Xu XT, Jiang MJ, Fu YL, Xie F, Li JJ, Meng QH. Incidence and efficacy of strategies for preventing hepatic encephalopathy following transjugular intrahepatic portosystemic shunt: A meta-analysis. World J Hepatol 2025; 17(4): 104890 [DOI: 10.4254/wjh.v17.i4.104890]
Corresponding Author of This Article
Qing-Hua Meng, Hepatic Disease and Oncology Minimally Invasive Interventional Center, Beijing Youan Hospital, Capital Medical University, No. 8 Xitoutiao, Youanmen Wai, Fengtai District, Beijing 100069, China. meng_qh0805@ccmu.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Meta-Analysis
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Xiao-Tong Xu, Jian-Jun Li, Qing-Hua Meng, Hepatic Disease and Oncology Minimally Invasive Interventional Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
Xiao-Tong Xu, Yun-Lai Fu, Fang Xie, Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
Min-Jie Jiang, Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
Co-corresponding authors: Jian-Jun Li and Qing-Hua Meng.
Author contributions: Li JJ and Meng QH contribute equally to this study as co-corresponding authors; Xu XT, Jiang MJ, and Fu YL contributed to the literature database retrieval, data collection, and data extraction; Xu XT, Xie F, Li JJ, and Meng QH conceptualized the topic; Li JJ, Xie F, and Meng QH reviewed the article; Li JJ and Meng QH participated and provided valuable feedback, ensuring the quality of the article and contributing as co-corresponding authors; all authors thoroughly reviewed and endorsed the final manuscript.
Conflict-of-interest statement: All authors disclosed no relevant relationships.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Qing-Hua Meng, Hepatic Disease and Oncology Minimally Invasive Interventional Center, Beijing Youan Hospital, Capital Medical University, No. 8 Xitoutiao, Youanmen Wai, Fengtai District, Beijing 100069, China. meng_qh0805@ccmu.edu.cn
Received: January 5, 2025 Revised: February 27, 2025 Accepted: April 7, 2025 Published online: April 27, 2025 Processing time: 109 Days and 21.6 Hours
Abstract
BACKGROUND
Hepatic encephalopathy (HE) is a primary complication following transjugular intrahepatic portosystemic shunt (TIPS), but the utility of pharmacological prophylaxis for HE is unclear.
AIM
To assess the HE incidence post-TIPS across various groups and the prophylactic efficacies of various medications.
METHODS
A thorough literature search was performed in PubMed, Web of Science, EMBASE, and the Cochrane Library databases from their inception to November 24, 2024, to collect data regarding HE incidence. The main outcome was HE incidence post-TIPS. A meta-analysis using a random effects model was performed to obtain odds ratios (ORs) and 95% confidence intervals. Statistical analyses were conducted using Stata and RevMan software.
RESULTS
This meta-analysis included nine studies with 1140 patients; 647 received pharmacological agents including lactulose, rifaximin, albumin, and l-ornithin-l-aspartate, and 493 did not (controls). (1) In the single-group meta-analysis, the control group had higher short- and long-term HE rates than the drug intervention group. Among patients with and without prior HE, the non-intervention group's HE rates were also higher; (2) Pharmacological prevention post-TIPS significantly reduced HE incidence [OR = 0.59 (0.45, 0.77), P = 0.0001]. Compared with the no prophylaxis, rifaximin reduced the risk of HE after TIPS [OR = 0.52 (0.29, 0.95), P = 0.03], but lactulose did not; (3) In patients without prior HE, pharmacological prevention significantly reduced post-TIPS HE incidence [OR = 0.62 (0.41,0.95), P = 0.03]; and (4) Network meta-analysis showed no significant differences among five prevention strategies.
CONCLUSION
The HE incidence after TIPS was relatively high, and the use of drugs after TIPS may reduce the HE incidence. However, research, especially large-scale randomized controlled trials, is still lacking.
Core Tip: Hepatic encephalopathy (HE) is a common complication after transjugular intrahepatic portosystemic shunt (TIPS) that affects the quality of life of patients and their families. However, controversy exists regarding about whether TIPS patients need medication to prevent and reduce HE occurrence after surgery. We found through a meta-analysis that the HE incidence after TIPS surgery is relatively high and that drug prevention can significantly reduce HE occurrence. Moreover, current prevention strategies are summarized to provide guidance for future clinical research.
Citation: Xu XT, Jiang MJ, Fu YL, Xie F, Li JJ, Meng QH. Incidence and efficacy of strategies for preventing hepatic encephalopathy following transjugular intrahepatic portosystemic shunt: A meta-analysis. World J Hepatol 2025; 17(4): 104890
The transjugular intrahepatic portosystemic shunt (TIPS) is a well-established intervention for the management of portal hypertension[1-4]. However, a common complication following TIPS is the development of hepatic encephalopathy (HE), with reported incidence rates ranging from 20% to 50%, which can significantly impact the quality of life of patients[5-7]. Post-TIPS HE is associated with the establishment of portosystemic shunt and underlying liver dysfunction. Current strategies to mitigate the risk of HE after TIPS include surgical interventions[8,9] and pharmacological prophylaxis. Commonly employed pharmacological agents for prevention include lactulose, rifaximin, and their combination. The necessity and effectiveness of HE pharmacological prevention after TIPS surgery remain controversial. A recent clinical guideline[10] advises against the routine use of prophylactic medications to prevent HE in patients undergoing TIPS, whereas another guideline suggests their use in patients with a history of HE[11]. Therefore, controversy still exists over whether empirical medication is needed to prevent postoperative HE in patients undergoing TIPS. This study aimed to summarize the current treatment plans for pharmacological prevention of HE after TIPS through a meta-analysis, evaluate the comparative effectiveness of different prophylactic strategies, and provide guidance for clinical decision-making.
MATERIALS AND METHODS
Search strategy
In our literature search, we systematically searched databases including PubMed, Web of Science, EMBASE, and the Cochrane Library. We employed medical subject headings (MeSH) terms “portasystemic shunt, transjugular intrahepatic” and “hepatic encephalopathy”. To ensure a comprehensive search, we also incorporated relevant free-text terms. We used the Boolean operator OR to combine MeSH terms and free-text words with similar meanings, and the operator AND to link search terms with different connotations. Data were retrieved from the earliest accessible date in the database until November 24, 2024. We also screened the references included in the literature, and conducted manual searches in addition to electronic searches. The search strategy is shown in Supplementary Table 1. This meta-analysis was conducted in accordance with the PRISMA guidelines and was registered with PROSPERO (CRD42024618731).
Inclusion and exclusion criteria
Inclusion criteria: (1) The research subjects were patients with cirrhosis who received TIPS treatment; (2) Some patients did not receive drug intervention as the control group, whereas others received drug intervention (including lactulose, rifaximin, l-ornithin-l-aspartate, etc.) to prevent the occurrence of HE after TIPS; (3) The study reported the incidence of HE during the follow-up period after TIPS for two groups of patients who received and did not receive drug prophylaxis; and (4) The diagnosis of HE was based on the West Haven criteria.
Exclusion criteria: (1) Duplicate studies; (2) Case reports; (3) Letters to editors; (4) Review or meta-analyses; (5) Animal studies; (6) Protocols or clinical trial registrations; (7) Studies with incomplete data and literature not published in English; (8) Patients without cirrhosis; (9) Lack of control group without drug intervention; and (10) Lack of data on HE.
Literature screening and quality evaluation
Literature selection was conducted by two independent reviewers (Xiao-Tong Xu and Min-Jie Jiang) based on the screening of titles and abstracts. Any discrepancies in study selection and data extraction were resolved through discussion. The Cochrane Collaboration’s tool was utilized for assessing the quality of randomized controlled trials[12], whereas the Newcastle-Ottawa Scale was applied for evaluating the quality of retrospective studies[13]. The filtering process is depicted in Figure 1, and the quality assessment details of the included articles are presented in Tables 1 and 2.
The following data were collected: Author, country, year, research type, patient age, sex, etiology of liver disease, history of HE, indications for TIPS, stent type, and incidence of HE. First, using Stata software, the incidence of HE in each study was calculated as the number of HE cases/sample size. The standard error of the incidence of HE in each original study was subsequently calculated. Afterwards, a random effects model was used for a single group rate meta-analysis to analyze the incidence of HE in the control group and the drug intervention group. Afterwards, the efficacy of drug intervention in preventing HE after TIPS was analyzed using RevMan. The pooled odds ratio (OR) with 95% confidence intervals was estimated for dichotomous outcomes. Heterogeneity between the included studies was analyzed using χ2 and I² tests. If I² < 50% and P > 0.01, there was no statistical heterogeneity in the research results, and a fixed effects model is used for analysis. In contrast, I² > 50% or P < 0.1, it indicated statistical heterogeneity between studies, and a random effects model was used for analysis[14]. Given the limited number of studies, we chose the random effects model. Sensitivity analysis was conducted on studies with significant heterogeneity using a one-by-one exclusion method, and the impact of individual studies on the stability of the overall results was analyzed by Stata. Funnel plots, Egger tests and Begg tests were used to evaluate publication bias with Stata. If P > 0.05 and the funnel plot was symmetrical, there was no publication bias[15]. Otherwise, publication bias may have been present. A network meta-analysis was performed in Stata, and the network combination command was used to analyze and process the data. A network diagram was drawn and inconsistency testing was performed when intervention measures form a closed loop[16]. The efficacy differences between different intervention measures were compared by calculating the cumulative area under the sorting curve, and a funnel plot draw to evaluate publication bias in the included studies[17].
RESULTS
In the final analysis, a total of 9 studies were included, including 1140 patients with cirrhosis who received a TIPS. The indications for TIPS surgery include gastrointestinal bleeding, ascites, or both. Among these, 647 patients were administered drug prophylaxis, whereas 493 were not. The prophylactic treatments included 284 patients receiving lactulose alone, 136 receiving rifaximin alone, 137 receiving a combination of lactulose and rifaximin, 23 receiving albumin, 21 receiving l-ornithin-l-aspartate, and 46 receiving other treatments (including lactulose with metronidazole, metronidazole alone, and neomycin alone). There is not much difference in the dosage of the same medication, mainly due to different usage cycles. The incidence rate of HE is the incidence rate during the intervention period. The diagnosis of HE is made by clinical physicians based on combination of neuropsychological tests, blood ammonia levels, physical signs, and the exclusion of other causes of mental changes. The grading is based on the West Haven criteria. The patients with covert HE (CHE) had only mild cognitive difficulties such as decreased attention, memory, and delayed responses. HE levels 2-4 are collectively referred to as overt HE (OHE). Patients with OHE may experience personality changes, comas, or other neurological abnormalities. Detailed information on each study is presented in Table 3.
Table 3 Relevant information included in the literature.
The incidence of HE after TIPS in the drug intervention group and the control group
First, a single group meta-analysis was conducted to summarize the incidence of HE after drug intervention and control group TIPS. A research period of one month or less was defined as short-term and a research period exceeding one month was defined as long-term. The research revealed that regardless of the drug intervention group or the non-intervention group, the incidence of HE increased with time. However, the incidence of HE in patients after drug intervention was lower than that in the intervention group. In the short term, the incidence of postoperative HE in the control group was 0.333 (0.176, 0.490), whereas the incidence of HE in the drug intervention group was 0.266 (0.092, 0.441). After longer observation, the incidence of HE in the control group was 0.404 (0.277, 0.530), whereas the incidence of HE in the drug intervention group was 0.322 (0.161, 0.482), as shown in Figure 2A. Later, on the basis of the history of HE, the incidence of HE after TIPS in the drug intervention group and the untreated group was analyzed. Among patients without previous HE, the incidence of HE after TIPS in the untreated group was 0.368 (0.201, 0.536), whereas in the drug intervention group it was 0.272 (0.124,0.421) in the drug intervention group. Among patients with a history of HE, the incidence of HE after TIPS was 0.591 (0.118, 1.065) in the non-intervention group and 0.234 (0.072, 0.396) in the drug intervention group. We found that regardless of the presence of a history of HE, the incidence of HE in patients after drug intervention was lower than that in the control group, as shown in Figure 2B.
Figure 2 The incidence of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in the drug intervention group and the untreated group.
A: The incidence of hepatic encephalopathy (HE) at different times; B: The incidence of HE after transjugular intrahepatic portosystemic shunt in patients with or without a history of HE.
The therapeutic effect of drug intervention in preventing HE after TIPS compared to the control group
An analysis of 9 studies revealed no significant difference in the incidence of HE after TIPS between the drug prevention group and the control group [OR = 0.72 (0.48, 1.08), I² = 51%, P = 0.11], as shown in Figure 3A. Afterwards, we conducted a sensitivity analysis and found that after removing the literature on Subramanian et al[18], there was a significant change in the summarized results, as shown in Figure 4A. We reviewed the characteristics of the patients in the literature and found that in this study[18] the proportion of patients with a history of HE in the drug-induced liver disease group was significantly greater than that in the control group. In the remaining literature, the proportion of patients with a history of HE in the drug-induced liver disease intervention group was relatively comparable to that in the control group, indicating that this study included heterogeneous sources. After this study was removed, heterogeneity disappeared, and the results revealed that drug intervention significantly reduced the occurrence of HE after TIPS [OR = 0.59 (0.45, 0.77), I² = 0%,P = 0.0001], as shown in Figure 3B. The results of the sensitivity analysis of the remaining 8 studies are shown in Figure 4B. Regardless of which study was excluded, the incidence of HE after TIPS in the prevention intervention group was significantly lower than that in the control group, and the results were stable. Afterwards, we evaluated publication bias. The funnel plot included in the literature is shown in Figure 5. The Begg test yielded P = 0.917, and the Egger test yielded P = 0.842, as shown in Figure 5. Both test results indicate P > 0.05, indicating no publication bias.
Figure 3 Efficacy of drug intervention in preventing hepatic encephalopathy after transjugular intrahepatic portosystemic shunt.
A: The analysis results of all literature; B: The analysis results after removing heterogeneous source literature.
Figure 4 Sensitivity analysis of the efficacy of drug intervention in preventing hepatic encephalopathy after transjugular intrahepatic portosystemic shunt.
A: Sensitivity analysis of all included literature; B: Sensitivity analysis after removing heterogeneous source articles.
Figure 5 Publication bias of the efficacy of drug intervention in preventing hepatic encephalopathy after transjugular intrahepatic portosystemic shunt.
A: Funnel plot; B: Begg test; C: Egger test.
Subgroup analysis based on different study types
To further clarify the efficacy of drug intervention for HE after TIPS, we conducted subgroup analysis on the basis of country type and research type. A summary of randomized controlled trials suggested that the incidence of HE after TIPS was significantly reduced after drug prevention intervention [OR = 0.54 (0.30, 0.96), I² = 12%, P = 0.03], as shown in Figure 6A. A summary of retrospective cohort studies revealed significant heterogeneity (I² = 66%), as shown in Supplementary Figure 1. Similarly, considering that Subramanian et al[18] as a source of heterogeneity, removing it reduced heterogeneity, and the results were consistent with those of randomized controlled trials [OR = 0.62 (0.44, 0.86), I² = 0%, P = 0.004], as shown in Figure 6A.
Figure 6 Subgroup analysis of the efficacy of drug intervention in preventing hepatic encephalopathy after transjugular intrahepatic portosystemic shunt.
A: Different study types; B: Different regions; C: The presence of hepatic encephalopathy.
Subgroup analysis based on different regions
Subsequently, subgroup analysis was conducted based on different countries, and Italy, Germany, and France were categorized as part of Europe. A summary of four studies from Europe revealed that drug intervention significantly reduced the incidence of HE after TIPS [OR = 0.66 (0.44, 0.99), I² = 19%, P = 0.04]. Four studies from the United States showed significant heterogeneity (I² = 75%) as shown in Supplementary Figure 2. Considering Subramanian et al[18] as the source of heterogeneity, the heterogeneity disappeared after exclusion, and the research results were consistent with those of European studies [OR = 0.52 (0.33, 0.81), I² = 0%, P = 0.004], as shown in Figure 6B. There is only one study from China, and the results of this study also suggest that drug intervention can reduce the occurrence of HE after TIPS. Therefore, drug intervention can reduce the occurrence of HE after TIPS.
Subgroup analysis of different drugs
The efficacy of lactulose, rifaximin, and their combination in preventing HE after TIPS was subsequently compared on the basis of different drugs used. We found no significant difference in the incidence of HE after TIPS between the lactulose drug prevention and non-intervention groups [OR = 0.96 (0.59, 1.56), I² = 23%, P = 0.87], as shown in Figure 7A. A comparison was then made between the rifaximin group and the non-intervention group. No significant difference in HE occurrence was noted between the two groups after TIPS [OR = 0.81 (0.26, 2.56), I² = 64%, P = 0.72], as shown in Supplementary Figure 3. After one study was removed[18], heterogeneity decreased and rifaximin significantly reduced the occurrence of HE after TIPS [OR = 0.52 (0.29, 0.95), I² = 11%, P = 0.03], as shown in Figure 7A. Finally, the effects of rifaximin combined with lactulose on the occurrence of HE after TIPS were compared, and no significant difference in the incidence of HE after TIPS was noted among the three groups, with high heterogeneity [OR = 1.68 (0.22, 12.88), I² = 88%, P = 0.62], as shown in Figure 7A.
Figure 7 The effectiveness and survival of drug intervention on hepatic encephalopathy after transjugular intrahepatic portosystemic shunt.
A: The therapeutic effects of different drug interventions for preventing hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt; B: Drug prevention intervention for the treatment of overt HE; C: The impact of drug prevention interventions on survival. LM: Lactulose monoprophylaxis; RM: Rifaximin monoprophylaxis; LR: Lactulose and rifaximin; NM: No prophylactic medication.
Subgroup analysis based on the presence of HE in the past
We further analyzed the efficacy of drug prevention in two groups of patients on the basis of their history of HE. In patients without previous HE, the incidence of HE after TIPS in the drug prevention intervention group was significantly lower [OR = 0.62 (0.41, 0.95), I² = 0%, P = 0.03], as shown in Figure 6C. In patients with previous HE, there was significant heterogeneity, as shown in Supplementary Figure 4. After excluding one study[19] due to the limited number of patients in the control group, the results also revealed that drug intervention reduced the recurrence of HE after TIPS [OR = 0.13 (0.03, 0.54), I² = 0%, P = 0.005], as shown in Figure 6C.
The impact of drug intervention on OHE
The diagnosis of HE is mainly based on the results of neuropsychological tests, psychiatric symptoms, signs of flapping tremors, and comprehensive diagnoses of blood ammonia levels. HE is mainly graded according to the West Haven criteria. In 5 out of 9 studies, the incidence of HE referred to the incidence of OHE. In 2 studies the incidence of HE was the sum of minimal HE (MHE) and OHE. In 2 studies it was not explicitly stated. Therefore, the incidence rate of HE in the above research results does not refer specifically to OHE or MHE. Five studies were conducted on the incidence of OHE after drug prevention via TIPS, four of which used lactulose or rifaximin as drugs, and one of which used albumin. Therefore, an analysis was conducted on those four studies. The results revealed that drug prevention can significantly reduce the occurrence of OHE after TIPS [OR = 0.54 (0.30, 0.96), I² = 12%, P = 0.03], as shown in Figure 7B.
The impact of drug intervention on survival
Further analysis of the impact of drug intervention on the survival rate revealed no significant difference in the survival rate between the two groups [OR = 1.88 (0.95, 3.74), I² = 34%, P = 0.07], as shown in Figure 7C.
Network meta-analysis of different drug prevention strategies
At present, the drug treatment options for preventing HE after TIPS include lactulose, rifaximin, combination therapy, l-ornithin-l-aspartate, and albumin. To further compare the efficacy of each prevention option, we conducted a network meta-analysis. To maintain consistency between studies, we excluded 6 patients who used rifaximin and lactulose[18] because the incidence of HE in 5 patients was significantly higher than that reported in other studies. The subsequent global and local inconsistency tests yielded P > 0.05, indicating good consistency. The network diagram revealed that the most common regimen for preventing HE after TIPS was lactulose. The sucra cumulative probability plot suggested that intervention with l-ornithin-l-aspartate and rifaximin was more effective in preventing HE after TIPS. However, the results in the league table revealed no significant differences among the five prevention strategies, as shown in Figure 8.
Figure 8 Network meta-analysis.
A: Network diagram; B: Funnel plot; C: Sucra cumulative probability plot. LM: Lactulose monoprophylaxis; RM: Rifaximin monoprophylaxis; LR: Lactulose and rifaximin; NM: No prophylactic medication; LOLA: L-ornithin-l-aspartate; ALB: Albumin. D: League chart. NM: No prophylactic medication; ALB: Albumin; LOLA: L-ornithin-l-aspartate; LR: Lactulose and rifaximin; RM: Rifaximin monoprophylaxis; LM: Lactulose monoprophylaxis.
DISCUSSION
TIPS surgery reduces portal pressure through the implantation of portal shunts, thereby reducing the risk of gastrointestinal bleeding and ascites, prolonging patient survival, and creating conditions for liver transplantation[20]. However, HE is a frequent complication following TIPS, which contributes to increased hospitalization rates, impairs patient quality of life, and may expedite the need for liver transplantation[21]. In this study, we included 9 articles, and the preventive medications that were used included lactulose, rifaximin, albumin, and l-ornithin-l-aspartate, with lactulose being the most frequently employed. Research has shown that probiotics can effectively prevent the occurrence of HE[22,23]. However, we found a gap in the research regarding the use of probiotics for the prevention of HE after TIPS.
In patients with cirrhosis, changes in the structure and function of the gut microbiota are closely related to the occurrence of HE[24-27]. The efficacy of probiotics in treating HE has not been consistent across previous studies[22-28]. Some studies have shown that probiotics and lactulose are equivalent in treating MHE and can prevent the occurrence of OHE[29]. However, some studies have also reported that probiotics have no significant effect on the efficacy of treating CHE compared with the control group[30]. Probiotics mainly regulate the gut microbiota, repair the intestinal barrier, reduce the absorption of intestinal toxins, and improve the incidence of HE. In recent years, studies have explored the role of fecal microbiota transplantation in the treatment of recurrent HE. The safety and tolerability of fecal microbiota transplantation have mainly been investigated in phase I and phase II clinical trials. The present study revealed that compared with the control, it not only did not increase the occurrence of adverse events, but also improved intestinal disorders. However, the effectiveness of fecal microbiota transplantation in the treatment of recurrent HE varies greatly among individuals[31-33]. In our literature search, we did not find any research on the use of probiotics for preventing or treating HE after TIPS. Therefore, probiotic intervention based on the gut microbiota may provide a new treatment approach for preventing the occurrence of HE after TIPS.
We first analyzed the incidence of post-TIPS HE in the medication intervention group compared with the control group. Within the same observation period, the incidence of post-TIPS HE in the medication intervention group was slightly lower than that in the control group. Then, we compared the incidence of postoperative HE between the medication intervention group and the control group on the basis of the presence of a history of HE. The results revealed that the incidence and recurrence of HE after TIPS in the drug intervention group was slightly lower than that in the control group. The overall incidence of HE ranges from 10% to 50%. The risk of postoperative HE is high, and frequent HE in the early stage can shorten the postoperative survival time of patients[34].
After a meta-analysis was conducted, the efficacy of the drug intervention group and the control group in preventing HE after TIPS was compared. An examination revealed no significant publication bias in the included literature. According to the sensitivity analysis, the incidence of HE after TIPS in the drug intervention group was significantly lower than that in the control group after one study with heterogeneous sources was removed. Afterwards, we conducted subgroup analyses on retrospective and randomized controlled studies based on different types of research. These results suggest that drug prevention interventions can reduce the occurrence of HE after TIPS. For further verification, we analyzed the research in Europe, the United States, and China different regions, and the research results are the same as previously noted. Therefore, we consider that drug prevention interventions for TIPS patients can reduce the incidence of HE after TIPS.
Of the included studies, some were conducted on patients without a history of HE, some on patients with a history of HE, and some included both individuals with and without a history of HE. Owing to the inconsistent proportions of patients with and without previous HE in the study, no analysis was conducted on this topic. Finally, we conducted subgroup analysis on the basis of whether there was a history of HE. We found that regardless of the presence of a history of HE, drug prevention could significantly reduce the incidence of HE after TIPS. Finally, we analyzed four studies on the prevention of OHE by TIPS and found that drug prevention significantly reduced the occurrence of OHE after TIPS. Owing to limitations in extractable data, we were unable to analyze the occurrence of MHE after drug prevention with TIPS. We also analyzed the impact of drug prevention on survival, but there was no significant difference between the two groups, possibly because most of the observational studies included in the study were conducted between 1 and 6 months, and long-term follow-up data are lacking.
The most commonly used drugs in this study were lactulose and rifaximin. However, differences in the dosage and timing of drug use were noted. In Riggio et al's study[35], 60 mg/day lactulose and 1200 mg/day rifaximin were used after TIPS surgery, with a medication cycle of one month. In the study of Bass et al[36], 550 mg 2/day rifaximin was used for a period of 6 months. In Bai et al's study[37], 30 g/day l-ornithine-l-aspartate was taken continuously for one week. In Riggio et al's study[38], albumin was administered at a dose of 1 g/kg for 2 days, followed by 0.5 g/kg on the 4th and 7th days after TIPS surgery. Finally, it was used once a week for 3 consecutive weeks. Owing to the limited literature, a stratified analysis of drug dosage and timing was not possible. Hence, it is possible that differences in drug dosage and duration may be one of the sources of heterogeneity.
On the basis of the different drugs that were used, the differences in efficacy between each drug group and the control group were analyzed separately. Given that there was only one study each on the use of albumin and l-ornithine-l-aspartate, a meta-analysis could not be conducted. Analysis of several other drugs revealed that rifaximin alone can significantly reduce the occurrence of HE after TIPS. However, lactulose did not significantly reduce the occurrence of HE. Among the 5 included studies, only 1 clearly stated that it was OHE, 1 included both MHE and OHE, and the remaining 3 did not specify the specific type of HE. Thus, further analysis on the basis of HE type was not conducted. To our surprise, the combination of lactulose and rifaximin did not significantly reduce the occurrence of HE after TIPS. We consider this to be related to the limited number of studies in this area, which are all retrospective studies. Given the preventive effect of rifaximin, theoretically, the preventive effect should be further improved when the two drugs are combined. Therefore, more clinical studies are needed for validation.
Rifaximin is an unabsorbed antibiotic that can inhibit bacteria that produce urinary enzymes. Studies have shown[39] that compared with the control, rifaximin can improve the occurrence of HE, which is consistent with our research results. Lactulose, an unabsorbed disaccharide, reduces intestinal ammonia absorption by acidifying the intestinal contents, increases the osmotic pressure of the intestinal lumen, facilitates the excretion of ammonia and other toxins, and acts as a prebiotic to promote the growth of beneficial bacteria, thereby decreasing the incidence of HE. A meta-analysis in patients with cirrhosis revealed that lactulose can reduce the incidence of HE and other liver related adverse events such as liver failure, and prolong survival[40]. This finding was not consistent with our results regarding the use of TIPS for liver cirrhosis. On the one hand, this may be related to the limited data in current related studies. On the other hand, it may be due to the occurrence of HE after TIPS related to portal shunts. Therefore, the preventive effect of lactulose was limited, but it cannot be denied that lactulose has a preventive effect on HE after TIPS. Another meta-analysis on HE reported[41] that compared with the use of lactulose alone, the addition of rifaximin can effectively reduce the occurrence of HE and reduce mortality. These findings also suggest that lactulose may need to be combined with other drugs to improve the preventive efficacy of HE.
Finally, we conducted a network meta-analysis and found no significant differences among the five drug prevention methods, which was consistent with previous research results[42]. However, not all included studies were randomized controlled trials, and the limited number of studies was one of the limitations of this study. The occurrence of HE after TIPS is related to many factors, including the portal pressure gradient, puncture site, history of HE, nutritional status, liver function status[5,43,44] and use of proton pump inhibitors[45]. Although the incidence of HE after TIPS is relatively high, effective prevention strategies are lacking. On the basis of our current meta-analysis, drug intervention may benefit TIPS patients with cirrhosis to some extent. However, there is still a lack of standards regarding when to start using preventive drugs and how long to continue using them. Therefore, more large-scale randomized controlled trials are needed to provide clinical references for this clinical issue.
This study has certain limitations: It is possible that differences in drug dosage and duration may be one of the sources of heterogeneity. Given the limited number of studies, further subgroup analysis has not yet been conducted. No further analysis has been conducted on preventing of the occurrence of CHE. Owing to the inclusion of both randomized controlled trials and retrospective studies in the literature, we chose OR for expression, which may also represent one of the sources of heterogeneity.
CONCLUSION
The prophylactic administration of medications following TIPS may decrease the incidence of post-HE. More large-scale studies are needed to confirm these findings.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade C, Grade D, Grade D
Novelty: Grade C, Grade C, Grade D
Creativity or Innovation: Grade B, Grade C, Grade D
Scientific Significance: Grade B, Grade C, Grade D
P-Reviewer: Hashimoto N; Li S S-Editor: Lin C L-Editor: A P-Editor: Zhao YQ
Fonio P, Discalzi A, Calandri M, Doriguzzi Breatta A, Bergamasco L, Martini S, Ottobrelli A, Righi D, Gandini G. Incidence of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt (TIPS) according to its severity and temporal grading classification.Radiol Med. 2017;122:713-721.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 27][Cited by in RCA: 34][Article Influence: 4.3][Reference Citation Analysis (0)]
Bureau C, Thabut D, Jezequel C, Archambeaud I, D'Alteroche L, Dharancy S, Borentain P, Oberti F, Plessier A, De Ledinghen V, Ganne-Carrié N, Carbonell N, Rousseau V, Sommet A, Péron JM, Vinel JP. The Use of Rifaximin in the Prevention of Overt Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt : A Randomized Controlled Trial.Ann Intern Med. 2021;174:633-640.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 39][Cited by in RCA: 101][Article Influence: 25.3][Reference Citation Analysis (0)]
Subramanian SK, Abraham F, Dutra BE, Patil P, Cohen AM, Purnak T, Reddy PM, Nevah MI, Machicao VI.
Tu1716 survival benefit of the use of lactulose and rifaximin as prophylaxis for portosystemic encephalopathy after transjugular intrahepatic portosystemic shunt. Gastroenterol 2020; 158: S1467-S1468.
[PubMed] [DOI] [Full Text]
Saji S, Kumar S, Thomas V. A randomized double blind placebo controlled trial of probiotics in minimal hepatic encephalopathy.Trop Gastroenterol. 2011;32:128-132.
[PubMed] [DOI]
Bajaj JS, Fagan A, Gavis EA, Sterling RK, Gallagher ML, Lee H, Matherly SC, Siddiqui MS, Bartels A, Mousel T, Davis BC, Puri P, Fuchs M, Moutsoglou DM, Thacker LR, Sikaroodi M, Gillevet PM, Khoruts A. Microbiota transplant for hepatic encephalopathy in cirrhosis: The THEMATIC trial.J Hepatol. 2025;.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 2][Reference Citation Analysis (0)]
Zuo L, Lv Y, Wang Q, Yin Z, Wang Z, He C, Guo W, Niu J, Bai W, Li K, Yu T, Yuan X, Chen H, Liu H, Xia D, Wang E, Luo B, Li X, Yuan J, Han N, Nie Y, Fan D, Han G. Early-Recurrent Overt Hepatic Encephalopathy Is Associated with Reduced Survival in Cirrhotic Patients after Transjugular Intrahepatic Portosystemic Shunt Creation.J Vasc Interv Radiol. 2019;30:148-153.e2.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 13][Cited by in RCA: 24][Article Influence: 4.0][Reference Citation Analysis (1)]
Ahmed Z, Hassan M, Arif SF, Aziz M, Iqbal U, Nawaz A, Farooq U, Smith WL, Badal J, Renno A, Javaid T, Nawras A, Saab S. Comparative Efficacy of Treatment Options for the Prevention of Post-TIPS Hepatic Encephalopathy: A Systematic Review and Network Meta-analysis.J Gastrointestin Liver Dis. 2023;32:70-76.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 3][Reference Citation Analysis (0)]
Wang C, Yao J, Niu H, Yang C, Liu J, Bai Y, Ju S, Xiong B. Dynamic changes in liver function after transjugular intrahepatic portosystemic shunt in patients with cirrhosis.J Interv Med. 2022;5:207-212.
[RCA] [PubMed] [DOI] [Full Text][Reference Citation Analysis (1)]
Kovalic AJ, Rudnick SR. Primary prophylaxis of hepatic encephalopathy [HE] among patients undergoing transjugular intrahepatic portosystemic shunt [TIPS] is associated with decreased development of HE.Hepatol. 2018;68:1155A-1156A.
[PubMed] [DOI]
