Ever since, the evolvement of intriguing techniques to impact KC function has paved the way for a deepened knowledge and enabled us to decipher detrimental as well as beneficial aspects of KC activity. These cells attracted much attention lately in the context of chronic liver inflammation due to their dual pro- and antifibrotic qualities ( Zimmermann and Tacke, 2011) but evidence for their critical involvement in fulminant hepatitis even date back several decades. There is a robust body of evidence that hepatic macrophages (traditionally called “Kupffer cells,” KCs) are essential players in the propagation of acute liver damage. Local and circulatory components of the innate immune system fundamentally shape the outcome of the immunological response to an acute hepatic insult. Despite remarkable progress in disease management and understanding of basic molecular mechanisms involved, disease-specific, targeted therapies cannot be provided in a considerable proportion of cases where liver transplantation constitutes the sole medical mean to prevent death. Owing to its devastating nature implications of liver failure rapidly affect virtually all vital organs eventually leading to multi-organ failure. In recent years, idiosyncratic, non-acetaminophen, drug-induced hepatotoxicity became a major etiology of ALF in Europe ( Canbay et al., 2011). In major parts of the western hemisphere acute dose-dependent acetaminophen (paracetamol) toxicity is the most prevalent cause of ALF, whereas viral agents (mainly hepatitis A, B, or E virus) predominate in developing countries. Miscellaneous causes of acute liver deterioration exist, and etiology is the best predictor of clinical outcome ( Ostapowicz et al., 2002). Drug-induced liver injury as a common underlying cause is estimated to affect 44,000 individuals in the US per year ( Bell and Chalasani, 2009). Due to insufficient surveillance and reporting systems and lack of consistent diagnostic criteria accurate data concerning the global epidemiology of ALI are scarce. The annual incidence of ALF is estimated at one to six cases per million in the developed world but may be higher in endemic regions of viral hepatitis ( Bernal et al., 2010).

The latter clinical condition is absent in ALI in which coagulation abnormalities are predominant. Clinical hallmarks of ALF are coagulopathy (defined as an INR > 1.5) and mental alterations (i.e., hepatic encephalopathy of any degree) within a 26-weeks time-frame after the initial symptoms ( Bernal et al., 2010). It is a dreaded disease condition due to its tremendous morbidity and mortality without adequate treatment. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation, and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in ALF.Īcute liver injury (ALI) and acute liver failure (ALF) represent different severity stages of a sudden deterioration of liver function without evidence for prior chronic liver disease.

In contrast, the chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1) are important negative regulators of monocyte infiltration by controlling their survival and differentiation into functionally diverse macrophage subsets upon injury. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 promote monocyte subset infiltration upon liver injury. Recent studies in mice demonstrated that these macrophage actions largely depend on the recruitment of monocytes into the liver, namely of the inflammatory Ly6c+ (Gr1+) monocyte subset as precursors of tissue macrophages.

Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g., via caspase activation, but also activate protective signaling pathways, e.g., via nuclear factor kappa B (NF-κB). Experimental murine models of liver injury highlighted the importance of hepatic macrophages, so-called Kupffer cells, for initiating and driving this inflammatory response by releasing proinflammatory cytokines and chemokines including tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1beta, or monocyte-chemoattractant protein-1 (MCP-1, CCL2) as well as activating other non-parenchymal liver cells, e.g., endothelial or hepatic stellate cells. Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation. Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germanyĭifferent etiologies such as drug toxicity, acute viral hepatitis B, or acetaminophen poisoning can cause acute liver injury or even acute liver failure (ALF).

Complete anatomy of the irritated liver