Maladaptive EG tied to poor outcomes in patients with decompensated cirrhosis

The risk of developing acute-on-chronic liver failure (ACLF) by 28 days and mortality by 90 days is increased among acutely decompensated cirrhosis (ADC) patients without ACLF who exhibit blood transcriptomic features of maladaptive emergency granulopoiesis (EG), suggests a study.

Researchers analysed whole-blood RNA-sequencing data obtained at admission in 1,260 ADC patients without ACLF. Of these, 124 (9.8 percent) developed ACLF and were considered to have pre-ACLF at admission.

Patients with pre-ACLF, compared with those without, had features of activated EG, including neutrophilia, upregulation of the STAT3 gene and its downstream target CEBPB (encoding a master transcription factor driving EG), upregulation of genes related to immature and mature neutrophils, and elevated circulating interleukin-6, an activator of the STAT3–CEBPB axis.

Furthermore, patients with pre-ACLD demonstrated upregulation of genes related to low-density neutrophils and granulocytic myeloid-derived suppressor cells, which are both known to suppress lymphocyte functions, features consistent with maladaptive EG. Baseline maladaptive EG occurred regardless of the presence or nature of clinically apparent precipitants.

In weighted gene co-expression network analysis, 22 gene modules were identified, including their respective eigengenes. Adjusted time-to-event analyses revealed that increased in the eigengenes representing the “neutrophil differentiation and immunosuppression” module and the “cycling cells” modules each correlated independently with an increased risk of ACLF development.

Moreover, new infections developed in a higher proportion of patients with pre-ACLF during hospitalization relative to those without pre-ACLF.

“These results strongly suggest that neutrophil-granulopoietic perturbations play a pathogenic role in the development of poor outcomes,” the researchers said. “These results should lead to the development of biological therapies targeting neutrophil-granulopoietic perturbations, which is an unmet need.”