incidences of 0.2%, 0.4%, and 1.5%, the model predicted 281, 565, and 2059 fewer HCC-related deaths, respectively, and 187, 374, and 1356 fewer total deaths per 100,000 screened patients, respectively. Combining alpha-fetoprotein screening to 6-month US led to 32, 63, and 230 fewer HCC-related deaths per 100,000 screened patients for annual incidences of 0.2%, 0.4%, and 1.5%, respectively. Compared to 6-month US, 3-month US reduced cancer-related mortality by 14%, predicting 61, 123, and 446 fewer HCC-related deaths per 100,000 screened patients with annual incidences of 0.2%, 0.4%, and 1.5%, respectively. Compared to 6-month US, 6-month MRI (-17%) and 12-month MRI (-6%) reduced HCC-related mortality. Compared to 6-month US, overall mortality reductions ranged from -0.1% to -1.3% when using 3-month US or MRI. A US surveillance interval of 6 months improves HCC-related and overall mortality compared to no surveillance. A shorter US interval or using MRI could reduce HCC-CFR and HCC-related mortality, with a modest effect on overall mortality.

Liver transplantation for NAFLD cirrhosis: Age and recent coronary angioplasty are major determinants of survival.

BACKGROUND AND AIMS: Liver transplantation (LT) is the treatment of end-stage non-alcoholic liver disease (NAFLD), that is decompensated cirrhosis and/or complicated by hepatocellular carcinoma (HCC). Few data on long-term outcome are available. The aim of this study was to evaluate overall patient and graft survivals and associated predictive factors. METHOD: This retrospective multicentre study included adult transplant patients for NAFLD cirrhosis between 2000 and 2019 in participating French-speaking centres. RESULTS: A total of 361 patients (69.8% of male) were included in 20 centres. The median age at LT was 62.3 years [57.4-65.9] and the median MELD score was 13.9 [9.1-21.3]; 51.8% of patients had HCC on liver explant. Between 2004 and 2018, the number of LT for NAFLD cirrhosis increased by 720%. A quarter of the patients had cardiovascular history before LT. Median follow-up after LT was 39.1 months [15.8-72.3]. Patient survival at 1, 5 and 10 years after LT was 89.3%, 79.8% and 68.1% respectively. The main causes of death were sepsis (37.5%), malignancies (29.2%) and cardiovascular events (22.2%). In multivariate analysis, three risk factors for overall mortality after LT were recipient pre-LT BMI < 32 kg/m2 at LT time (OR: 2.272; p = .012), pre-LT angioplasty during CV check-up (OR: 2.916; p = .016), a combined donor and recipient age over 135 years (OR: 2.020; 95%CI: p = .035). CONCLUSION: Survival after LT for NAFLD cirrhosis is good at 5 years. Donor and recipient age, and cardiovascular history, are major prognostic factors to consider.

Morbid obesity increases death and dropout from the liver transplantation waiting list: A prospective cohort study.

Liver transplant (LT) candidates with a body mass index (BMI) over 40 kg/m2 have lower access to a liver graft without clear explanation. Thus, we studied the impact of obesity on the waiting list (WL) and aimed to explore graft proposals and refusal. METHOD: Data between January 2007 and December 2017 were extracted from the French prospective national database: CRISTAL. Competing risk analyses were performed to evaluate predictors of receiving LT. Competitive events were (1) death/WL removal for disease aggravation or (2) improvement. The link between grade obesity, grafts propositions, and reason for refusal was studied. RESULTS: 15,184 patients were analysed: 10,813 transplant, 2847 death/dropout for aggravation, 748 redirected for improvement, and 776 censored. Mortality/dropout were higher in BMI over 35 (18% vs. 14% 1 year after listing) than in other candidates. In multivariate analysis, BMI>35, age, hepatic encephalopathy, and ascites were independent predictors of death/dropout. Candidates with a BMI ≥ 35 kg/m2 had reduced access to LT, without differences in graft proposals. However, grafts refusal was more frequent especially for 'morphological incompatibility' (14.9% vs. 12.7% p < 0.01). CONCLUSION: BMI over 35 kg/m2 reduces access to LT with increased risk of dropout and mortality. Increased mortality and dropout could be due to a lower access to liver graft secondary to increased graft refusal for morphological incompatibility.

Lung Infection Affects Access to Treatment and Short-Term Outcome in Patients With Severe Alcohol-Related Hepatitis Treated With Corticosteroids.

INTRODUCTION: Severe alcohol-related hepatitis (AH) is associated with an increased risk of infection, but the impact of pneumonia has not been specifically analyzed in a specific cohort. METHODS: All patients admitted for severe AH between 2002 and 2020 were prospectively included. Systematic screening for infection was performed at admission and renewed in the case of clinical suspicion. RESULTS: We included 614 patients (60.4% men, mean age 49.9 years, median model for end-stage liver disease [MELD] 25.2, bilirubin 18.1 mg/dL), 202 (32.9%) with infections at admission (73 lung infections). Encephalopathy ( P = 0.006), MELD score ( P = 0.0002), and tobacco exposure (past vs never smokers: P = 0.002 or active vs past smokers: P = 0.005) were associated with lung infection at admission on multivariate analysis. Factors independently associated with death before steroid initiation were encephalopathy ( P = 0.003), MELD score ( P = 0.05), and especially lung infection ( P < 0.0001). Thus, patients with a lung infection had a lower probability of receiving steroids than those with other infections and noninfected patients: 54.8 vs 88.4 vs 98.1% ( P < 0.0001). One hundred forty-six of the 558 patients who received corticosteroids developed infection, including 57 (39.04%) pneumonias. The risk of respiratory and nonrespiratory infection was higher in nonresponders to steroids (Lille score ≥0.45) than in responders: 13% vs 7.6%, P = 0.03 and 27.9% vs 10.6%, P < 0.001, respectively. The variables independently associated with 3-month mortality after steroid initiation were lung infection ( P = 0.004), nonresponse to steroids ( P < 0.0001), MELD score ( P = 0.0003), ascites ( P = 0.003), and encephalopathy ( P = 0.018), whereas nonrespiratory infections were not ( P = 0.91). DISCUSSION: Lung infection is frequent during severe AH and influences mortality at admission and after steroid initiation. These results emphasize the need for specific management of lung infection during the course of AH.

Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study.

BACKGROUND: Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence. METHODS: We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794. FINDINGS: Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% [95% CI -∞ to 21·1]; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% [95% CI 5·8-27·6]) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 [95% CI -0·07 to 0·55]), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 [95% CI 0·17-0·82]). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio [HR] 0·87 [95% CI 0·33-2·26]); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 [95% CI 0·16-0·47] and 0·21 [0·13-0·32]). INTERPRETATION: We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis. FUNDING: The present study has been granted by the French Ministry of Health-Programme Hospitalier de Recherche Clinique 2010.

Loss of hepatocyte identity following aberrant YAP activation: A key mechanism in alcoholic hepatitis.

BACKGROUND & AIMS: Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, as the molecular mechanisms leading to death are not well understood. This study evaluates the Hippo/Yes-associated protein (YAP) pathway which has been shown to play a role in liver regeneration. METHOD: The Hippo/YAP pathway was dissected in explants of patients transplanted for AH or alcohol-related cirrhosis and in control livers, using RNA-seq, real-time PCR, western blot, immunohistochemistry and transcriptome analysis after laser microdissection. We transfected primary human hepatocytes with constitutively active YAP (YAPS127A) and treated HepaRG cells and primary hepatocytes isolated from AH livers with a YAP inhibitor. We also used mouse models of ethanol exposure (Lieber de Carli) and liver regeneration (carbon tetrachloride) after hepatocyte transduction of YAPS127A. RESULTS: In AH samples, RNA-seq analysis and immunohistochemistry of total liver and microdissected hepatocytes revealed marked downregulation of the Hippo pathway, demonstrated by lower levels of active MST1 kinase and abnormal activation of YAP in hepatocytes. Overactivation of YAP in hepatocytes in vitro and in vivo led to biliary differentiation and loss of key biological functions such as regeneration capacity. Conversely, a YAP inhibitor restored the mature hepatocyte phenotype in abnormal hepatocytes taken from patients with AH. In ethanol-fed mice, YAP activation using YAPS127A resulted in a loss of hepatocyte differentiation. Hepatocyte proliferation was hampered by YAPS127A after carbon tetrachloride intoxication. CONCLUSION: Aberrant activation of YAP plays an important role in hepatocyte transdifferentiation in AH, through a loss of hepatocyte identity and impaired regeneration. Thus, targeting YAP is a promising strategy for the treatment of patients with AH. LAY SUMMARY: Alcoholic hepatitis is characterized by inflammation and a life-threatening alteration of liver regeneration, although the mechanisms behind this have not been identified. Herein, we show that liver samples from patients with alcoholic hepatitis are characterized by profound deregulation of the Hippo/YAP pathway with uncontrolled activation of YAP in hepatocytes. We used human cell and mouse models to show that inhibition of YAP reverts this hepatocyte defect and could be a novel therapeutic strategy for alcoholic hepatitis.