Background & aims: In patients with acutely decompensated cirrhosis (ADC) who present with clinically apparent precipitants (i.e., infections, acute liver injury), alterations in blood markers of inflammation associate with progression toward severe phenotypes (e.g., acute-on-chronic liver failure [ACLF]). However, it is unclear whether alterations in blood inflammatory markers associate with progression of ADC independently of precipitants.

Methods: We prospectively enrolled 394 patients admitted for ADC who were classified into four phenotypes of increasing severity: no organ dysfunction (n = 168), organ dysfunction alone (n = 72), organ failure without ACLF (n = 91), and ACLF (n = 63). Clinical blood cell counts and serum levels of inflammatory markers (including soluble markers related to type-1, type-2, and type-3 inflammation) were obtained at enrollment. Ordinal regression with adjacent categories logit model adjusted for confounders (including precipitants) was used to analyze associations between changes in each blood inflammatory marker and the worsening of ADC.

Results: Inflammatory markers that were associated with a higher risk of progressing to the next more severe stage were as follows: increasing neutrophil counts (adjusted common odds ratio [cOR] 1.17, 95% CI 1.06-1.28); increasing levels of the type-2 cytokine interleukin (IL)-25 (cOR 1.21, 95% CI 1.06-1.39), type-3 cytokines IL-6 (cOR 1.15, 95% CI 1.02-1.28) and IL-22 (cOR 1.16, 95% CI 1.03-1.30), or anti-inflammatory soluble CD163 (cOR 1.94, 95% CI 1.58-2.38); decreasing lymphocyte counts (cOR 0.77, 95% CI 0.68-0.87); or decreasing levels of the type-1 cytokine IFN-γ (cOR 0.85, 95% CI 0.75-0.95).

Conclusions: Among patients with ADC, alterations in blood levels of cytokines related to type-1, type-2 and type-3 inflammation, together with neutrophilia, lymphopenia and elevated anti-inflammatory signals were individually associated with an increased risk of progressing toward ACLF, independently of the presence of clinically apparent precipitants.

Impact and implications: This study reveals that among patients with acutely decompensated cirrhosis, alterations in blood levels of cytokines related to type-1, type-2 and type-3 inflammation, together with neutrophilia, lymphopenia and elevated anti-inflammatory signals were individually associated with increased risk of progressing toward acute-on-chronic liver failure, independently of the presence of clinically apparent precipitants. These findings raise questions about the role of impaired barrier tissues and dysregulated production of blood immune cells in the pathophysiology of severe phenotypes of acutely decompensated cirrhosis, stimulating research to identify potential new biomarkers and targets for novel therapeutic approaches.