Abstract
ACLF is a specific, but complex and multifactorial form of acute decompensation of cirrhosis and is characterized by an extraordinary dynamic natural course, rapidly evolving organ failure, and high short-term mortality. Dysbalanced immune function is central to its pathogenesis and outcome with an initial excessive systemic inflammatory response that drives organ failure and mortality. Later in its course, immuno-exhaustion/immunoparalysis prevails predisposing the patient to secondary infectious events and reescalation in end-organ dysfunction and mortality. The management of patients with ACLF is still poorly defined. However, as its pathophysiology is gradually being unravelled, potential therapeutic targets emerge that warrant further study such as restoring or substituting albumin via plasma exchange or via albumin dialysis and evaluating usefulness of TLR4 antagonists, modulators of gut dysbiosis (pre- or probiotics), and FXR-agonists.
Highlights
acute-on-chronic liver failure (ACLF) is a specific, but complex and multifactorial form of acute decompensation of cirrhosis and is characterized by an extraordinary dynamic natural course, rapidly evolving organ failure, and high short-term mortality
Immuno-exhaustion/immunoparalysis prevails predisposing the patient to secondary infectious events and reescalation in end-organ dysfunction and mortality
As its pathophysiology is gradually being unravelled, potential therapeutic targets emerge that warrant further study such as restoring or substituting albumin via plasma exchange or via albumin dialysis and evaluating usefulness of TLR4 antagonists, modulators of gut dysbiosis, and Farnesoid X-Receptor (FXR)-agonists
Summary
Acute clinical deterioration of a patient with cirrhosis remains a decisive time point in terms of medical management, since it is frequently associated with rapidly evolving multiorgan dysfunction, significant morbidity, and high short-term mortality. The CANONIC-trial taught us that ACLF patients, who had earlier episodes of acute hepatic decompensation, developed a less dramatic course of ACLF with lower levels of inflammatory mediators and lower mortality rates compared to patients presenting with a first episode. This suggests that ACLF is associated with exaggerated inflammatory response and with tolerance, a host defence strategy that reduces the negative impact of inflicted injury on host fitness [4]. We will focus first on the basic mechanisms of inflammation (resistance and tolerance), secondly on the different elements contributing to this dysfunction and predominantly in the context of ACLF in patients with underlying cirrhosis (cirrhosis-associated immune dysfunction), and thirdly on additional reinforcing accomplices
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