RATIONALE: Liver cirrhosis and its complications increase the risk of death associated with end-stage liver disease. Liver transplantation is an option, but the procedure may have significant morbidity and mortality risks, in addition to the shortage of liver donors. Human stem cell interventions are expected to be able to remodel injured liver tissue and to maintain liver function in people with decompensated cirrhosis. So far, results of randomised clinical trials on the effects of human stem cells in adults with decompensated cirrhosis have been inconsistent.
OBJECTIVES: To assess the benefits and harms of human stem cell intervention in adults with decompensated cirrhosis, regardless of ethnicity, sex, types of stem cell, route of stem cell injection, and administered dose.
SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group (CHBG) Controlled Trials Register, CENTRAL, MEDLINE, five other databases and four trials registers, in addition to reference checking, citation searching, and contacting study authors to identify the trials for inclusion. Last date of search - 4 October 2024.
ELIGIBILITY CRITERIA: Randomised clinical trials comparing any stem cell type versus placebo, conventional, or no active treatment for people (≥ 18 years old) with decompensated cirrhosis. We included trials with any route of administration, frequency, and number of stem cells administered in people with decompensated cirrhosis and irrespective of the reported outcomes of interest to our review, language, year, format, and status of publication. We excluded quasi-randomised studies.
OUTCOMES: Our critical outcomes were all-cause mortality, serious adverse events, and quality of life. Our important outcomes were complications, non-serious adverse events, and liver function.
RISK OF BIAS: We assessed the risk of bias (RoB) in the outcome results of interest to our review, using the RoB 2 tool.
SYNTHESIS METHODS: We conducted our meta-analyses, including outcome results, irrespective of our risk of bias judgements. Our primary analyses, on which we based our conclusions, included outcome data at the longest follow-up. We presented the results of dichotomous outcomes as risk ratios (RR) and continuous outcomes as mean difference or standardised mean difference (SMD), with 95% confidence intervals (CI). We used the random-effects model for our primary analyses. We used the Restricted Maximum Likelihood (REML) estimator to estimate the differences in the random-effects model with the inverse-variance method, which includes a measure of the degree of heterogeneity in the study weights. We employed the Hartung-Knapp-Sidik-Jonkman (HKSJ) method to compute a CI for the meta-analysis effect estimate in situations with at least three trials and an estimate of heterogeneity greater than zero. In the case of pooled analyses of two trials or where the estimate of heterogeneity equals zero, we used the Wald-type method, following the guidance in the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADEPro to construct a summary of findings table. We assessed the certainty of the evidence of the outcomes in our review, applying the five GRADE domains, i.e. risk of bias in the outcome result, inconsistency of effect, indirectness, imprecision (using the minimally contextualised approach), and publication bias.
INCLUDED STUDIES: Twelve trials (Brazil, China, Egypt, Iran, Korea, and Switzerland), with 823 adults (range n = 27 to 219; 68% males), assessed human stem cells in adults with decompensated cirrhosis. The experimental interventions (bone marrow-derived mesenchymal stem cells, bone marrow-derived mononuclear stem cells, umbilical cord-derived mesenchymal stem cells, autologous bone marrow stem cells, and CD34/133+, and CD133+) were compared with control (placebo or conventional treatments). Stem cell transplantation was performed through the hepatic artery (in six trials), portal vein (in two trials), upper extremity veins (in two trials), and intravenously (in one trial). One trial did not provide this information. Two trials were funded by industry, seven by research grants, and three provided no information.
SYNTHESIS OF RESULTS: All 12 trials provided data for at least one outcome in our review. We pooled the outcome results in analyses, at their maximal follow-up (1 month to 75 months after end of treatment), and irrespective of their risk of bias. All evidence was assessed as having very low certainty; we downgraded the evidence due to risk of bias, inconsistency, and imprecision of the results. The evidence is very uncertain regarding the effect of stem cells on all-cause mortality (RR 0.52, 95% CI 0.24 to 1.11; I² = 54%; 7 studies, 577 participants; very low-certainty evidence), on serious adverse events (RR 0.70, 95% CI 0.38 to 1.31; I² = 73%; 9 studies, 678 participants; very low-certainty evidence), and on whether stem cells may improve health-related quality of life (SMD -1.32, 95% CI -2.00 to -0.64; I² = 42%; 2 studies, 73 participants; very low-certainty evidence). The evidence is also very uncertain on whether stem cells may reduce the development of complications (RR 0.67, 95% CI 0.39 to 1.14; I² = 0%; 3 studies, 304 participants; very low-certainty evidence), on whether stem cells may increase non-serious adverse events during treatment (RR 6.50, 95% CI 1.96 to 21.56; I² = 0%; 5 studies, 437 participants; very low-certainty evidence), and on whether stem cells may improve liver function tests (RR 0.96, 95% CI 0.64 to 1.44; I² = 0%; 3 studies, 112 participants; very low-certainty evidence). One trial with three references is awaiting assessment. Twelve studies are ongoing.
AUTHORS' CONCLUSIONS: Due to the overall very low certainty of the evidence, insufficient trials and outcome data, we cannot determine with certainty the effects of human stem cells (bone marrow-derived mesenchymal stem cells, bone marrow-derived mononuclear stem cells, umbilical cord-derived mesenchymal stem cells, autologous bone marrow stem cells, CD34/133+, and CD133+) versus control on all-cause mortality, serious adverse events, quality of life, complications, non-serious adverse events, and liver function. We lack properly conducted randomised clinical trials with different human stem cell types, assessing their effects on clinically critical and important outcomes in adults with decompensated cirrhosis. The ongoing randomised clinical trials may provide knowledge on the benefits and harms of stem cell therapy for clinically important outcomes, provided they are well-designed and of high quality.
FUNDING: This Cochrane Review had no dedicated funding.
REGISTRATION: Protocol available via DOI: 10.1002/14651858.CD015173.
