A randomized study of ceftriaxone for the prevention of infections in hospitalized patients with advanced cirrhosis.

BACKGROUND: Infections frequently complicate hospital admission among patients with cirrhosis and are associated with adverse outcomes. In specific settings, administration of prophylactic antibiotics has been shown to improve outcomes. In this pilot study, we aimed to assess the feasibility of a randomized study of whether prophylactic ceftriaxone (CTX), administered to hospitalized patients with advanced cirrhosis (Model for End-Stage Liver Disease-Sodium ≥ 18) without known infection, could reduce the incidence of infection. We also sought to determine whether we could identify patients most likely to benefit through the use of clinical and laboratory parameters. METHODS: Hospitalized patients with cirrhosis, with Model for End-Stage Liver Disease-Sodium ≥ 18 and no known infection after evaluation, were randomly assigned in a double-blinded fashion to receive either CTX 1 gr/day or placebo for up to 7 days. Subjects were monitored for incident infection and other outcomes of interest, including adverse reactions such as the development of C. difficile infection. Biomarkers of interest, including C-reactive protein and procalcitonin, were measured before initiation of treatment. RESULTS: Thirty subjects were enrolled and received CTX or placebo (15 subjects each) per protocol. There were no observed statistically significant differences between groups in incidence of infection, mortality, length of stay, or key laboratory parameters, including C-reactive protein and procalcitonin. Adverse events related to treatment were rare and clinically of minor significance. CONCLUSIONS: Overall, enrollment of subjects proved feasible, and results from this pilot study, while inadequate for confirmation of the potential efficacy of CTX, provide evidence of study feasibility for future, more definitive clinical trials.

Multicellular Liver Organoids: Generation and Importance of Diverse Specialized Cellular Components.

Over 40,000 patients in the United States are estimated to suffer from end-stage liver disease and acute hepatic failure, for which liver transplantation is the only available therapy. Human primary hepatocytes (HPH) have not been employed as a therapeutic tool due to the difficulty in growing and expanding them in vitro, their sensitivity to cold temperatures, and tendency to dedifferentiate following two-dimensional culture. The differentiation of human-induced pluripotent stem cells (hiPSCs) into liver organoids (LO) has emerged as a potential alternative to orthotropic liver transplantation (OLT). However, several factors limit the efficiency of liver differentiation from hiPSCs, including a low proportion of differentiated cells capable of reaching a mature phenotype, the poor reproducibility of existing differentiation protocols, and insufficient long-term viability in vitro and in vivo. This review will analyze various methodologies being developed to improve hepatic differentiation from hiPSCs into liver organoids, paying particular attention to the use of endothelial cells as supportive cells for their further maturation. Here, we demonstrate why differentiated liver organoids can be used as a research tool for drug testing and disease modeling, or employed as a bridge for liver transplantation following liver failure.

Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis.

BACKGROUND AND AIMS: Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched LDL-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcohol-associated hepatitis (AH) and interrogate the biology behind its formation. APPROACH AND RESULTS: We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z-index ≤ 0.6 and a decline of Z-index by ≥0.1 in 2 weeks predicted 90-day survival. RNA-sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z. CONCLUSIONS: Impaired lipoprotein metabolism in AH leads to the accumulation of LP-Z in the circulation, which is hepatotoxic from excessive FC. A Z-index ≤ 0.6 predicts 90-day survival independent from conventional biomarkers for disease prognostication.