Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes

Abstract

ObjectiveSystemic inflammation promotes the development of clinical events in patients with advanced chronic liver disease (ACLD). We assessed whether (1) non-selective beta blocker (NSBB) treatment initiation impacts biomarkers of systemic inflammation and (2) whether these changes in systemic inflammation predict complications and mortality.DesignBiomarkers of systemic inflammation, that is, white blood cell count (WBC), C reactive protein (CRP), interleukin-6 (IL-6) and procalcitonin (PCT) were determined at sequential hepatic venous pressure gradient (HVPG) measurements without NSBB and under stable NSBB intake. The influence of NSBB-related changes in systemic inflammation on the risk of decompensation and liver-related death was analysed using competing risk regression.ResultsOur study comprised 307 stable patients with ACLD (Child-A: 77 (25.1%), Child-B: 161 (52.4%), Child-C: 69 (22.5%), median HVPG: 20 (IQR 17–24) mm Hg) including 231 (75.2%) with decompensated disease.WBC significantly decreased upon NSBB therapy initiation (median: −2 (IQR −19;+13)%, p=0.011) in the overall cohort. NSBB-related reductions of WBC (Child-C: −16 (−30;+3)% vs Child-B: −2 (−16;+16)% vs Child-A: +3 (−7;+13)%, p<0.001) and of CRP (Child-C: −26 (−56,+8)% vs Child-B: −16 (−46;+13)% vs Child-A: ±0 (−33;+33)%, p<0.001) were more pronounced in advanced stages of cirrhosis. The NSBB-associated changes in WBC correlated with changes in CRP (Spearman’s ρ=0.228, p<0.001), PCT (ρ=0.470, p=0.002) and IL-6 (ρ=0.501, p=0.001), but not with changes in HVPG (ρ=0.097, p=0.088).An NSBB-related decrease in systemic inflammation (ie, WBC reduction ≥15%) was achieved by n=91 (29.6%) patients and was found to be an independent protective factor of further decompensation (subdistribution HR, sHR: 0.694 (0.49–0.98), p=0.038) in decompensated patients and of liver-related mortality in the overall patient cohort (sHR: 0.561 (0.356–0.883), p=0.013).ConclusionNSBB therapy seems to exert systemic anti-inflammatory activity as evidenced by reductions of WBC and CRP levels. Interestingly, this effect was most pronounced in Child-C and independent of HVPG response. An NSBB-related WBC reduction by ≥15% was associated with a decreased risk of further decompensation and death.

Decreasing von Willebrand Factor Levels Upon Nonselective Beta Blocker Therapy Indicate a Decreased Risk of Further Decompensation, Acute-on-chronic Liver Failure, and Death

“…7 Accordingly, there is a need for novel biomarkers to assess the expectable benefits in an individual patient, because the assessment of HVPG response is invasive and only available in few academic centers. 2 Moreover, NSBB therapy exerts additional nonhemodynamic effects, [9][10][11] which could be the mechanisms by which NSBB treatment prevents SBP 12 and ameliorates the course of acute-on-chronic liver failure (ACLF). 13,14 Von Willebrand factor (VWF) is a marker of endothelial dysfunction and has primarily been studied as a noninvasive test (NIT) for clinically significant portal hypertension (CSPH) in patients with compensated advanced chronic liver disease.…”

Patterns of acute decompensation in hospitalized patients with cirrhosis and course of acute‐on‐chronic liver failure

“…Therefore, inflammation may represent an early indicator of ACLF development as well as a potential therapeutic target. 32 Interestingly, HVPG was comparable between patients in the different prognostic groups. These findings are in line with Turco et al 33 The authors reported that while HVPG strongly increased in earlier clinical stages of cirrhosis (from Baveno stage 1 [compensated ACLD with subclinical portal hypertension] to stage 4 [patients experiencing first decompensation]), HVPG leveled off in later stages (i.e., numerical differences between clinical stages 4 and 5 were rather small).…”

Establishment of liver tumor cell lines from atherogenic and high fat diet fed hepatitis C virus transgenic mice

“…However, the expression of these molecules is regulated by multiple factors including MAPK, PI3K, AKT HIF1, STAT3, and NF-κB 22 . Moreover, a recent report showed that the activation of Wnt signaling could be related to resistance against anti-PD1 therapy 23 . Shh and Wnt signaling are co-operating signaling pathways that are essential for embryonic development 24 .…”