Reassessing the impact of post-transjugular intrahepatic portosystemic shunt hepatic encephalopathy on mortality in patients with cirrhosis

Nardelli et al. (1) conducted a multi-center observational study to assess the mortality risk in patients with and without overt hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS). In their paper, the authors disclosed that post-TIPS overt HE was not linked to an increased risk of mortality in patients with cirrhosis during a median follow-up of 30 months (1). However, many other studies have reported that post-TIPS HE is significantly associated with a higher risk of mortality based on long-term follow-up in patients with cirrhosis (2-6). Given this inconsistency, we conducted a meta-analysis to evaluate the association between post-TIPS HE and mortality, using both unadjusted and adjusted effect estimates in patients with cirrhosis.

A systematic search was conducted in PubMed, Web of Science, and Embase databases to identify all relevant studies through December 22, 2023. The search terms included “cirrhosis”, “hepatic encephalopathy”, “HE”, “transjugular intrahepatic portosystemic shunt”, “TIPS”, “survival”, “death”, “mortality”, and “prognosis”. We included articles that reported the association between post-TIPS HE and mortality in patients with cirrhosis, providing unadjusted or adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Non-original studies, animal or cell studies, duplicate studies, studies evaluating pre-TIPS HE, and those with incomplete or unavailable data were excluded. Two authors independently conducted the literature search and data extraction. In addition, reference lists of included studies and relevant reviews were reviewed to identify potential articles. This meta-analysis adheres to the reporting guidelines outlined in the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) checklist (7).

The unadjusted and adjusted HRs with their corresponding 95% CIs were pooled using the random-effects model. Heterogeneity between studies was evaluated using Cochran’s Q test and I² statistic, with P≤0.1 or I²≥50% considered significant heterogeneity. Publication bias was assessed by examination of the funnel plot and Egger’s test in the adjusted analysis. The trim-and-fill method was used to observe changes in pooled estimates following the imputation of data from potentially unpublished articles when publication bias was identified. All of the statistical analyses were conducted using R package meta (version 4.0.2), with two-sided P<0.05 considered statistically significant.

Seven cohort studies involving 1,712 patients with cirrhosis were included in this meta-analysis (1,3-6,8,9). The results showed that post-TIPS HE was associated with a significantly higher risk of mortality in both unadjusted (4 studies, n=929) and adjusted analyses (6 studies, n=1,408). The pooled crude HR was 3.47 (95% CI: 1.68–7.18), while the adjusted HR was 2.64 (95% CI: 1.23–5.65) (Figure 1A). However, both analyses exhibited very high heterogeneity (I²=85%, P<0.01; I²=88%, P<0.01). The funnel plot displayed visual asymmetry, and Egger’s test (P<0.05) suggested significant publication bias in the adjusted analysis (Figure 1B). Consequently, we used the trim-and-fill method by adding estimated HRs from three potentially unpublished articles to achieve symmetry in the funnel plot (Figure 1C). The resulting pooled adjusted HR was 1.21 (95% CI: 0.55–2.65), which was significantly different from the adjusted HR before using the trim-and-fill method.

Figure 1 Forest and funnel plots for assessing the association between post-TIPS HE and mortality. (A) Forest plot for unadjusted and adjusted HRs relating post-TIPS HE to the risk of mortality. The HRs and 95% CIs were pooled using the random-effects model. An HR >1 indicates an increased risk, an HR <1 suggests a decreased risk, and the 95% CI including 1 indicates no statistically significant difference. (B) Funnel plot for assessing potential publication bias. The Egger’s test was used for quantitative analysis, and P<0.05 indicated the presence of publication bias. (C) Funnel plot after application of the trim-and-fill method, which was conducted using a non-parametric method, and the estimated HRs from three potentially unpublished articles were added to achieve symmetry. TIPS, transjugular intrahepatic portosystemic shunt; HE, hepatic encephalopathy; TE, treatment effect; seTE, standard error of TE; HR, hazard ratio; CI, confidence interval.

This meta-analysis had several limitations. First, there was high heterogeneity among studies in both the unadjusted and adjusted analyses, likely due to variations in clinical characteristics. Notably, the frequency of HE after TIPS may be the main source of heterogeneity. The study by Nardelli et al. (1) showed that persistent HE, but not episodic HE, following TIPS may increase the risk of long-term mortality. This finding aligns with the results reported by Zuo et al. (8), and is also consistent with clinical observations. In addition to the study by Nardelli et al. (1), three other studies reported the proportions of episodic HE following TIPS, which were 56%, 56%, and 46%, respectively (3,8,9). These proportions were significantly lower than those reported by Nardelli et al. (80%) (1), suggesting the potential overestimation of death risk in all post-TIPS HE patients. The lower proportions of episodic HE could be attributed to variations in the follow-up duration for post-TIPS HE occurrence and may be associated with selection bias introduced by the small sample size or the inclusion of a greater number of hospitalized HE patients. In addition, high heterogeneity may also be linked to other clinical differences, such as follow-up time after HE and adjusted confounding factors. Due to the limited number of studies and unavailable data, we could not perform corresponding subgroup analyses, sensitivity analyses, or meta-regression. Second, publication bias significantly impacted the independent association between post-TIPS HE and mortality, underscoring the need for future research to address this issue. Third, given the nature of observational studies, the included studies are prone to residual confounding. Critical variables, such as sarcopenia and comorbidities, should be considered for adjustment in the multivariable analysis. Lastly, the credibility of the results in the included study is commonly influenced by immortal time bias, as the starting points of follow-up differ between the HE and non-HE groups.

In summary, the association between post-TIPS HE and long-term mortality still requires confirmation through high-quality, multicenter prospective cohort studies. We commend Nardelli et al. (1) for their excellent work. However, separate multivariable analyses for episodic, recurrent, and persistent HE after TIPS may provide clearer insights into the mortality risks within these subpopulations.

Acknowledgments

Funding: This work was supported by grant from Xi’an Science and Technology Plan Project (22YXYJ0122).

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-148/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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