In a pilot study from the October issue of Clinical Gastroenterology and Hepatology, colony stimulating factor 3 (CSF3, also called GCSF) improved liver function and increased survival times in patients with severe alcohol-associated hepatitis (AH), compared with standard therapy. Addition of N-acetyl cysteine (NAC) to GCSF did not improve patient outcomes.
Patients with severe AH are frequently treated with prednisolone, which does not increase survival beyond 1 month—possibly because this drug increases risk of infections in these patients. NAC is effective treatment for acetaminophen toxicity, and might reduce infections and increase survival in patients with AH. GCSF was reported to reduce infection and increase survival of patients with AH, but additional studies were needed to establish the efficacy and safety of this treatment for patients with AH.
Virendra Singh et al. therefore performed a prospective study of 57 patients with AH at a single center in India. The patients received standard medical therapy (with pentoxifylline) plus GCSF for 5 days (GCSF group; n = 18), standard medical therapy plus GCSF and intravenous NAC for 5 days (combination group; n = 19), or standard medical therapy alone (n = 20).
Significantly higher proportions of patients in the GCSF group (16/18) and the combination group (13/19) survived for 90 days than in the standard medical therapy group (6/20). In Kaplan-Meier analysis, there was significantly higher 90-day survival in the GCSF group and combination group compared with the standard medical therapy group (see figure). However, there was no significant difference in 90-day survival between the combination and GCSF groups.
There was a significant increase in total leukocyte counts and in number of CD34+ cells in the peripheral blood on day 6 in the GCSF and combination therapy groups, compared with baseline and standard medical therapy groups. There was no significant increase in total leukocyte count or CD34+ cells on day 6 in the standard medical therapy group compared with baseline.
The GCSF group (but not the combination group) had significantly larger median reductions in modified discriminant function scores at study months 1 (reduction of 60.36%), 2 (reduction of 75.36%), and 3 (reduction of 88.73%) vs the standard medical therapy group. The GCSF group had a significantly larger median reduction in model for end-stage liver disease score at 3 months (reduction of 55.77%), but not in Child Turcotte Pugh score, compared with the standard medical therapy group. All groups had similar numbers of complications.
The authors conclude that that treatment with GCSF increases chances of 90-day survival compared with standard medical therapy alone, for patients with AH. Importantly, the combination of NAC and G-CSF was not found to be superior to GCSF alone in reducing 90-day mortality.
How does GCSF increase survival of these patients? Morgan proposes that the cytokine increases neutrophil function and clearance of bacterial infections. In this trial, 8 subjects in the standard of care group died from sepsis compared with no patients in the 2 other groups. Among the patients receiving GCSF, deaths were caused by progressive liver failure, often with variceal bleeding, renal failure, encephalopathy, and pneumonia or infection.
Impaired hepatocyte regeneration also has been proposed as the reason for liver failure in patients with AH. GCSF causes the release of pluripotent cells (CD34+) from the bone marrow, which localize to the liver and differentiate into hepatocytes, to replentish the hepatocyte populatoin. GCSF might also bind receptors on hepatocytes and oval cells in the liver to induce hepatocyte differentiation and replication.
Further studies are needed into the effects of GCSF on hepatocellular regeneration in patients with AH. Further research could lead to new treatment approaches for AH—there have been no proven effective drugs in the past 45 years, and as many as one-third of patients die within the first 90 days.