Liver — guardian, modifier and target of sepsis

Key Points The liver represents a key integrator of microbial responses During microbial infection, the liver switches from tolerogenic towards immunogenic responses and initiates the production of acute-phase proteins Overwhelming inflammatory responses contribute to development of liver injury in sepsis and to progression of acute-on-chronic liver failure in patients with liver cirrhosis Sepsis-induced liver injury comprises hypoxic hepatitis, sepsis-induced cholestasis and secondary sclerosing cholangitis of critically ill patients Patients with liver cirrhosis have an increased risk of microbial infections and are at high risk of death from sepsis, therefore, a fast and risk-adjusted antimicrobial therapy is important The liver regulates immune defence during sepsis, but is also a target for sepsis-related injury. Liver dysfunction can affect the prognosis of sepsis, particularly in patients with cirrhosis. In this Review, the importance of the liver in sepsis, the factors contributing to sepsis in patients with liver cirrhosis and new therapeutic strategies are discussed. Sepsis and septic shock are characterized by life-threatening organ dysfunction caused by a dysregulated host response to infection. The liver has a central role during sepsis, and is essential to the regulation of immune defence during systemic infections by mechanisms such as bacterial clearance, acute-phase protein or cytokine production and metabolic adaptation to inflammation. However, the liver is also a target for sepsis-related injury, including hypoxic hepatitis due to ischaemia and shock, cholestasis due to altered bile metabolism, hepatocellular injury due to drug toxicity or overwhelming inflammation, as well as distinct pathologies such as secondary sclerosing cholangitis in critically ill patients. Hence, hepatic dysfunction substantially impairs the prognosis of sepsis and serves as a powerful independent predictor of mortality in the intensive care unit. Sepsis is particularly problematic in patients with liver cirrhosis (who experience increased bacterial translocation from the gut and impaired microbial defence) as it can trigger acute-on-chronic liver failure — a syndrome with high short-term mortality. Here, we review the importance of the liver as a guardian, modifier and target of sepsis, the factors that contribute to sepsis in patients with liver cirrhosis and new therapeutic strategies.