Role of granulocyte colony stimulating factor in the treatment of cirrhosis of liver: a systematic review

Abstract

Objective

We performed a systematic review to analyze the benefits of and risk factors associated with granulocyte colony stimulating factor (GCSF) in patients with liver cirrhosis.

Methods

PubMed, Scopus, and Embase were searched for randomized controlled trials and case–control studies that compared the use of GCSF with another treatment or control group. The Jadad and Newcastle–Ottawa scales were used to assess the risk of bias in the included studies. The primary outcome studied was mortality; and the secondary outcomes were the disease severity score, liver transplantation criteria, complications, CD34⁺ cell count, adverse events, and health-related quality of life (HRQOL). PROSPERO registration number CRD42023416014.

Results

The initial search yielded 2,235 studies, of which seven studies of 670 patients with liver cirrhosis were included. Multiple cycles of GCSF significantly improved the survival rate, disease severity score, CD34⁺ cell count, and HRQOL; and significantly reduced the incidences of liver transplantation, ascites, infection, and hepatic encephalopathy. Fatigue and backache were the most commonly reported adverse events.

Conclusion

GCSF significantly improves the survival rate and disease severity scores, and reduces the incidence of complications in patients with liver cirrhosis. The administration of GCSF is likely to be effective in patients awaiting liver transplantation.

Keywords

Liver cirrhosis granulocyte colony-stimulating factor therapy mortality disease severity score liver transplantation survival adverse event complication

Introduction

Liver cirrhosis is a leading cause of morbidity globally. Cirrhosis is defined as the development of nodules, surrounded by fibrous bands, in response to repetitive chronic liver injury, and it ultimately leads to portal hypertension and end-stage liver disease.^1,2 In addition, cirrhosis of the liver is associated with a higher risk of liver cancer.³ Liver transplantation is currently the definitive treatment for liver cirrhosis. However, recent advances in the management of liver cirrhosis have improved treatment outcomes and health-related quality of life (HRQOL).⁴ A few recent studies have shown that bone marrow-derived cells, including multipotent stem cells, are capable of self-renewal and differentiation into various adult cell types, including hepatocytes.^5–7 In addition, one study has demonstrated a positive effect of bone marrow cells in vitro in models of acute and chronic liver damage, and that they can populate the liver and contribute to hepatic regeneration.⁸ Granulocyte colony stimulating factor (GCSF) administration has been shown to be an effective, well-tolerated, and non-invasive means of mobilizing bone marrow cells.^9,10 Most human tissues can secrete GCSF in response to stimulation by interleukin-1, lipopolysaccharide, or tumor necrosis factor-alpha, which are produced by macrophages, endothelial cells, fibroblasts, and other mesenchymal cells.^11–13 GCSF receptor is expressed by neutrophils and their precursors, and signals through the janus kinase-signal transducer and activator of transcription pathway or through the phosphorylation of Lyn, activating the phosphoinositol 3-kinase/AKT pathway, which is involved in the development of liver fibrosis. GCSF also plays a role through the activation of the Ras-mitogen-activated protein kinase (MAPK) pathway via the tyrosine kinases Lyn and Hck.^14,15

The Ras-MAPK pathway has been implicated in the development and progression of hepatocellular carcinoma in patients with liver cirrhosis.^16,17 Ordelheide et al. reported that GCSF promotes free fatty acid-induced insulin resistance; and patients with liver cirrhosis who have co-morbidities such as obesity, metabolic syndrome, and insulin resistance, and are being administered GCSF, are at higher risk of disease progression.¹⁸ Furthermore, Stroncel et al. reported a mean 20% increase in splenic size in patients administered GCSF at 10 μg/kg/day for 5 days.¹⁹ Larger spleens receive greater blood flow, which is associated with portal hypertension, a condition that can cause the progression of liver cirrhosis-related complications. The effects of GCSF to improve liver function and ameliorate fibrosis have been identified through the study of CD34⁺ bone marrow-derived cell mobilization. Recent studies have shown beneficial effects of the administration of GCSF to patients with acute-on-chronic liver failure (ACLF)²⁰ or alcoholic hepatitis.²¹ However, studies regarding the effects of GCSF when administered to patients with liver cirrhosis, with respect to safety profile, quality of life, long-term outcomes, and the optimal dose and duration of administration, have been few in number to date. Therefore, in the present study, we aimed to evaluate the effects of GCSF in patients with liver cirrhosis by conducting a systematic review of randomized controlled trials and case–control studies of the use of this substance.

Because the study was a systematic review, the requirements for ethics approval and the informed consent of the participants were waived.

Methods

Literature search

An extensive literature search was performed using PubMed, Scopus, and Embase. In the first phase of the search, we used “granulocyte-colony stimulating factor”, “GCSF”, “G-CSF”, “lenograstim”, “filgrastim”, “pegfilgrastim”, and “lipegfilgrastim” as search terms; and in the second phase we used “liver cirrhosis”, “decompensated cirrhosis”, and “cirrhosis”. The results of the first and second search phases were combined, and citations were imported into Zotero v.5.0 (Corporation for Digital Scholarship, Vienna, VA, USA). Two authors (SR and PBM) independently screened the eligible studies, and a third author (BM) helped settle any disagreement regarding the application of the inclusion and exclusion criteria (Figure 1).

Figure 1.

Preferred reporting items for systematic reviews and meta-analyses flow diagram.

Inclusion and exclusion criteria

We selected all the randomized controlled trials and case–control studies conducted between May 2013 and August 2022 that concerned liver cirrhosis and GCSF and involved a comparison with standard medical therapy and/or placebo. The primary outcome was mortality or survival rate; and the secondary outcomes of the changes in the model for end-stage liver disease (MELD)/MELD-Na and Child–Turcotte–Pugh (CTP) scores, the improvement in liver cirrhosis and related complications, hospitalization, spontaneous bacterial peritonitis, variceal hemorrhage, the requirement for liver transplantation, adverse events, and quality of life. Only publications in English were considered; and review articles, case reports, case series, editorials, and studies with insufficient or incomplete data were excluded. In cases of duplicate publication, the data from the most recent publication were included.

Data extraction

Two authors (SR and PBM) independently assessed the eligible studies for the following information: (i) study description, including author name, year of publication, study location, target population, study design and size, treatment used, and the nature of the control group; (ii) liver cirrhosis-related findings, including CTP score, MELD or MELD-Na score, ascites, spontaneous bacterial peritonitis, sepsis, acute kidney injury, variceal hemorrhage, hepatic encephalopathy, mortality or survival rate, liver function, the requirement for liver transplantation, HRQOL, and adverse events.

Quality assessment

Two independent reviewers (SR and PBM) evaluated the risk of bias associated with, and the quality of, each study using the Newcastle–Ottawa Scale (NOS)²² and Jadad²³ scales. The NOS is used to evaluate the selection of cases and controls, their comparability, and outcome assessments. The Jadad score consists of three parameters: randomization, masking, and the accounting for all the participants, including withdrawals. The first five questions were scored as one each if the answer is yes, and minus one if the method of randomization or blinding was inappropriate. The overall score varies from 0 (very poor) to 5 (rigorous).

Data synthesis and analysis

We tabulated the results or outcomes from each study in detail to more readily identify patterns within the data. We performed a narrative data synthesis because we considered that the data were unsuitable for a formal quantitative meta-analysis owing to the considerable variation in study design, reported outcomes, and outcome metrics. The study was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines.²⁴

Registration

We did not prospectively register this trial, but it was registered retrospectively with PROSPERO, with registration number CRD42023416014.

Results

Search results and included studies

The initial search yielded 2235 records (PubMed, 646; Scopus, 686; and Embase, 929). After screening of the titles and for duplicates, 583 records were analyzed, of which 572 did not meet the inclusion criteria. Of the remaining 11, 4 more studies were excluded because two were review articles and two were original studies comparing the use of a GCSF-erythropoietin combination with placebo. The remaining seven studies met the inclusion criteria and were included in the systematic review (Figure 1).

Study characteristics

Of the seven selected studies,^25–31 five were randomized controlled trials^25,28–31 and two were case–control studies^26,27 with a control group. Five studies were conducted in India,^{25,26,28–30} one in Italy,²⁷ and one in the UK.³¹ All the included studies involved the administration of GCSF to the treatment group and the use of standard medical therapy in both the treatment and control groups. Newsome et al.³⁰ and Verma et al.³¹ presented additional data regarding the use of a stem cell infusion and growth hormone, respectively. Collectively, the studies presented data for 670 patients with liver cirrhosis (n; = 377 in the treatment group and n; = 293 in the control group). In all the included studies, CTP, MELD, CD34⁺ cells, liver function, and liver cirrhosis-related complications and adverse events were assessed. In one study, a historical control group was used for patient matching,²⁵ HRQOL was assessed in two studies,^26,29 and the relationship between splenic diameter and CD34⁺ cell count was assessed in one study²⁷ (Tables 1 and 2).

Table 1.

Characteristics of the included case–control studies and randomized controlled trials.

First author, Country	Study design	Study criteria		Study size		Intervention		Outcomes
First author, Country	Study design	Inclusion criteria	Exclusion criteria	Treatment	Control	Treatment	Control	Outcomes
De, India²⁵	Open-label RCT	Age 18–80 years DLC, irrespective of etiology	ACLF, spleen ≥18 cm, HCC, PVT, recent variceal hemorrhage, alcoholic hepatitis, cardiac dysfunction, recent alcohol intake	50	50	GCSF 5 μg/kg sc BD for 5 days at 3 monthly intervals for four cycles	SMT	12-month survival rate, CTP, and MELD score were significantly better in the treatment group Significant increase in peripheral CD34⁺ and leukocyte counts on day 6 Better control of ascites in the treatment group after 6 and 12 months Less frequent infection and hospitalization in the treatment group Significantly lower LSM values Significantly better HRQOL in the treatment group Vast majority of the patients in both groups died because of sepsis Fatigue and back pain were the most common adverse events, followed by bone pain, pyrexia, arthralgia, and nausea in the treatment group
Venkitaraman, India²⁹	Double-blind RCT	Age ≥18 years DLC, irrespective of etiology	ACLF, spleen >18 cm, HCC, variceal hemorrhage during the preceding 7 days, PVT, uncontrolled diabetes, renal dysfunction, alcohol use during the preceding 3 months	33	33	GCSF 5 μg/kg s/c Q12h for 5 days, once every 3 months over 4 cycles, plus SMT	Placebo + SMT	Overall survival and the incidence of hospitalization tended to be better in the treatment group Significantly larger spleen and higher CD34⁺ count in the treatment group on day 6 Significantly lower CTP in the treatment group after 12 months No significant difference in the median MELD score after 12 months Significantly lower incidence of infection in the treatment group Superior ascites control in the treatment group Significantly lower incidence of SBP in the treatment group. However, with respect to non-SBP infection, there was no significant difference No significant improvement in QOL Body ache, backache, headache, and fever were the most frequently reported adverse effects Majority of patients died because of multi-organ failure and sepsis
Prajapati, India²⁸	Open-label RCT	Age 18–75 years Patients with DLC CTP score 9–13 Listed for LT	HCC or other malignancy, sepsis, cardiopulmonary disease, HRS, HE grades III & IV, active variceal hemorrhage, HIV, pregnancy	126	127	GCSF (Filgrastim) 300 μg s/c BD for 5 days	SMT	6-month survival was superior in the treatment group CTP score significantly lower or similar in the treatment group vs. the control group. Significantly higher peripheral TLC and CD34⁺ count in the treatment group on day 6. In both groups the majority of the patients died because of multiple organ failure, including gastrointestinal hemorrhage, HE, SBP, ACS, HRS, renal failure, sepsis, and pneumonia Body ache, nausea, and vomiting were the most common adverse events in the treatment group
Gaia, Italy²⁷	Case–control	Age 18–80 years DLC, irrespective of etiology CTP >6 and MELD>12 At least one episode of liver failure, including ascites, variceal hemorrhage, porto-systemic encephalopathy	LT candidate, spleen diameter >180 mm, HCC or other malignancy, gastrointestinal hemorrhage owing to PHTN, recurrent episode of PVT, renal or cardiac dysfunction, acute infection, active use of alcohol	15	15	GCSF (Linograstim) 5 μg/kg BD for 3 consecutive days, repeated every 3 months plus SMT	SMT	Significantly higher peripheral CD34⁺ count, with significantly lower peaks during cycles 1 to 4 Similar or higher CD34⁺ cell count in peritoneal ascites fluid on the peak day of mobilization Significant inverse relationship between spleen size and CD34⁺ cell mobilization Significant improvement in the CTP score, but no difference in the MELD score Liver function did not show a significant change between baseline and follow-up Similar incidences of liver-related complications Significantly higher CFU-GM on day 4 in the treatment group Significantly larger splenic diameter Bone pain was reported by four patients
Philips, India²⁶	Case–control	Age ≥18 years DLC with active ascites or jaundice Prior hepatic encephalopathy unrelated to portosystemic shunting Prior SBP, AKI-HRS, or severe sepsis, or a combination	HCC, IHD, alcoholic hepatitis, shunt-related refractory HE, history of TIPS, CKD, maintenance hemodialysis, use of alternative medicine	56	24	GCSF (Filgrastim 5 μg/kg BD for 5 days, followed by OD every third day (total of 12 doses) plus SMT	SMT	Significantly lower CTP and MELD scores at all time points Significantly less ascites after 3, 6, and 12 months, with substantial worsening between 6 and 12 months in the treatment group Incidence of AVB tended to be higher in the treatment group Significantly lower HE at all time points (3, 6, and 12 months) Significantly lower incidence of AKI after 3 months Significantly higher incidence of AKI after 6 months Significantly less frequent ICU admission after 3 months, but this was significantly more frequent after 6 and 12 months Significantly lower incidence of sepsis after 3 months, but significantly higher incidence after 6 and 12 months Significantly lower total bilirubin after 6 months, but this was slightly higher after 12 months Significantly higher albumin at all time points (3, 6, and 12 months) Mortality was significantly higher in the treatment group after 12 months

ACS, acute coronary syndrome; AKI, acute kidney injury; AVB, acute variceal bleeding; BD, twice a day; CFU-GM, colony-forming unit-granulocyte–macrophage; CTP, Child–Turcotte–Pugh; HE, hepatic encephalopathy; HRQOL, health-related quality of life; HRS, hepatorenal syndrome; ICU, intensive care unit; LSM, liver stiffness measurement; MELD, model for end-stage liver disease; OD, once a day; SBP, spontaneous bacterial peritonitis; SC, subcutaneous; SMT, standard medical therapy, DLC, decompensated liver cirrhosis.

Table 2.

Characteristics of the included randomized controlled trials.

First author, country	Type of study	Inclusion criteria	Exclusion criteria	Number of participants undergoing Treatment 1	Number of participants undergoing Treatment 2	Number of controls	Treatment 1	Treatment 2	Control	Outcomes
Newsome, UK³⁰	Open-label RCT	Age ≥18 years, irrespective of etiology MELD score of 11–15	Alcohol consumption within the preceding 6 months, well-controlled ascites with no change in diuretic use, active HE, PHTN hemorrhage with an episode requiring hospitalization, HCC, and auto-immune hepatitis	26	27	23	GCSF (Lenograstim) 15 μg/kg OD for 5 days + SMT	GCSF (Lenograstim) 15 μg/kg OD for 5 days + stem cell infusion on days 5, 30, and 60 + SMT	SMT	No significant differences in mortality or the need for liver transplantation No significant differences in HRQOL No significant differences in liver-related parameters No significant differences in the MELD or UKELD scores between days 0 and 360 More adverse events in the GCSF + stem cell infusion group than in the GCSF group
Verma, India³¹	Open-label RCT	Age ≥18 years DLC, irrespective of etiology	ACLF, AKI, uncontrolled diabetes, HCC, PVT, variceal hemorrhage during the preceding 7 days, alcohol abuse during the preceding 3 months, pregnancy	21	23	21	GCSF 5 μg/kg Q12h for 5 days, then every 3 months for 3 days until 12 months + SMT	GH 1 U s/c per day for 12 months + GCSF 5 μg/kg Q12h for 5 days, then every 3 months for 3 days until 12 months + SMT	SMT	Significantly lower mortality in the GCSF + GH group than in the GCSF and SMT group Significantly better TFS in the GCSF and GCSF + GH groups than in the control group Significantly larger numbers of leukocytes and CD34⁺ cells in the GCSF and GCSF + GH groups on day 6 Significantly lower MELD and CTP scores in the GCSF and GCSF + GH groups after 12 months Significantly less requirement for LT in the GCSF and GCSF + GH groups Significantly less LVP, ascites, HE, and liver stiffness in the GCSF and GCSF + GH groups Significantly lower incidence of sepsis in the GCSF and GCSF + GH groups Backache, fatigue, bone pain, and fever were the most frequently reported adverse events

ACLF, acute on chronic liver failure; AKI, acute kidney injury; CTP, Child–Turcotte–Pugh; DLC, decompensated liver cirrhosis; GCSF, granulocyte colony stimulating factor; GH, growth hormone; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; HRQOL, health-related quality of life; LT, liver transplantation; LVP, large volume paracentesis; MELD, model for end-stage liver disease; OD, once a day; PHTN, portal hypertension; PVT, portal vein thrombosis; RCT, randomized controlled trial; SC, subcutaneous; SMT, standard medical therapy; TFS, transplant-free survival.

Risk of bias and quality assessment

The evaluation method and the inclusion and exclusion criteria were explained prior to the enrolment of the participants in all the included studies. In addition, the same diagnostic tests were performed for both the treatment and control groups over similar periods of time. None of the studies were excluded on the basis of the results of the risk of bias assessment (Table 3).

Table 3.

Results of the quality assessment of the included studies

Study	Jadad Scale
	Randomization		Blinding		Accounts for all patients	Total score
	Information regarding randomization	Appropriate randomization	Information regarding blinding	Appropriate blinding	Accounts for all patients	Total score
De²⁵	1	1	1	0	1	4/5
Prajapati²⁸	1	1	1	0	1	4/5
Venkitaraman²⁹	1	1	1	1	1	5/5
Newsome³⁰	1	1	1	0	1	4/5
Verma³¹	1	1	1	0	1	4/5
Study	NOS Scale
Study	Selection				Comparability	Exposure			Total
	Adequacy of the selection definition	Representativeness of the treated participants	Selection of controls	Definition of controls	Comparability of treated participants and controls on the basis of the design or analysis	Ascertainment of exposure	Same method of ascertainment for treated patients and controls	Non-exposure rate
Gaia²⁷	1	1	1	1	1 + 1	1	1	1	9
Philips²⁶	1	1	1	1	1 + 1	1	1	1	9

Outcomes

Mortality

Three of the seven studies^25,28,31 showed significantly lower mortality in the GCSF group. However, Philips et al.²⁶ reported an increase in mortality after 12 months of GCSF treatment, and Newsome et al.³⁰ reported no difference in mortality between the GCSF and control groups. Venkitaramen et al.²⁹ reported less mortality in the GCSF group, although the difference from the control group was not significant. De et al.,²⁵ Prajapati et al.,²⁸ and Venkitaraman et al.²⁹ reported that the majority of their participants died because of sepsis and multi-organ failure (Tables 1 and 2).

Disease severity score

Six of the studies showed improvements in CTP score from baseline.^25–29,31 In addition, the MELD score was reported as an outcome in six of the studies,^{25–27,29–31} three of which^25,28,31 showed significant improvements in the MELD score. Gaia et al.,²⁷ Venkitaraman et al.,²⁹ and Newsome et al.³⁰ reported no change in the MELD score from baseline (Tables 1 and 2).

Liver transplantation

Two of the studies^25,31 showed that significantly fewer participants in the GCSF group fulfilled the criteria for liver transplantation (Tables 1 and 2). In addition, Newsome et al.³⁰ reported a non-significant difference in the requirement for liver transplantation in the GCSF and GCSF-plus-stem cell infusion groups vs. the control group.

Complications

Liver cirrhosis-related complications were reported in four of the studies.^25,26,29,31 Significantly less ascites,^25,26,29 less frequent infections,^25,29 a lower incidence of spontaneous bacterial peritonitis (SBP),²⁹ a lower incidence of hospitalization,²⁶ less frequent hepatic encephalopathy,^26,31 and less acute kidney injury²⁶ were reported. However, Philips et al.²⁶ reported non-significantly higher incidence of acute variceal hemorrhage and significantly higher incidences of acute kidney injury and sepsis after 3 months of treatment (Tables 1 and 2).

Change in CD34⁺ count

Outcomes related to CD34⁺ cell count were reported in five studies.^{25,27–29,31} All five studies showed significantly higher peripheral CD34⁺ cell count in the treatment group. However, Gaia et al.²⁷ reported a significant inverse relationship between splenic size and CD34⁺ cell mobilization. In addition, the authors reported comparable or higher CD34⁺ cell count in the peritoneal ascitic fluid of the participants on the peak day of mobilization (Tables 1 and 2).

Adverse events

Adverse events were reported in five of the studies,^{25,27–29,31} but none were severe or life-threatening. Fatigue, bone pain, back pain, nausea, and vomiting were the most commonly reported adverse events (Tables 1 and 2).

Health-related quality of life

HRQOL was reported in two of the studies. De et al.²⁵ and Venkitaraman et al.²⁹ reported significantly and non-significantly higher HRQOL, respectively, in the treatment group (Table 1).

Discussion

Liver cirrhosis progresses through several clinical phases, and culminates in death or liver transplantation. The effects of GCSF in patients with liver cirrhosis have varied in previous studies. Therefore, we performed a systematic review and quantitative analysis of five randomized controlled trials and two case–control studies to better understand its effects. These studies were published between 2013 and 2022, and included a total of 377 participants who received GCSF therapy.

Most importantly, we noted a positive effect of GCSF on the survival of patients with liver cirrhosis. In addition, the included studies showed superior CTP scores, but no significant difference in the MELD scores, in the participants in the GCSF group. The movement of bone marrow cells to the liver is the most likely mechanism for GCSF-induced liver regeneration. Consistent with this, the meta-analysis conducted by Marot et al.²¹ showed that the use of GCSF is associated with a reduction in mortality of > 70% after 3 months in patients with acute hepatitis vs. controls. However, we cannot be certain whether this survival benefit may be the result of a non-significant reduction in mortality rate, and the precise mechanism whereby GCSF has clinical benefits remains unclear.

The mode of action of GCSF may involve the direct stimulation of liver regeneration by hepatic progenitor cell proliferation or an increase the mobilization of bone marrow stem cells (CD34⁺), which differentiate and proliferate into mature hepatocytes.^32,33 The success of the treatment can be attributed to an improvement in immune cell function and fewer infectious complications, as well as the larger numbers of CD34⁺ stem cells in the liver, which may facilitate its recovery from injury. A comparable improvement in survival was shown in further studies of patients with acute alcoholic hepatitis or decompensated cirrhosis who were treated with GCSF. ³⁴ In the present review, we found that the administration of GCSF significantly increased the CD34⁺ stem cell count, which is noteworthy, because studies that have demonstrated the mobilization of CD34⁺ showed superior outcomes. Similar results regarding CD34⁺ cells have been obtained in four previous studies of patients with ACLF 6 days following GCSF administration, compared with controls.^25,35–37

There were no notable findings regarding liver transplantation-related outcomes in GCSF-treated patients in the present review. However, we also investigated whether there is a relationship between GCSF administration and the complications related to liver cirrhosis. Previously, significant improvements in ascites,^25,26,29 infection,^25,29 SBP,²⁹ hospitalization,²⁶ hepatic encephalopathy,^26,31 and acute kidney injury²⁶ have been identified in GCSF-treated patients. There is evidence that the stimulation of CD34⁺ cells following their mobilization by GCSF treatment ameliorates the features of cirrhosis: it reduces the volume of ascites fluid and improves albumin and bilirubin synthesis.³⁸ A meta-analysis conducted by Huang et al.³⁹ showed that there are lower incidences of hepatic encephalopathy, sepsis, and hepatorenal syndrome in GCSF-treated patients. The prevalence of infection in patients that were treated with GCSF or not was 25% and 32%, respectively.

Regarding adverse events, in the present review, we identified such events in the GCSF group, but none were categorized as being severe or life-threatening. The most commonly reported adverse events were fatigue, bone pain, back pain, nausea, and vomiting, as documented in Tables 1 and 2. In a multi-center randomized trial (the GRAFT study) conducted by Engelmann et al.,²⁰ adverse events were also recorded in the GCSF group, and the systematic review and meta-analysis by Chavez-Tapia et al.⁴⁰ documented mild adverse effects, such as fever, rash, herpes zoster infection, headache, and nausea.

The quantification of HRQOL is essential as part of the assessment of the status of patients with liver cirrhosis, but in only two of the included studies^25,29 the values of this metric were compared between the groups.

We have revealed superior outcomes relating to certain aspects of cirrhosis in patients treated with GCSF, but it is important to note that the magnitude of the differences may not be particularly biologically significant. Therefore, its overall impact on patients with liver cirrhosis may not be substantial. However, to optimize the therapeutic and safety profile, more high-quality research is necessary to better characterize the role of GCSF in liver cirrhosis therapy.

We acknowledge that the present review has several limitations. First, only seven studies were included, the majority of which generated heterogeneous data and lacked qualitative and quantitative results. Second, five of the studies showed promising results of using GCSF in patients with liver cirrhosis, which introduces social desirability bias into the present study. Finally, the number of participants enrolled and analyzed in the studies differed, which weakens the reliability of the findings.

In conclusion, the role of GCSF in the treatment of liver cirrhosis remains controversial. However, it may be useful in patients with liver cirrhosis who are awaiting liver transplantation. The majority of the studies of its use have shown significantly lower mortality and liver cirrhosis-related complications, but because most lacked sufficient quantitative and qualitative data, we recommend that further randomized controlled trials are performed to assess the effects of GCSF in patients with liver cirrhosis more comprehensively.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231207064 - Supplemental material for Role of granulocyte colony stimulating factor in the treatment of cirrhosis of liver: a systematic review

Supplemental material, sj-pdf-1-imr-10.1177_03000605231207064 for Role of granulocyte colony stimulating factor in the treatment of cirrhosis of liver: a systematic review by Siddheesh Rajpurohit, Balaji Musunuri, Pooja Basthi Mohan, Ganesh Bhat and Shiran Shetty in Journal of International Medical Research

Footnotes

Author contributions

SR: Conceptualization, methodology, resources, writing - original draft, writing - review and editing.

BM: Conceptualization, writing - review and editing, supervision.

PBM: writing - original draft, writing - review and editing.

GB: writing - review and editing, supervision.

SS: writing - review and editing, supervision.

Declaration of conflicting interests

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

ORCID iD

Shiran Shetty

References

Dooley

Garcia-Tsao

Lok

, et al. Sherlock’s diseases of the liver and biliary system. 6th ed. Wiley Blackwell 2018.

Schuppan

Afdhal

Liver cirrhosis. Lancet 2008; 371: 838–851.

Musunuri

Shetty

Bhat

, et al. Profile of patients with hepatocellular carcinoma: an experience from a tertiary care center in India. Indian J Gastroenterol 2022; 41: 127–134.

Rajpurohit

Musunuri

Shailesh , et al. Novel drugs for the management of hepatic encephalopathy: still a long journey to travel. J Clin Exp Hepatol 2022; 12: 1200–1214.

Haga

Wakabayashi

Shimazu

, et al. In vivo visualization and portally repeated transplantation of bone marrow cells in rats with liver damage. Stem Cells Dev 2007; 16: 319–328.

Chan

Shek

, et al. High frequency of chimerism in transplanted livers. Hepatology 2003; 38: 989–998.

Gaia

Cappia

Smedile

, et al. Epithelial microchimerism: consistent finding in human liver transplants. J Gastroenterol Hepatol 2006; 21: 1801–1806.

Schwartz

Reyes

Koodie

, et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 2002; 109: 1291–1302.

Tarella

Ferrero

Bregni

, et al. Peripheral blood expansion of early progenitor cells after high-dose cyclophosphamide and rhGM-CSF. Eur J Cancer 1991; 27: 22–27.

10.

Levesque

Winkler

Mobilization of hematopoietic stem cells: state of the art. Curr Opin Organ Transplant 2008; 13: 53–58.

11.

Cheers

Haigh

Kelso

, et al. Production of colony-stimulating factors (CSFs) during infection: separate determinations of macrophage-, granulocyte-, granulocyte-macrophage-, and multi-CSFs. Infect Immun 1988; 56: 247–251.

12.

Vellenga

Rambaldi

Ernst

, et al. Independent regulation of M-CSF and G-CSF gene expression in human monocytes. Blood 1988; 71: 1529–1532.

13.

Sano

Ohashi

Sato

, et al. A possible role of autogenous IFN-beta for cytokine productions in human fibroblasts. J Cell Biochem 2007; 100: 1459–1476.

14.

Jones

Chan

Interleukin-17 stimulates the expression of interleukin-8, growth-related oncogene-alpha, and granulocyte-colony-stimulating factor by human airway epithelial cells. Am J Respir Cell Mol Biol 2002; 26: 748–753.

15.

Tian

Tapley

Sincich

, et al. Multiple signaling pathways induced by granulocyte colony-stimulating factor involving activation of JAKs, STAT5, and/or STAT3 are required for regulation of three distinct classes of immediate early genes. Blood 1996; 88: 4435–4444.

16.

Delire

Stärkel

The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications. Eur J Clin Invest 2015; 45: 609–623.

17.

Zhao

Shi

, et al. The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC. Oncol Lett 2016; 12: 3045–3050.

18.

Ordelheide

Gommer

Böhm

, et al. Granulocyte colony-stimulating factor (G-CSF): a saturated fatty acid-induced myokine with insulin-desensitizing properties in humans. Mol Metab 2016; 5: 305–316.

19.

Stroncek

Shawker

Follmann

, et al. G-CSF-induced spleen size changes in peripheral blood progenitor cell donors. Transfusion 2003; 43: 609–613.

20.

Engelmann

Herber

Franke

, et al. Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: a multicenter randomized trial (GRAFT study). J Hepatol 2021; 75: 1346–1354.

21.

Marot

Singal

Moreno

, et al. Granulocyte colony-stimulating factor for alcoholic hepatitis: A systematic review and meta-analysis of randomised controlled trials. JHEP Rep 2020; 2: 100139.

22.

Jadad

Moore

Carroll

, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 1–12.

23.

Ottawa Hospital Research Institute [Internet]. Ohri.ca. 2022 [cited 11 June 2022]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

24.

Moher

Liberati

Tetzlaff

, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: B2535.

25.

Kumari

Singh

, et al. Multiple cycles of granulocyte colony-stimulating factor increase survival times of patients with decompensated cirrhosis in a randomized trial. Clin Gastroenterol Hepatol 2021; 19: 375–383.e5.

26.

Philips

Augustine

Rajesh

, et al. Granulocyte colony-stimulating factor use in decompensated cirrhosis: lack of survival benefit. J Clin Exp Hepatol 2020; 10: 124–134.

27.

Gaia

Olivero

Smedile

, et al. Multiple courses of G-CSF in patients with decompensated cirrhosis: consistent mobilization of immature cells expressing hepatocyte markers and exploratory clinical evaluation. Hepatol Int 2013; 7: 1075–1083.

28.

Prajapati

Arora

Sharma

, et al. Granulocyte colony-stimulating factor improves survival of patients with decompensated cirrhosis. Eur J Gastroenterol Hepatol 2017; 29: 448–455.

29.

Venkitaraman

Verma

, et al. Multiple cycles of granulocyte colony-stimulating factor in decompensated cirrhosis: a double-blind RCT. Hepatol Int 2022; 16: 1127–1136.

30.

Newsome

Fox

King

, et al. Granulocyte colony-stimulating factor and autologous CD133-positive stem-cell therapy in liver cirrhosis (REALISTIC): an open-label, randomised, controlled phase 2 trial. Lancet Gastroenterol Hepatol 2018; 3: 25–36.

31.

Verma

Kaur

Sharma

, et al. Outcomes after multiple courses of granulocyte colony‐stimulating factor and growth hormone in decompensated cirrhosis: a randomized trial. Hepatology 2018; 68: 1559–1573.

32.

Dubuquoy

Louvet

Lassailly

, et al. Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis. Gut 2015; 64: 1949–1960.

33.

Moreau

Rautou

G-CSF therapy for severe alcoholic hepatitis: targeting liver regeneration or neutrophil function?

Am J Gastroenterol 2014; 109: 1424–1426.

34.

Singh

Keisham

Bhalla

, et al. Efficacy of granulocyte colony-stimulating factor and N-acetylcysteine therapies in patients with severe alcoholic hepatitis. Clin Gastroenterol Hepatol 2018; 16: 1650–1656.e2.

35.

Garg

Khan

, et al. Granulocyte colony-stimulating factor mobilizes CD34(+) cells and improves survival of patients with acute-on-chronic liver failure. Gastroenterology 2012; 142: 505.e1–512.e1.

36.

Singh

Sharma

Narasimhan

, et al. Granulocyte colony-stimulating factor in severe alcoholic hepatitis: a randomized pilot study. Am J Gastroenterol 2014; 109: 1417–1423.

37.

Duan

Liu

Tong

, et al. Granulocyte-colony stimulating factor therapy improves survival in patients with hepatitis B virus-associated acute-on-chronic liver failure. World J Gastroenterol 2013; 19: 1104–110.

38.

Sharma

Rao

Sasikala

, et al. Autologous mobilized peripheral blood CD34+ cell infusion in non-viral decompensated liver cirrhosis. World J Gastroenterol 2015; 21: 7264–7271.

39.

Huang

, et al. Effectiveness of granulocyte colony-stimulating factor for patients with acute-on-chronic liver failure: a meta-analysis. Ann Saudi Med 2021; 41: 383–391.

40.

Chavez-Tapia

Mendiola-Pastrana

Ornelas-Arroyo

, et al. Granulocyte-colony stimulating factor for acute-on-chronic liver failure: systematic review and meta-analysis. Ann Hepatol 2015; 14: 631–641.

Supplementary Material

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Role of granulocyte colony stimulating factor in the treatment of cirrhosis of liver: a systematic review

Abstract

Objective

Methods

Results

Conclusion

Keywords

Introduction

Methods

Literature search

Inclusion and exclusion criteria

Data extraction

Quality assessment

Data synthesis and analysis

Registration

Results

Search results and included studies

Study characteristics

Risk of bias and quality assessment

Outcomes

Mortality

Disease severity score

Liver transplantation

Complications

Change in CD34+ count

Adverse events

Health-related quality of life

Discussion

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231207064 - Supplemental material for Role of granulocyte colony stimulating factor in the treatment of cirrhosis of liver: a systematic review

Footnotes

Author contributions

Declaration of conflicting interests

Funding

ORCID iD

References

Supplementary Material

Change in CD34⁺ count