Systemic Inflammation and Acute-on-Chronic Liver Failure: Too Much, Not Enough

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.

Figure 1

Proof of dysbalanced inflammatory response: relationship between the degree of inflammatory reaction, as estimated by the leukocyte count and C-reactive protein, and the severity of ACLF.

Figure 2

The dynamic course of immune function in evolving cirrhosis: cirrhosis-associated immune: (a) early cirrhosis sets the stage for ACLF; (b) evolving cirrhosis primes the systemic immune system and finally culminates in ACLF (c).