G-CSF for Acute Liver Injury

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Motivation: When patients do not respond to steroids for acute alcoholic hepatitis, there is little else you can do - besides watching them wither away.  While observing another such tragedy, I wondered if there is anything else to do.  Most patients with acute alcohol use do not qualify for a liver transplant.  I came across this paper published recently evaluating the remarkable potency of G-CSF for acute on chronic liver injury.

For background, the theory is that G-CSF mobilizes bone marrow derived stem cells (CD 34+), and one hopes that with more stem cells floating around, some will engraft in the liver and lead to regeneration.

Paper: Garg, V., Garg, H., Khan, A. et. al. "Granulocyte Colony-Stimulating Factor Mobilizes CD34+ Cells and Improves Survival of Patients with Acute-on-Chronic Liver Failure" Gastroenterology (2012); 142: 505-512.

Methods: Blinded randomized trial in a hospital in New Delhi, India.   Between December 2008 and August 2010, consecutive patients with acute on chronic liver failure (defined as acute rise in bilirubin, INR, ascites, or encephalopathy in patients with known liver disease) were randomized to placebo or 5 ug/kg G-CSF (12 doses over month).  Exclusion criteria included hepatocellular carcinoma, portal vein thrombosis, multi-organ failure, sepsis, or grade 3 or 4 encephalopathy.  Primary end point was survival at day 60.

Results:
Cohort: In total, 47 patients were randomized with 23 patients to G-CSF and 24 patients to placebo.  Majority of patients were male in each group (3 females in each group).  Mean age was 40 in either arm.  Both groups were balanced in terms of MELD score, grade of varices, CTP score, liver enzyme levels, and encephalopathy.  Most patients had acute alcoholic hepatitis.  The placebo group had more HBV reactivation liver injury.

CD 34 Cells: To verify whether G-CSF actually led to stem cell engrafment, authors compared CD34 cells in liver at baseline and at day 30.  Compared to baseline value of 27.5% CD34 cells in sinusoids (based on cell counting in immunohistochemistry), G-CSF treatment resulted in 45% CD34 cells in sinusoids.  No increase was seen in the placebo group (CD34 cells decreased from 30% to 20%).

Survival: The actuarial probability of survival was 66% with G-CSF versus 26% with placebo (p=0.001).  In total, 7 patients died in G-CSF group versus 17 deaths in placebo arm (majority from progressive multi-organ failure, mostly HRS)

MELD Scores: .Median change in MELD score at days 7, 30, and 60 was -7.4%, -18.23%, and -15.34% in G-CSF group versus +3.33%, +6.25%, and +11.76% in placebo group.

Adverse Effects: G-CSF treatment resulted in three adverse events - one had transient rash, one had herpes zoster, and one had high fevers.  Other patients completed therapy without reported adverse effects.

Discussion: This small randomized trial suggests that G-CSF has significant mortality benefit in acute on chronic liver failure!  In the two month trial period, there were 10 fewer deaths in the G-CSF group suggesting an amazingly large benefit.  There are, of course, a few caveats to this trial.  With the number of recruited patients numbering in the 20s in each group, there is no guarantee that the groups were actually well-balanced.  Also, with two month follow-up, it is unclear whether the effects of G-CSF are persistent or transient.  Clearly, this smaller trial calls for a larger, better designed randomized trial.  In the meantime, if someone with acute on chronic liver failure is perishing on standard therapy, I would strongly consider G-CSF therapy.