Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH

A Histologic Scoring System for Prognosis of Patients With Alcoholic Hepatitis

There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90 day) mortality

Interstellar anatomy of the TeV gamma-ray peak in the IC443 supernova remnant★

International audienceContext. Supernova remnants (SNRs) represent a major feedback source from stars in the interstellar medium of galaxies. During the latest stage of supernova explosions, shock waves produced by the initial blast modify the chemistry of gas and dust, inject kinetic energy into the surroundings, and may alter star formation characteristics. Simultaneously, γ-ray emission is generated by the interaction between the ambient medium and cosmic rays (CRs), including those accelerated in the early stages of the explosion.Aims. We study the stellar and interstellar contents of IC443, an evolved shell-type SNR at a distance of 1.9 kpc with an estimated age of 30 kyr. We aim to measure the mass of the gas and characterize the nature of infrared point sources within the extended G region, which corresponds to the peak of γ-ray emission detected by VERITAS and Fermi.Methods. We performed 10′ × 10′ mapped observations of 12CO, 13CO J = 1–0, J = 2–1, and J = 3–2 pure rotational lines, as well as C18O J = 1–0 and J = 2–1 obtained with the IRAM 30 m and APEX telescopes over the extent of the γ-ray peak to reveal the molecular structure of the region. We first compared our data with local thermodynamic equilibrium models. We estimated the optical depth of each line from the emission of the isotopologs 13CO and C18O. We used the population diagram and large velocity gradient assumption to measure the column density, mass, and kinetic temperature of the gas using 12CO and 13CO lines. We used complementary data (stars, gas, and dust at multiple wavelengths) and infrared point source catalogs to search for protostar candidates.Results. Our observations reveal four molecular structures: a shocked molecular clump associated with emission lines extending between −31 and 16 km s−1, a quiescent, dark cloudlet associated with a line width of ~2 km s−1, a narrow ring-like structure associated with a line width of ~1.5 km s−1, and a shocked knot. We measured a total mass of ~230, ~90, ~210, and ~4 M⊙, respectively, for the cloudlet, ring-like structure, shocked clump, and shocked knot. We measured a mass of ~1100 M⊙ throughout the rest of the field of observations where an ambient cloud is detected. We found 144 protostar candidates in the region.Conclusions. Our results emphasize how the mass associated with the ring-like structure and the cloudlet cannot be overlooked when quantifying the interaction of CRs with the dense local medium. Additionally, the presence of numerous possible protostars in the region might represent a fresh source of CRs, which must also be taken into account in the interpretation of γ-ray observationsin this region

A Histologic Scoring System for Prognosis of Patients With Alcoholic Hepatitis

Background & Aims: There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90 day) mortality. Methods: We analyzed data from 121 patients admitted to the Liver Unit (Hospital Clinic, Barcelona, Spain) from January 2000 through January 2008 with features of AH, and developed a histologic scoring system to determine risk of death using logistic regression. The system was tested and updated in a test set of 96 patients from 5 academic centers in the US and Europe, and a semi-quantitative scoring system was developed, called the alcoholic hepatitis histologic score (AHHS). The system was validated in an independent set of 109 patients. Inter-observer agreement was evaluated by weighted statistic analysis. Results: Degree of fibrosis, neutrophil infiltration, type of bilirubinostasis, and presence mega-mitochondria were independently associated with 90 day mortality. We used these 4 parameters to develop the AHHS to identify patients with low (0–3 points), moderate (4–5 points), and high (6–9 points) risks of death within 90 days (3%, 19%, and 51%, respectively; P<.0001). The AHHS estimated 90 day mortality in the training and test sets with an area under the receiver operating characteristic value of 0.77 (95% confidence interval, 0.71–0.83). Inter-rate agreement values were 0.65 for fibrosis, 0.86 for bilirubinostasis, 0.60 for neutrophil infiltration, and 0.46 for megamitochondria. Interestingly, the type of bilirubinostasis predicted the development of bacterial infections. Conclusions: We identified histologic features associated with severity of AH and developed a patient classification system that might be used in clinical decision making

MELD 3.0 adequately predicts mortality and renal replacement therapy requirements in patients with alcohol-associated hepatitis

Model for End-Stage Liver Disease (MELD) score better predicts mortality in alcohol-associated hepatitis (AH) but could underestimate severity in women and malnourished patients. Using a global cohort, we assessed the ability of the MELD 3.0 score to predict short-term mortality in AH. This was a retrospective cohort study of patients admitted to hospital with AH from 2009 to 2019. The main outcome was all-cause 30-day mortality. We compared the AUC using DeLong's method and also performed a time-dependent AUC with competing risks analysis. A total of 2,124 patients were included from 28 centres from 10 countries on three continents (median age 47.2 ± 11.2 years, 29.9% women, 71.3% with underlying cirrhosis). The median MELD 3.0 score at admission was 25 (20-33), with an estimated survival of 73.7% at 30 days. The MELD 3.0 score had a better performance in predicting 30-day mortality (AUC:0.761, 95%CI:0.732-0.791) compared with MELD sodium (MELD-Na; AUC: 0.744, 95% CI: 0.713-0.775; p = 0.042) and Maddrey's discriminant function (mDF) (AUC: 0.724, 95% CI: 0.691-0.757; p = 0.013). However, MELD 3.0 did not perform better than traditional MELD (AUC: 0.753, 95% CI: 0.723-0.783; p = 0.300) and Age-Bilirubin-International Normalised Ratio-Creatinine (ABIC) (AUC:0.757, 95% CI: 0.727-0.788; p = 0.765). These results were consistent in competing-risk analysis, where MELD 3.0 (AUC: 0.757, 95% CI: 0.724-0.790) predicted better 30-day mortality compared with MELD-Na (AUC: 0.739, 95% CI: 0.708-0.770; p = 0.028) and mDF (AUC:0.717, 95% CI: 0.687-0.748; p = 0.042). The MELD 3.0 score was significantly better in predicting renal replacement therapy requirements during admission compared with the other scores (AUC: 0.844, 95% CI: 0.805-0.883). MELD 3.0 demonstrated better performance compared with MELD-Na and mDF in predicting 30-day and 90-day mortality, and was the best predictor of renal replacement therapy requirements during admission for AH. However, further prospective studies are needed to validate its extensive use in AH. Severe AH has high short-term mortality. The establishment of treatments and liver transplantation depends on mortality prediction. We evaluated the performance of the new MELD 3.0 score to predict short-term mortality in AH in a large global cohort. MELD 3.0 performed better in predicting 30- and 90-day mortality compared with MELD-Na and mDF, but was similar to MELD and ABIC scores. MELD 3.0 was the best predictor of renal replacement therapy requirements. Thus, further prospective studies are needed to support the wide use of MELD 3.0 in AH

Trajectory of Serum Bilirubin Predicts Spontaneous Recovery in a Real-World Cohort of Patients with Alcoholic Hepatitis.

BACKGROUND AND AIMS Alcoholic hepatitis (AH) is a severe condition with poor short-term prognosis. Specific treatment with corticosteroids slightly improves short-term survival but is associated with infection and is not used in many centers. A reliable method to identify patients who will recover spontaneously will minimise the numbers of patients who experience side effects of available treatments. METHODS We analysed the trajectory of serum bilirubin concentration over the course of hospital admissions in patients with AH to predict spontaneous survival and the need for treatment. RESULTS data from 426 patients were analysed. Based on bilirubin trajectory, patients were categorized into three groups: 'fast fallers' (bilirubin 0.9 - <1.2 x admission value) and 'rapid risers' (bilirubin of ≥1.2 x admission bilirubin). Fast fallers had significantly better 90-day survival compared to other groups (log rank p<0.001), and showed no benefit of corticosteroid therapy (OR for survival at 28 days of treatment, 0.94, 95% CI 0.06 - 8.41). These findings remained even amongst patients with severe disease based on initial DF, GAHS or MELD scores. CONCLUSIONS We present an intuitive method of classifying patients with AH based on the trajectory of bilirubin over the first week of admission. It is complimentary to existing scores that identify candidates for corticosteroid treatment or assess response to treatment. This method identifies a group of patients with AH who recover spontaneously and can avoid corticosteroid therapy