Background
Acute-on-chronic liver failure (ACLF) is a global medical problem, with high prevalence and being serious, life-threatening in risk populations [
1,
2]. ACLF occurs in patients with undiagnosed or previously diagnosed chronic liver disease (CLD) and was distinguished from acute hepatic damages such as coagulopathy and jaundice and complicated within 4 weeks because of sites and/or encephalopathy [
3]. ACLF is usually accompanied by multiple organ failure, rapid progression and low survival rate. Liver transplantation is the sole solution that has proven beneficial, but the rapid disease progression and lack of donors limit its application [
4]. Therefore, it is urgent to find a safe and effective therapeutic approach to ACLF.
Nowadays, a novel therapeutic strategy, stem cell therapy, is beginning to apply in the treatment of ACLF. Stem cells are a kind of undifferentiated cells, which capable of unlimited proliferation [
5]. Cells such as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and unsorted bone marrow cells (BMCs) have all been used in the stem cell therapy for liver diseases.
Several clinical researches have studied the consequences of stem cell therapy in patients with ACLF [
6‐
8]. Ranged from early conceptual studies [
9] to larger random controlled trials (RCTs), the results of those studies showed that stem cell therapy is safe and has beneficial effects on ACLF. However, these studies have several deficiencies such as the small size of the samples and the lacking of the control groups. Meanwhile, some studies have provided conflicting results about the effect of stem cell therapy [
5,
10]. Therefore, it is still debatable for the effect of stem cell therapy in the treatment of ACLF. The purpose of this review is to evaluate the clinical efficiency of stem cell therapy in the treatment of patients with ACLF.
Methods
This meta-analysis was adhered to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
Literature search strategies and selection
We performed our data selection through four databases (PUBMED, EMBASE, Cochrane Library, and OVID) to Dec. 2017. The following medical subject heading (MeSH) terms were used: “hematopoietic stem cells”, “mesenchymal stromal cells”, “bone marrow”, “stem cells”, or “stem cell therapy”; “end stage liver disease”, “liver cirrhosis”, or “acute-on-chronic liver failure”. All literatures used in this study were published on humans and in English.
Two reviewers checked the abstract and title of publication independently. If the two reviewers identified the information relevant, we acquired the full text for a total review. Should any disagreements exist, we will discuss it with a third reviewer until there is a final conclusion.
Data extraction and conversion
The picked articles were managed through EndNote X7 (Thomson Reuters, USA). Two independent investigators assessed the qualification of studies by the sequence of title, abstract, and full text. The following data were recorded from the articles: title, first author, journal, year of publication, characteristics of patients (i.e. age, sex), timing of detection (baseline, ongoing/post treatment), and accuracy of in vitro test (sensitivity and specificity).
Inclusion criteria and outcome assessment
The inclusion criteria were as bellows: (1) specific reporting the indications for stem cell therapy; (2) compared one of the following outcomes at least: alanine transaminase (ALT), total bilirubin (TBIL), albumin (ALB), international normalized ratio (INR), model for end-stage liver disease (MELD) score.
Exclusion criteria
The following trials were excluded: (1) it was difficult to extract or reasonably evaluate the data from the reliably articles; (2) those without clear outcomes; (3) abstracts, expert opinions, editorials, case reports, letters, and studies without control groups.
Statistical analysis
The quality of evidence was assessed by GRADEpro [
11,
12]. It is preferred that the data showed as changes. When changes were not available, but could be managed through the calculation of the data, they will be calculated through appropriate methods [
13]. We performed the Meta-analysis by Review Manager (version 5.3). We use a random-effects model to evaluate the heterogeneity and I
2 > 50% with p < 0.10 was statistically significant. The analysis of continuous variables was preceded by the mean difference (MD) as the summary statistic through the Inverse-Variance method, and the result was shown with a 95% confidential interval (CI). It was considered to be significant when p < 0.05.
Discussion
ACLF is a serious life-threatening disease with high prevalence. Due to the rapid progression and low survival rate of ACLF, it is urgent to find a safe and effective therapeutic approach to ACLF [
1‐
3]. In this study, we found that stem cell therapy was able to improve liver function and alleviate liver damage. Meanwhile, stem cell therapy can also reduce the MELD score for ACLF patients. These results suggested that stem cell therapy can be considered to be a potential supplementary therapeutic approach to improve liver function in patients with ACLF.
The immunomodulatory and reparative functions of stem cells have been demonstrated to be therapeutically valuable for treating various diseases, including autoimmune diseases, diabetes, myocardial infarction, and organ therapy rejection [
15‐
17]. The present systematic review and meta-analysis underlines the feasibility of stem cell treatment for patients with ACLF. In the process of transplantation, stem cells, especially MSCs, can not only differentiate into corresponding tissue cells, but also have strong immunoregulatory effects in various organs, such as inhibiting the proliferation of T cells in the recipient, altering the proportion of T cell subsets and the function of B cells, inhibiting dendritic cell differentiation and NK cell proliferation, reducing the number of inflammatory cytokines, increasing anti-inflammatory cytokines quantity, adjusting immune abnormalities and disorders, and improving the inflammatory environment around the damaged area [
18,
19]. However, regardless of substantial clinical data, which proved the safety of stem cell therapy, there were no considerable supporting reports to confirm the immunological status of patients. As the immune profile of patients is the key to foresee the short and long-term graft clinical outcome, subsequent studies need to focus on monitoring of both clinical as well as immunological parameters [
20]. Immunological parameters include T cells, regulatory T cells, B cells, NK cells, dendritic cell and intracellular cytokine expression.
As for the clinical monitoring, this study demonstrated that stem cell therapy improved the liver synthesis functions. ALB levels increased significantly 9, 12, 24 months after the stem cell therapy. But heterogeneity was still high among these studies during the 9, 12 months of follow-up, and could not be explained by only one or two studies. As for the heterogeneity of ALB level data, we considered that ALB transfusion may affect the serum ALB levels during the treatment of ACLF. Meanwhile, there existed heterogeneity at the baseline of ALB level in this study. In fact, ACLF is a dynamic process in which the variables at the time of hospitalization are predicted to vary over time, so the clinical processes and outcomes change accordingly [
21‐
23]. Therefore, the change of ALB level between stem cell therapy and control group may be better for the assessment of liver function improvement than the assessment based on static baseline variables. However, there were not enough ΔALB data for this systematic review and meta-analysis now.
The INR levels did not show any obvious change compared with the control groups (p = 0.64). The reason may be that patients received plasma after admission. However, heterogeneity was high in these studies, although subgroup analysis was done (I2= 82–95%). More RCTs are urgently needed.
Stem cell therapy significantly decreased the TBIL levels at 1, 3, 12 months (p = 0.0008; p = 0.04; p = 0.007). The ALT level in the stem cell therapy group also gradually decreased and was lower than baseline and the corresponding controls at the 1 week, 1 month and 6 months time points. However, there were no significant differences in ALT level at 9, 12 and 24 months after stem cell therapy. Meanwhile, no significant difference was found in TBIL level compared with the control group at 9 and 24 months time points. It is indicated that stem cell therapy can alleviate liver damage in patients with ACLF in the short-term, but the long-term outcome for ACLF patients is not remarkable.
The MELD scores have been used to predict mortality of cirrhosis patients awaiting liver therapy, as well as prioritize liver allocation [
24‐
27]. In this study, a significant difference can be found between the stem cell therapy and control groups (p = 0.008). It is suggested that stem cell therapy can reduce the MELD score and improve the prognosis of ACLF patients, so as to relieve the social burden for lack of liver donors.
There are some limitations in this study. We pooled different stem cell types in the publications, leading to a high heterogeneity degree. However, it was impossible to conduct all subgroup analyses according to the stem cell type. Because there were no enough data for us to do the subgroup analysis. Thus, we only selected 3 months for the subgroup analysis. It seems that the subgroup analysis can better reduce the heterogeneity in some degree. Compared with other types of stem cells, UC-MSCs had a better effect on increasing the ALB (p = 0.006). After the subgroup analyses on the effects of stem cell type at 3 months of follow-up for ALT and INR, BM-MSCs can obviously reduce the ALT level and INR, which is better than other stem cell types (p < 0.00001; p = 0.004). As for TBIL, it seems that UC-MSCs had a better effect on reducing the TBIL than BM-MNCs and BM-MSCs (p = 0.01). It is suggested that UC-MSCs and BM-MNCs can significantly decrease the MELD score, which is better than BM-MNCs at 3 months of follow-up (p < 0.00001; p < 0.0001). Above all, in our study, MSCs may be better than BM-MNCs in the stem cells transplantation of ACLF. However, more clinical trials with different stem cell types are needed to verify the clinical outcomes.
Authors’ contributions
RX wrote the manuscript paper. QM designed the study. JL, JD, YZ, QY and HY collected data, performed some analysis. All authors read and approved the final manuscript.