Key messages
In people with chronic liver disease with diffuse scarring (called cirrhosis) and impairment of liver function, the infusion of granulocyte colony-stimulating factor (G-CSF) may reduce the risk of death in comparison with standard treatment. Unexpected effects were either poorly reported, or the information was unclear. G-CSF is a protein that stimulates the growth and spread of undifferentiated cells (immature cells that do not have specialised structures or functions) or partially differentiated (incompletely specialised) cells into the bloodstream and organs, such as the liver. G-CSF may be administered alone or in combination with another drug. As we are not confident in the evidence provided by the available studies that assessed G-CSF, the results of this review are likely untrustworthy. Also, the included studies in the review were too different from each other to allow us to draw firm conclusions based on the evidence.
Why is it important to treat people with advanced chronic liver disease?
A wide range of diseases can cause continuous and repeated damage to the liver, which leads to progressive scarring and impairment of the liver function. When damage to the liver is irreversible, it is defined as chronic. Globally, advanced chronic liver disease is considered responsible for more than one million deaths every year. No treatment is available to specifically target liver scarring, and liver transplantation remains the only curative option. Many researchers are investigating strategies to restore the functions of the liver to avoid or slow progression towards end-stage liver disease (that is, the final stage of a progressive liver condition, such as cirrhosis of the liver, progressive hepatitis (for example, viral hepatitis type C), or liver cancer), which ultimately requires a rescue liver transplantation.
What is granulocyte colony-stimulating factor?
Granulocyte colony-stimulating factor is a protein that stimulates the bone marrow to produce white blood cells and immature cells and release them into the bloodstream. This protein can be produced with recombinant DNA technology (DNA molecules formed by laboratory methods) and is currently used to preserve a safe level of white blood cells in people on chemotherapy for cancer. Also, G-CSF might regulate inflammation and improve the capacity of the liver to replace lost cells and survival in people with advanced chronic liver disease.
What did wewant to find out?
We wanted to find out if G-CSF, administered alone or in combination with other drugs to people with advanced chronic liver disease, compared with sham treatment or no treatment, is able to improve survival. We were also interested in assessing unwanted or harmful effects of this treatment, complications due to the liver disease, and the treatment effect on well-being.
What did we do?
We searched for randomised clinical trials that assessed the effect of multiple courses of G-CSF alone or in combination with other drugs in people with advanced chronic liver disease. In randomised controlled trials, study participants are assigned to groups that receive different treatments by chance (that is, at random).
What did we find?
We included a total of 20 studies with 1419 participants. A total of 188 out of 738 (25.4%) participants randomised to the G-CSF group, compared with 302 out of 681 (44.3%) participants in the control group, died. (The control group received standard medical therapy and other supportive measures.) The follow-up in the studies varied between 2 and 12 months. The studies were conducted from 2008 to 2022: 15 in Asia, 4 in Europe, and 1 in the USA. Eight studies included only people with alcoholic liver disease, and the other studies included people with different causes of liver disease, mainly chronic hepatitis B or C. Only few studies reported data on unwanted or harmful effects of the treatment and well-being. G-CSF seemed to reduce the proportion of participants with liver-related complications that may increase the risk of dying. We could not draw any firm conclusions for any of the studied outcomes because of the poor study designs, as this resulted in no confidence in the evidence. Therefore, we cannot be sure if there is a beneficial, harmful, or neutral effect of G-CSF compared with no treatment or sham treatment on the risk of death, unwanted or harmful effects of the treatment, and complications due to liver disease.
What are the limitations of the evidence?
Our confidence in the evidence is very low because the studies show many limitations, which can potentially lead to prejudiced results. There are not enough studies to be certain about the result estimates. Therefore, we need further randomised clinical studies of high quality.
How up to date is this evidence?
The evidence is up to date to 4 October 2022.
G-CSF, alone or in combination, seems to decrease mortality in people with decompensated advanced chronic liver disease of whatever aetiology and with or without acute-on-chronic liver failure, but the certainty of evidence is very low because of high risk of bias, inconsistency, and imprecision. The results of trials conducted in Asia and Europe were discrepant; this could not be explained by differences in participant selection, intervention, and outcome measurement. Data on serious adverse events and health-related quality of life were few and inconsistently reported. The evidence is also very uncertain regarding the occurrence of one or more liver disease-related complications. We lack high-quality, global randomised clinical trials assessing the effect of G-CSF on clinically relevant outcomes.
Advanced chronic liver disease is characterised by a long compensated phase followed by a rapidly progressive 'decompensated' phase, which is marked by the development of complications of portal hypertension and liver dysfunction. Advanced chronic liver disease is considered responsible for more than one million deaths annually worldwide. No treatment is available to specifically target fibrosis and cirrhosis; liver transplantation remains the only curative option. Researchers are investigating strategies to restore liver functionality to avoid or slow progression towards end-stage liver disease. Cytokine mobilisation of stem cells from the bone marrow to the liver could improve liver function. Granulocyte colony-stimulating factor (G-CSF) is a 175-amino-acid protein currently available for mobilisation of haematopoietic stem cells from the bone marrow. Multiple courses of G-CSF, with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, might be associated with accelerated hepatic regeneration, improved liver function, and survival.
To evaluate the benefits and harms of G-CSF with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, compared with no intervention or placebo in people with compensated or decompensated advanced chronic liver disease.
We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two trial registers (October 2022) together with reference-checking and web-searching to identify additional studies. We applied no restrictions on language and document type.
We only included randomised clinical trials comparing G-CSF, independent of the schedule of administration, as a single treatment or combined with stem or progenitor cell infusion, or with other medical co-interventions, with no intervention or placebo, in adults with chronic compensated or decompensated advanced chronic liver disease or acute-on-chronic liver failure. We included trials irrespective of publication type, publication status, outcomes reported, or language.
We followed standard Cochrane procedures. All-cause mortality, serious adverse events, and health-related quality of life were our primary outcomes, and liver disease-related morbidity, non-serious adverse events, and no improvement of liver function scores were our secondary outcomes. We undertook meta-analyses, based on intention-to-treat, and presented results using risk ratios (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI) and I2 statistic values as a marker of heterogeneity. We assessed all outcomes at maximum follow-up. We determined the certainty of evidence using GRADE, evaluated the risk of small-study effects in regression analyses, and conducted subgroup and sensitivity analyses.
We included 20 trials (1419 participants; sample size ranged from 28 to 259), which lasted between 11 and 57 months. Nineteen trials included only participants with decompensated cirrhosis; in one trial, 30% had compensated cirrhosis. The included trials were conducted in Asia (15), Europe (four), and the USA (one). Not all trials provided data for our outcomes. All trials reported data allowing intention-to-treat analyses. The experimental intervention consisted of G-CSF alone or G-CSF plus any of the following: growth hormone, erythropoietin, N-acetyl cysteine, infusion of CD133-positive haemopoietic stem cells, or infusion of autologous bone marrow mononuclear cells. The control group consisted of no intervention in 15 trials and placebo (normal saline) in five trials. Standard medical therapy (antivirals, alcohol abstinence, nutrition, diuretics, β-blockers, selective intestinal decontamination, pentoxifylline, prednisolone, and other supportive measures depending on the clinical status and requirement) was administered equally to the trial groups.
Very low-certainty evidence suggested a decrease in mortality with G-CSF, administered alone or in combination with any of the above, versus placebo (RR 0.53, 95% CI 0.38 to 0.72; I2 = 75%; 1419 participants; 20 trials). Very low-certainty evidence suggested no difference in serious adverse events (G-CSF alone or in combination versus placebo: RR 1.03, 95% CI 0.66 to 1.61; I2 = 66%; 315 participants; three trials). Eight trials, with 518 participants, reported no serious adverse events. Two trials, with 165 participants, used two components of the quality of life score for assessment, with ranges from 0 to 100, where higher scores indicate better quality of life, with a mean increase from baseline of the physical component summary of 20.7 (95% CI 17.4 to 24.0; very low-certainty evidence) and a mean increase from baseline of the mental component summary of 27.8 (95% CI 12.3 to 43.3; very low-certainty evidence).
G-CSF, alone or in combination, suggested a beneficial effect on the proportion of participants who developed one or more liver disease-related complications (RR 0.40, 95% CI 0.17 to 0.92; I2 = 62%; 195 participants; four trials; very low-certainty evidence).
When we analysed the occurrences of single complications, there was no suggestion of a difference between G-CSF, alone or in combination, versus control, in participants in need of liver transplantation (RR 0.85, 95% CI 0.39 to 1.85; 692 participants; five trials), in the development of hepatorenal syndrome (RR 0.65, 95% CI 0.33 to 1.30; 520 participants; six trials), in the occurrence of variceal bleeding (RR 0.68, 95% CI 0.37 to 1.23; 614 participants; eight trials), and in the development of encephalopathy (RR 0.56, 95% CI 0.31 to 1.01; 605 participants; seven trials) (very low-certainty evidence). The same comparison suggested that G-CSF reduces the development of infections (including sepsis) (RR 0.50, 95% CI 0.29 to 0.84; 583 participants; eight trials) and does not improve liver function scores (RR 0.67, 95% CI 0.53 to 0.86; 319 participants; two trials) (very low-certainty evidence).