The problem

Mechanisms of systemic inflammation that drives the severity of acutely decompensated cirrhosis are poorly understood. To date, there is no established treatment against systemic inflammation among patients with acutely decompensated cirrhosis. Progress in the knowledge about the mechanisms underlying cirrhosis-associated systemic inflammation would help to identify novel therapeutic approaches that improve outcomes, including the requirement for liver transplantation.

The approach

Multiple approaches are required to investigate the mechanisms of systemic inflammation in acutely decompensated cirrhosis, including the enrolment of large, prospective observational cohorts of well-annotated patients who are followed up for months or years; collection of blood samples at different time points enabling large-scale studies of the metabolome, proteome and transcriptome; collection of stools enabling metagenomics studies; and finally genotyping enabling GWAS studies of clinical and biological traits.

Main discoveries and innovations

• 2020-21: First description of the blood metabolome landscape among patients with acutely decompensated cirrhosis showing that nutrients (glucose, fatty acids, and amino acids) are skewed toward metabolically hyperactive immune cells at the expense of peripheral tissues.
• 2021: First description of the dichotomic landscape of circulating immune cells among patients with ACLF using whole-blood transcriptomics. This showed an activation of innate immune cells, mainly neutrophils, contrasting with lymphopenia involving T cells and NK cells.
• 2018: Publication of the results of the largest double-blind randomized clinical trial of norfloxacin vs. placebo showing for the first time that the antibiotic improves survival among patients with ascites fluid protein concentration of less than 15 g/L but not among those with higher concentrations.
• 2013: First evidence-based description of ACLF (CANONIC study).
• 2007: Publication of the results of the first double-blind randomized clinical trial of albumin among patients requiring large-volume paracentesis. This trial showed beneficial effect on outcomes in patients receiving albumin.
• 2010: First comprehensive description of kidney pathology among patients with HRS.
• 2002: Publication of the first study describing the beneficial effects of terlipressin on renal function among a large series of patients with type 1 HRS. This study resulted in the approval of terlipressin as a treatment of type 1 HRS in France.
• 1990: First description of hemodynamic and metabolic characteristics of septic shock among patients with cirrhosis as compared with patients without cirrhosis.
• 1988: First description of systemic hypometabolism among patients with advanced cirrhosis.
• 1985: Publication of the first study showing that, among critically ill patients with cirrhosis, scores assessing the function of the six major organ systems provided more accurate prognostic information than scores assessing only liver function.