Liver transplantation for acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) occurs in the context of advanced liver disease and is associated with hepatic and extrahepatic organ failure, eventually leading to a major risk of short-term mortality. To date, there are very few effective therapeutic options for ACLF. In many cases, liver transplantation is the only life-saving treatment that has acceptable outcomes in carefully selected recipients. This Review addresses key aspects of the use of liver transplantation for patients with ACLF, providing an in-depth discussion of existing evidence regarding candidate selection, the optimal window for transplantation, potential prioritisation of liver grafts for this indication, and the global management of ACLF to bridge patients to liver transplantation.

Defining characteristics and long-term prognosis of drug-induced autoimmune-like hepatitis: A retrospective cohort study.

BACKGROUND: Drug-induced autoimmune-like hepatitis (DI-AILH) is poorly defined and more data are required to better characterise and manage this disease entity. OBJECTIVES: The aim of this study was to evaluate the clinical characteristics, histology and long-term outcomes of DI-AILH compared with idiopathic autoimmune hepatitis (AIH). METHODS: This retrospective cohort study reviewed 28 DI-AILH and 39 AIH patients in a single centre. The new (2022) and simplified (2008) AIH histology criteria were used to assess DI-AILH. RESULTS: DI-AILH were more likely to present with jaundice (p = 0.004) and higher bilirubin levels (p = 0.04) than AIH. AIH patients had higher rate of immunosuppression (IS) use including second- and third-line agents, though the time to reach biochemical remission were comparable. AIH patients had more advanced fibrosis than DI-AILH (Ishak fibrosis score 3.5 vs. 1.9, p < 0.0001). DI-AILH more commonly had eosinophilic aggregates (18% vs. 3%, p = 0.031) and less commonly showed plasma cell aggregates (61% vs. 97%, p < 0.001) than AIH. The simplified AIH histology criteria identified 1 atypical histology within the DI-AILH cohort, although this patient required long-term IS. The new AIH histology criteria classified 23 (82%) as likely AIH and 5 (18%) as possible AIH. Two of the possible DI-AILH did not require IS and one patient had successful IS withdrawal. Four DI-AILH patients with fibrosis stage ≤3 had successful IS withdrawal compared with none in the AIH group. Four patients underwent liver transplantation (LT) in both cohorts with significantly shorter time to LT in DI-AILH as the indication was for (sub)acute liver failure. Two DI-AILH patients died within 60 days of LT. CONCLUSION: The new AIH histology criteria may be better at identifying DI-AILH. Immunosuppression withdrawal in those without significant fibrosis may be considered. DI-AILH is at risk of (sub)acute liver failure and early discussions with a transplant centre would be desirable.

Potential therapies for acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a syndrome that develops in approximately 30% of patients hospitalised with cirrhosis and is characterised by an acute decompensation of liver function associated with extra-hepatic organ failures and a high short-term mortality. At present, no specific therapies are available for ACLF, and current management is limited to treatment of the precipitating event and organ support. Given the high prevalence and high mortality of this severe liver disease, there is an urgent need for targeted treatments. There is increasing evidence of the important role played by systemic inflammation and immune dysfunction in the pathophysiology of ACLF and a better understanding of these immune processes is resulting in new therapeutic targets. The aim of this review is to present an overview of ongoing studies of potentially promising therapies and how they could be utilised in the management of ACLF.

Managing hepatic complications of pregnancy: practical strategies for clinicians.

Liver disorders specific to pregnancy are rare but can have potentially serious consequences for mother and fetus. Pregnancy-related liver disorders are the most common cause of liver disease in otherwise healthy pregnant women and pose a challenge to physicians because of the need to take into account both maternal and fetal health. A good knowledge of these disorders is necessary as prompt diagnosis and appropriate management results in improved maternal and fetal outcomes. This review will focus on pregnancy-specific disorders and will aim to serve as a guide for physicians in their diagnosis, management and subsequent monitoring.

BNC1 regulates cell heterogeneity in human pluripotent stem cell-derived epicardium.

The murine developing epicardium heterogeneously expresses the transcription factors TCF21 and WT1. Here, we show that this cell heterogeneity is conserved in human epicardium, regulated by BNC1 and associated with cell fate and function. Single cell RNA sequencing of epicardium derived from human pluripotent stem cells (hPSC-epi) revealed that distinct epicardial subpopulations are defined by high levels of expression for the transcription factors BNC1 or TCF21. WT1+ cells are included in the BNC1+ population, which was confirmed in human foetal hearts. THY1 emerged as a membrane marker of the TCF21 population. We show that THY1+ cells can differentiate into cardiac fibroblasts (CFs) and smooth muscle cells (SMCs), whereas THY1- cells were predominantly restricted to SMCs. Knocking down BNC1 during the establishment of the epicardial populations resulted in a homogeneous, predominantly TCF21high population. Network inference methods using transcriptomic data from the different cell lineages derived from the hPSC-epi delivered a core transcriptional network organised around WT1, TCF21 and BNC1. This study unveils a list of epicardial regulators and is a step towards engineering subpopulations of epicardial cells with selective biological activities.