Efficacy of Granulocyte Colony-Stimulating Factor and N-Acetylcysteine Therapies in Patients With Severe Alcoholic Hepatitis.

BACKGROUND & AIMS: Patients with alcoholic hepatitis (AH) have high mortality, so new therapies are needed. Administration of granulocyte colony stimulating factor (G-CSF) increases survival times of patients with AH. It is not known whether addition of N-acetyl cysteine (NAC) to G-CSF could further increase survival time. We performed a randomized controlled pilot study to compare the efficacy of standard medical therapy with pentoxifylline to treatment with a combination of G-CSF and standard medical therapy as well as to the combination of NAC, G-CSF, and standard medical therapy in patients with severe AH. METHODS: We performed an open-label, single-center study of 57 patients with severe AH admitted to a Liver Intensive Care unit in India from October 2014 through March 2017. Patients were randomly assigned to groups that received standard medical therapy (with pentoxifylline) plus G-CSF for 5 days (G-CSF group; n = 18), standard medical therapy plus G-CSF and intravenous NAC for 5 days (combination group; n = 19), or standard medical therapy alone (n = 20). Clinical data and blood samples were collected at baseline; on day 6; and 1, 2, and 3 months after the study began. CD34+ cells were measured in blood samples collected on days 0 and 6. The primary outcome was proportion of patients surviving for 90 days. Secondary outcomes were mobilization of CD34+ cells at day 6, as well as Child Turcotte Pugh, model for end-stage liver disease, and modified discriminant function scores until day 90. RESULTS: Significantly higher proportions of patients in the G-CSF group (16/18) and the combination group (13/19) survived for 90 days than in the standard medical therapy group (6/20) (P = .0001 for G-CSF group and P = .037 and combination group). The GGSF and combination groups each had increased numbers of CD34+ cells from baseline until day 6, compared with the standard medical therapy group. The G-CSF 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 (P = .02; P = .05; and P = .00, respectively). The G-CSF group had a significantly larger median reduction in model for end-stage liver disease score at 3 months (reduction of 55.77%; P = .01), but not in Child Turcotte Pugh score, compared with the standard medical therapy group. All groups had similar numbers of complications. CONCLUSION: In a pilot randomized controlled trial, we found administration of G-CSF to improve liver function and increase survival times in patients with severe AH, compared with standard therapy. We found no evidence for benefit of adding NAC to G-CSF. These findings require confirmation in larger trials. ClincialTrials.gov, number: NCT02971306.

Outcomes after multiple courses of granulocyte colony-stimulating factor and growth hormone in decompensated cirrhosis: A randomized trial.

Decompensated cirrhosis (DC) carries a high mortality. Liver transplantation (LT) is the treatment of choice; however, the limited availability of donor organs has resulted in high waitlist mortality. The present study investigated the impact of multiple courses of granulocyte-colony stimulating factor (G-CSF) with or without growth hormone (GH) in these patients. Sixty-five patients with DC were randomized to standard medical therapy (SMT) plus G-CSF 3 monthly plus GH daily (group A; n = 23) or SMT plus G-CSF (group B; n = 21) or SMT alone (group C; n = 21). The primary outcome was transplant-free survival (TFS) at 12 months. Secondary outcomes were mobilization of CD34+ cells at day 6 and improvement in clinical scores, liver stiffness, nutrition, episodes of infection, and quality of life (QOL) at 12 months. There was significantly better 12-month TFS in groups A and B than in group C (P = 0.001). At day 6 of therapy, CD34+ cells increased in groups A and B compared to baseline (P < 0.001). There was a significant decrease in clinical scores, improvement in nutrition, better control of ascites, reduction in liver stiffness, lesser infection episodes, and improvement in QOL scores in groups A and B at 12 months as compared to baseline (P < 0.05). The therapies were well tolerated. CONCLUSION: Multiple courses of G-CSF improved 12-month TFS, mobilized hematopoietic stem cells, improved disease severity scores, nutrition, fibrosis, QOL scores, ascites control, reduced infections, and the need for LT in patients with DC. However, the use of GH was not found to have any additional benefit. (Hepatology 2017).

Granulocyte colony-stimulating factor in severe alcoholic hepatitis: a randomized pilot study.

OBJECTIVES: Severe alcoholic hepatitis has high short-term mortality. The aim of this study was to test the hypothesis that treatment of patients with alcoholic hepatitis with granulocyte colony-stimulating factor (G-CSF) might mobilize bone marrow-derived stem cells and promote hepatic regeneration and thus improve survival. METHODS: Forty-six patients with severe alcoholic hepatitis were prospectively randomized in an open study to standard medical therapy (SMT) plus G-CSF (group A; n=23) at a dose of 5 µg/kg subcutaneously every 12 h for 5 consecutive days or to SMT alone (group B; n=23) at a tertiary care center. We assessed the mobilization of CD34(+) cells on day 6, Child-Turcotte-Pugh (CTP), model for end-stage liver disease (MELD), and modified Maddrey's discriminant function (mDF) scores, and survival until day 90. RESULTS: There was a statistically significant increase in the number of CD34(+) cells in peripheral blood in group A as compared with group B (P=0.019) after 5 days of G-GSF therapy. There was a significant reduction in median Δ change% in CTP, MELD, and mDF at 1, 2, and 3 months in group A as compared with group B (P<0.05). There was marked improvement in survival in group A as compared with group B (78.3% vs. 30.4%; P=0.001) at 90 days. CONCLUSIONS: G-CSF is safe and effective in the mobilization of hematopoietic stem cells and improves liver function as well as survival in patients with severe alcoholic hepatitis.