The Current Status of Granulocyte-Colony Stimulating Factor to Treat Acute-on-Chronic Liver Failure

Abstract

Patients with acute-on-chronic liver failure (ACLF) have a devastating prognosis and therapeutic options are limited. Granulocyte-colony stimulating factor (G-CSF) mobilizes immune and stem cells and possess immune-modulatory and proregenerative capacities. In this review, we aim to define the current evidence for the treatment with G-CSF in end-stage liver disease. Several smaller clinical trials in patients with different severity grades of end-stage liver disease have shown that G-CSF improves survival and reduces the rate of complications. Adequately powered multicenter European trials could not confirm these beneficial effects. In mouse models of ACLF, G-CSF increased the toll-like receptor (TLR)-mediated inflammatory response which led to an increase in mortality. Adding a TLR4 signaling inhibitor allowed G-CSF to unfold its proregenerative properties in these ACLF models. These data suggest that G-CSF requires a noninflammatory environment to exert its protective properties.

Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study)

“…[6][7][8][9] Bone marrow-derived stem cells have been shown to be potent in modulating immune functions and promoting regenerative capacities, thus mitigating various types of liver injury in experimental and clinical studies. [10][11][12] However, costs, high technical requirements and peri-interventional complications limit the general applicability of this approach.…”

Mesenchymal stem cells-based therapy in liver diseases

“…For example, therapeutic agents targeting inflammation and fibrosis in NASH, CCR2/CCR5, TLR4, ASK1 and lysine oxidase were considered ineffective in recent clinical trials to alleviate endpoint outcomes in NASH, particularly fibrosis [ 10 , 338 ]. Furthermore, although several smaller clinical trials in patients with end-stage liver disease of varying severity have shown that G-CSF improves patient survival and reduces complications [ 339 ]. However, in a recent multicenter controlled trial, G-CSF did not have a significant beneficial effect in patients with chronic acute liver failure, suggesting that it should not be used as standard of care for end-stage liver diseases [ 340 ].…”

Alcohol and Acute-on-Chronic Liver Failure

“…However, results from small trials were positive but larger multicentre European studies have not shown survival benefit [83][84][85] . Inhibition of TLR4 combined with G-CSF application is a novel combinatorial approach that improves mortality, tissue injury, and reduces cytokine levels in animal models of ACLF 86 .…”