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.

Background: There is a lack of consensus on the social determinants of Deaths of Despair (DoD), i.e., an increase in mortality attributed to drug overdose, alcohol-related liver disease, and suicide in the United States (USA) during recent years. The objective of this study was to review the scientific literature on DoD with the purpose of identifying relevant social determinants and inequalities related to these mortality trends. Methods: Scoping review focusing on the period 2015–2022 based on PubMed search. Articles were selected according to the following inclusion criteria: published between 1 January 2000 and 31 October 2021; including empirical data; analyzed DoD including the three causes defined by Case and Deaton; analyzed at least one social determinant; written in English; and studied DoD in the USA context only. Studies were excluded if they only analyzed adolescent populations. We synthesized our findings in a narrative report specifically addressing DoD by economic conditions, occupational hazards, educational level, geographical setting, and race/ethnicity. Results: Seventeen studies were included. Overall, findings identify a progressive increase in deaths attributable to suicide, drug overdose, and alcohol-related liver disease in the USA in the last two decades. The literature concerning DoD and social determinants is relatively scarce and some determinants have been barely studied. However different, however, large inequalities have been identified in the manner in which the causes of death embedded in the concept of DoD affect different subpopulations, particularly African American, and Hispanic populations, but blue collar-whites are also significantly impacted. Low socioeconomic position and education levels and working in jobs with high insecurity, unemployment, and living in rural areas were identified as the most relevant social determinants of DoD. Conclusions: There is a need for further research on the structural and intermediate social determinants of DoD and social mechanisms. Intersectional and systemic approaches are needed to better understand and tackle DoD and related inequalities.

Confirm in patients with cirrhosis and gastrointestinal bleeding the safety of ornithine phenylacetate (OP) and assess the pharmacokinetic profile of OP and its effects on plasma ammonia. OP is a drug that has shown experimentally to decrease hyperammonemia and improve hepatic encephalopathy. OP is safe in healthy subjects and in stable patients with cirrhosis, but there are no data in decompensated cirrhosis. We performed a study to assess safety and tolerance of OP in cirrhotic patients after an episode of upper gastrointestinal bleeding.Ten patients were included within 24 hours of an upper gastrointestinal bleeding. OP was administered as a continuous infusion up to a maximum of 10 g/24 h (0.42 g/h) for 5 days. The infusion was started at 33% of the target dose and increased at 12-hour intervals achieving target dose at 24 hours. Ammonia was also assessed in control group of 10 patients. No severe adverse events were observed. Mild adverse events were reported in 4 patients. Plasma ammonia (baseline: 80±43 μmol/L) showed a progressive drop between baseline and 36 hours (42±15 μmol/L), 72 hours (44±15 μmol/L), 96 hours (40±24 μmol/L), and 120 hours (33±14 μmol/L). Plasma ammonia at 24 hours was significantly higher in the control group. Plasma glutamine showed a significant decrease (-37% at day 5) and its excretion in urine as phenylacetylglutamine, a progressive rise (52±35 mmol at day 5). OP is a safe and well-tolerated drug in decompensated cirrhotics that may decrease plasma ammonia by inducing its appearance as phenylacetylglutamine in urine.