Therapeutic effect and safety of stem cell therapy for chronic liver disease: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background: Stem cell therapy is becoming an emerging therapeutic option for chronic liver disease (CLD). However, whether stem cell therapy is more effective than conventional treatment remains questionable. We performed a large-scale meta-analysis of randomized controlled trials (RCTs) to evaluate the therapeutic effects and safety of stem cell therapy for CLD.

Methods: We systematically searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases for the period from inception through March 16, 2020. Primary outcomes were all-cause mortality and adverse events related to stem cell therapy. Secondary outcomes included the model for end-stage liver disease score, total bilirubin, albumin, alanine aminotransferase, prothrombin activity, and international normalized ratio. The standardized mean difference (SMD) and odds ratio (OR) with 95% confidence interval (CI) were calculated using a random-effects model.

Results: Twenty-four RCTs were included and the majority of these studies showed a high risk of bias. The meta-analysis indicated that compared with conventional treatment, stem cell therapy was associated with improved survival and liver function including the model of end-stage liver disease score, total bilirubin, and albumin levels. However, it had no obvious beneficial effects on alanine aminotransferase level, prothrombin activity, and international normalized ratio. Subgroup analyses showed stem cell therapy conferred a short-term survival benefit for patients with acute-on-chronic liver failure (ACLF), a single injection was more effective than multiple injections, hepatic arterial infusion was more effective than intravenous infusion, and bone marrow-derived stem cells were more effective than those derived from the umbilical cord. Thirteen trials reported adverse events related to stem cell therapy, but no serious adverse events were reported.

Conclusions: Stem cell therapy is a safe and effective therapeutic option for CLD, while patients with ACLF benefit the most in terms of improved short-term survival. A single injection administration of bone marrow-derived stem cells via the hepatic artery has superior therapeutic effects.

Keywords: Acute-on-chronic liver failure; Cell transplantation; Liver disease; Stem cell therapy.

Fig. 1

Flow diagram of the selection of studies

Fig. 2

a Risk of bias summary: review of authors’ judgments about each risk of bias item for each included study. b Risk of bias graph: overview of authors’ judgments about each risk of bias item presented as percentages across all included studies

Fig. 3

Forest plot of the comparison of the effect of stem cell therapy versus conventional treatment on all-cause mortality

Fig. 4

Forest plot of the comparison of the effect of stem cell therapy versus conventional treatment on the model of end-stage liver disease (MELD) score

Fig. 5

Forest plot of the comparison of the effect of stem cell therapy versus conventional treatment on total bilirubin (TBIL) level

Fig. 6

Forest plot of the comparison of the effect of stem cell therapy versus conventional treatment on albumin (ALB) level

Fig. 7

Forest plot of the comparison of the effect of stem cell therapy versus conventional treatment on alanine aminotransferase (ALT) level

Fig. 8

Forest plot of the comparison of the effect of stem cell therapy versus conventional treatment on prothrombin activity (PTA) level

Fig. 9

Forest plot of the comparison of the effect of stem cell therapy versus conventional treatment on international normalized ratio (INR) level

Fig. 10

Subgroup analyses by the liver disease type, cell type, delivery route, and frequency of administration. Red indicates a significant improvement in the stem cell therapy group compared with the conventional treatment group; blue indicates no significant improvement. CLD chronic liver disease, ACLF acute-on-chronic liver failure, BM-MSC bone marrow-derived mesenchymal stem cell, UC-MSC umbilical cord-derived mesenchymal stem cell, BM-MNC bone marrow-derived mononuclear stem cell