Abstract
ACLF is characterized by a systemic inflammatory response, but the cytokines involved in this process have not been well studied. The aim of this study was to characterize the systemic inflammatory response in patients with cirrhosis and ACLF and its relationship with prognosis. Fifty-five patients with cirrhosis, 26 with ACLF, were studied prospectively. Systemic inflammatory response was analyzed by measuring a large array of plasma cytokines by using a multiplex kit. A principal component analysis show noticeable differences between ACLF and decompensated cirrhosis without ACLF. Patients with ACLF had significant abnormal levels of 12 cytokines compared to those without ACLF, including: VCAM-1, VEGF-A, Fractalkine, MIP-1α, Eotaxin, IP-10, RANTES, GM-CSF, IL-1β, IL-2, ICAM-1, and MCP-1. Cytokines showing the most marked relationship with ACLF were VCAM-1 and VEGF-A (AUCROC 0.77; p = 0.001). There was a significant relationship between some of inflammatory mediators and 3-month mortality, particularly VCAM-1, ICAM-1, and GM-CSF (AUCROC>0.7; p < 0.05). Functional Enrichment Analysis showed that inflammatory markers differentially expressed in ACLF patients were enriched in leukocyte migration, particularly monocytes and macrophages, and chemotaxis pathways. In conclusion, ACLF is characterized by a marked inflammatory reaction with activation of mediators of adhesion and migration of leukocytes. The intensity of the inflammatory reaction correlates with prognosis.
Highlights
“chronic” inflammatory response may lead to a paralysis of the immune system, which in turn may be pathogenically related to the high frequency of severe infections that occur in patients with cirrhosis[8,9]
The findings of the current study indicate that acute-on-chronic liver failure (ACLF) syndrome is associated with an abnormal plasma cytokine profile, characterized by alterations of cytokines mainly related to chemotaxis and migration of leukocytes, monocytes and macrophages
Main findings of this study were: 1/ systemic inflammation, as assessed by leukocyte count and C-reactive protein (CRP) levels, seems to be an important pathogenic component of the ACLF syndrome; 2/ systemic inflammation in ACLF is independent of the existence of bacterial infections; and 3/ systemic inflammation is associated with poor short-term mortality[13]
Summary
“chronic” inflammatory response may lead to a paralysis of the immune system, which in turn may be pathogenically related to the high frequency of severe infections that occur in patients with cirrhosis[8,9]. The hypothesis has been raised that ACLF is associated with a remarkable inflammatory state that contributes to the pathogenesis and progression of this syndrome[10,12] This hypothesis is based on the findings of increased leukocyte count and C-reactive protein (CRP) levels in patients with ACLF compared to those of patients with cirrhosis without ACLF and their correlation with prognosis[13]. Bacterial infections are very common as precipitating events of ACLF, it has been suggested that the inflammatory reaction in ACLF may occur in the absence of bacterial infections, at least undetectable by current standard diagnostic methods[10,13] Despite these suggestive findings, there is very little information on the type of inflammatory mediators that are increased in ACLF and its relationship with outcomes. The levels of some of these cytokines are associated with prognosis, a finding that links the inflammatory reaction with outcome in ACLF
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