1. Figure 3 The mechanism of injury in ACLF
Figure 3 | The mechanism of injury in ACLF. (1) An acute hepatic insult from viral infection or alcohol activates Kupffer cells present in hepatic sinusoids, through TLR4, complement receptors (C3R and C5R) and DAMPs and results in increased release of inflammatory mediators, regulatory cytokines, eicosanoids, and lysosomal and proteolytic enzymes. (2) Increased gut permeability in the altered milieu allows immune cells as well as endotoxins and LPS to migrate towards the liver. (3) Activation of hepatic stellate cells by Kupffer cells produces endothelin-1, thromboxane A2, nitric oxide and prostaglandins leading to hepatic microcirculatory dysfunction and an increase in portal pressure. (4) Release of nitric oxide causes inflammation-induced hepatocyte cell death via necrosis or apoptosis, which damages neighbouring parenchymal as well as nonparenchymal cells. (5) A relative deficiency of DCs, more so of myeloid DCs, exists in response to endotoxin resulting in inefficient immune modulation and injury containment. (6) Neutrophil infiltration, leads to release of reactive oxygen species (ROS) and in combination with the cytokine burst, leads to mitochondrial stress and hepatic apoptosis and necrosis. Inhibition of IFNγ production from CD8+ T cells and TREG cells, directly and indirectly deactivates monocytes and macrophages, resulting in fewer TH17 cells. Neutrophils are also dysfunctional, with poor phagocytic functions and increased ROS generation. (7 and 8) Ongoing hepatocyte loss and cytokine release leads to persistent injury, immunoparalysis, with SIRS, CARS and high probability of sepsis. Unabated hepatic injury, sepsis leads to MODS and eventually, to organ failure. Abrogation of hepatic injury along with immune modulation could prevent sepsis and or MODS and improve patient survival. ACLF, acute-on-chronic liver failure; CARS, compensatory anti-inflammatory response syndrome; DAMP, damage-associated molecular pattern; DCs, dendritic cells; eNOS, endothelial nitric oxide synthase; LPS, lipopolysaccharide; MODS, multiorgan dysfunction syndrome; PV, portal vein; SIRS, systemic inflammatory response syndrome; TGFβ, transforming growth factor beta; TH17 cell, type 17 T helper cell; TREG cell, regulatory T cell.
Sarin, S. K. & Choudhury, A. (2016) Acute‑on‑chronic liver failure: terminology, mechanisms and management
Nat. Rev. Gastroenterol. Hepatol. doi: /nrgastro