Hepatic response to sepsis: Interaction between coagulation and inflammatory processes

Objectives: a) To review the hepatic response to sepsis and to establish ho w this response contributes to coagulation and inflammatory processes; b) t o review the physiologic and biochemical mechanisms that suggest hepatic dy sfunction may occur during sepsis, enhance procoagulant and proinflammatory activities, and participate in the potential evolution to multiple organ d ysfunction syndrome. Data Sources: A summary of published medical literature from MEDLINE search files and published reviews on liver function in experimental and human se psis, Data Summary: In sepsis, the liver plays a major role in host defense mecha nisms. Kupffer cells are responsible for bacterial scavenging, bacterial pr oducts inactivation, and inflammatory mediators clearance and production. H epatocytes, via receptors for many proinflammatory cytokines, modify their metabolic pathway toward gluconeogenesis, amino-acid uptake, and increased synthesis of coagulant and complement factors and protease inhibitors, The acute-phase protein (APP) response also contributes to the procoagulant sta te, especially by enhancing the inhibition of protein C (alpha (1)-antitryp sin and alpha (2)-macroglobulin) and by decreasing liver synthesis of prote in C and antithrombin (negative APPs), Elevated C-reactive protein levels ( positive APPs) promote the expression of tissue factor by mononuclear cells . Increased liver production of thrombin-activatable fibrinolytic inhibitor (positive APPs) enhances fibrinolysis inhibition. Conversely, such hepatic inflammatory and coagulation processes in sepsis may alter the function of this organ. Indeed, the liver can be injured by activated Kupffer cells th at release chemokines, attract blood neutrophils into the liver, and activa te them. Neutrophils upregulate their surface adhesion molecules, tissue fa ctor, and Kupffer cells, whereas tissue factor pathway inhibitor and thromb omodulin are almost undetectable in endothelial cells. This may lead to mic rocirculatory disturbances, fibrin deposition, hepatocyte injury, endotoxin and bacteria spillover, and multiple organ failure. Conclusions: In sepsis, the liver participates in host defense and tissue r epair through hepatic cell cross-talk that controls most of the coagulation and inflammatory processes. When this control is not adequate, a secondary hepatic dysfunction may occur and may sometimes lead to bacterial products spillover, enhanced procoagulant and inflammatory processes, and in turn, multiple organ failure and death.