Granulocyte colony stimulating factor (G-CSF) to treat acute (on chronic) liver failure: effect on immune and stem cell mobilisation

Background and aims: Granulocyte stimulating factor (G-CSF) is a potential new treatment option for patients with severe acute (on-chronic) liver failure that mobilises hematopoetic stem cells (CD34+) and improves patients' outcome. But until now its mechanism of action leading to an improvement of liver regeneration could not have been clarified. In this investigation the impact of immune- and stem-cell mobilisation into the blood on patients' outcome was evaluated.

Methods: Filgrastim was administered as an individualised treatment with 12 subcutaneous doses (5 µg/kg day 1 – 5 daily, day 6 – 26 every third day) between 03/2013 and 01/2014 to eight patients with acute (on chronic) liver failure refractory to standard therapy (alcoholic hepatitis n = 6, flupirtin induced liver failure n = 2). Patients gave informed consent to the off-label use of G-CSF prior to drug administration.

Results: Two patients died and one patient was successfully transplanted (non survivors) within two weeks due to severe liver failure (28-day transplant-free mortality 37,5%). Five patients survived 28 days or longer (survivors). Gender, age as well as renal and liver function test did not differ between groups prior to treatment initiation. In all patients mobilisation of macrophages, neutrophils and CD39+Immune-cells by G-CSF could be demonstrated. In contrast to survivors, non-survivors showed an up-regulation of regulatory T cells (CD4+CD25+CD39+) already at baseline that could not further be stimulated in the line of G-CSF administration. These patients did not respond to G-CSF regarding stem cell mobilisation [CD133+ (CD39+)]. Several diagnostic markers like γ-glutamyl transferase, creatinine or bilirubin correlated significantly with blood levels of different cell-subsets.

Conclusions: With these preliminary observations we could show that survivors and non-survivors had at least in parts different pattern of immune and stem cells in peripheral blood during G-CSF stimulation. Tregs might be an immune-cell subset indicating a worse prognosis of patients with severe liver failure. Therefore monitoring stem and immune cell levels might help to indicate subgroups of patients who really benefit from G-CSF administration.