Acute-on-chronic liver failure is characterized by hepatic inflammation and impaired liver regeneration despite Stat3 activation

Background Acute-on-chronic liver failure (ACLF) is associated with excessive systemic inflammation, cell death and organ failures. Yet, little is known about the hepatic histopathology of ACLF. In the present study, we therefore aimed to characterize hepatic inflammation, cell death and liver regeneration in ACLF.

Methods To this end, histological specimens of patients with compensated (N=37) or decompensated (N=40) cirrhosis, and of patients with ACLF with (N=18) or without (N=10) cirrhosis were analyzed for morphological features and for key components of the pro-regenerative Stat3 pathway. Additionally, refractoriness of the Stat-pathway was assessed in vitro.

Results In conventional pathology, ACLF was associated with higher levels of lobular inflammation, tissue necrosis and apoptosis than compensated and decompensated cirrhosis (P< 0.05). Of note, lobular inflammation was more pronounced in ACLF with versus without cirrhosis, whereas necrosis and apoptosis were predominant in ACLF without cirrhosis. The percentage of pStat3 positive hepatocytes was increasing with disease severity (3.5 %/10.4 %/21 %; P< 0.001) for compensated/decompensated/ACLF-cirrhosis), but lower in ACLF without versus with cirrhosis (21 % vs. 13 %; P = 0.02). In contrast, Ki67 positive cells were significantly higher in patients with cirrhosis and ACLF versus compensated or decompensated cirrhosis (1.3 %/1.8 %/5 %; P< 0.05), but much lower in ACLF with versus without cirrhosis (5 % vs. 13.5 %; P = 0.01). In line, the ratio of Ki67 to pStat3 was highest in ACLF without cirrhosis, and a significant association between Ki67/Stat3 ratio and 3-month survival was observed (P = 0.008). Complementary in vitro studies revealed refractoriness of the Stat-signaling pathway after repetitive stimulation (which may mimic the situation in ACLF) with IL-6 or IL-22, two predominant inducers of the pro-regenerative pStat3 pathway.

Conclusion Our study reveals a predominance of inflammation over cell death in ACLF with versus without cirrhosis, which seems to be associated with ineffective Stat3 signaling.

Publication History

Article published online:
07 September 2021