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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 2  |  Page : 461-469

Meta-analysis of the efficacy of glycyrrhizin for postoperative liver preservation in patients with liver cancer


1 Department of Laboratory Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, P. R. China
2 Department of Laboratory Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University; Department of Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, P. R. China
3 Department of Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, P. R. China

Date of Submission11-Oct-2021
Date of Decision05-Feb-2022
Date of Acceptance07-Feb-2022
Date of Web Publication20-May-2022

Correspondence Address:
Sumei Lu
Department of Laboratory Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014; Department of Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014
P. R. China
Wanshan Ma
Department of Laboratory Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014; Department of Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014
P. R. China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_1811_21

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 > Abstract 


Objective: This meta-analysis comprehensively summarizes the current clinical research on compound glycyrrhizin (CG) treatment for liver cancer and protecting liver function to guide clinical treatment.
Methods: Eighteen English-language articles were retrieved from PubMed, SinoMed, Cochrane, Embase, Web of Science, and three Chinese databases: The Wan Fang database, China National Knowledge Infrastructure (CNKI), and the VIP database.
Results: CG treatment improved the patient's alanine aminotransferase (ALT) level (in the metastatic liver cancer group: mean deviation (MD) = −13.78, 95% confidence interval (CI) = [−17.29, 10.27]; in the primary liver cancer group: MD = −32.15, 95% CI = [−35.48, 28.81]); aspartate aminotransferase (AST) level (in the primary liver cancer group: MD = −21.63, 95% CI = [−24.29, 18.96]; in the metastatic liver cancer group: MD = −15.64, 95% CI = [−19.08, −12.20]); serum total bilirubin (TBIL) level (MD = −1.61, 95% CI = [−2.71, −0.51]); and serum albumin (ALB) level (MD = 2.80, 95% CI = [1.85, 3.74]). CG treatment was efficient than the control (relative risk [RR] = 1.66, 95% CI = [1.35, 2.04]). Although adverse reactions, including fever, were higher than in the control group (RR = 1.13, 95% CI = [0.89, 1.43]), they were controllable.
Conclusion: CG affects liver preservation in treating liver cancer, which can reduce ALT, AST, and TBIL levels in patients; increase the ALB level; and protect liver cells. The CG-treated group showed improvement compared with the control group; although adverse reactions occurred in the treated group, the duration was shortened.

Keywords: Compound glycyrrhizin, licorice, liver cancer, meta-analysis, Stronger Neo-Minophagen C, treatment


How to cite this article:
Li Y, Hao M, Zhang B, Wang P, Zhang D, Lu S, Ma W. Meta-analysis of the efficacy of glycyrrhizin for postoperative liver preservation in patients with liver cancer. J Can Res Ther 2022;18:461-9

How to cite this URL:
Li Y, Hao M, Zhang B, Wang P, Zhang D, Lu S, Ma W. Meta-analysis of the efficacy of glycyrrhizin for postoperative liver preservation in patients with liver cancer. J Can Res Ther [serial online] 2022 [cited 2022 Jul 7];18:461-9. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/461/345532




 > Introduction Top


Liver cancer is a malignant disease, and the incidence of this cancer is associated with hepatitis virus infection, chronic alcoholism, metabolic diseases, and aflatoxin. As of 2019, liver cancer was the fourth most common cause of cancer-related deaths globally and ranked sixth in terms of incidence,[1] posing a major threat to human health.

Licorice is a widely used herbal medicine in China. Clinical studies have found that licorice, glycyrrhizin, and glycyrrhetinic acid (GA) extracts play significant anti-inflammatory,[2] antioxidant, and antitumor roles and can be used to treat psoriasis vulgaris,[3] chronic urticaria, viral hepatitis, SARS, and the recent outbreak of COVID-19.[4] Compound glycyrrhizin (CG) is a compound prepared with glycyrrhizin as the main ingredient, with the brand name Stronger Neo-Minophagen C (SNMC). In this article, we summarized current clinical studies on CG treatment of liver cancer and reviewed the effectiveness of CG treatment of liver cancer for clinical reference.


 > Methods and Analysis Top


Literature retrieval

Computer-based searches of the databases PubMed, SinoMed, Cochrane, Embase, Web of Science, and three Chinese databases, namely the Wanfang, CNKI, and the VIP, were conducted to find English-language articles published since the databases were built, with keywords including “compound glycyrrhizin” and its commodity name “SNMC” merging the mesh word for liver cancer and various free-forms, and using the search terms “OR” and “AND” to connect. The retrieval strategy for each database was adjusted according to its characteristics; we show the search steps for PubMed as an example in [Table 1]. The other studies were supplemented by manually retrieving the original articles and references. Finally, the searched documents were imported into EndNote X9 document management software for further screening.
Table 1: Retrieval policies for different databases

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Screening of the literature

The literature was incorporated and excluded according to the following criteria:

Patients included in the study

According to the diagnostic criteria, the patients included in the study were diagnosed with primary or secondary liver cancer, regardless of age or region. The methods for diagnosis included fetal serum protein testing, B-scan ultrasonography, CT, and liver puncture biopsy pathology. Patients diagnosed with cirrhosis or hepatitis but without liver cancer were excluded.

Interventions and controls

Patients in the control group were treated with medicines that can replenish energy or other basic treatments after tumor removal, trans-hepatic arterial chemotherapy embolism (TACE) intervention, or chemotherapy medication treatment.

The patients in the observation group received CG injections or oral preparations, in contrast to the control group. Studies with noncomplex glycyrrhizin treatment and nonrandomized controlled trials were excluded.

Results included in the study

The liver function of the patients was tested through routine blood tests and biochemical blood examinations. The statistical parameters included ALT (U/L), AST (U/L), TBIL (μmol/L), ALB (g/L), γ-GT (U/L), and TB (μmol/L).

The number of patients with adverse reactions and the duration (days) was measured, including nausea and vomiting, fever, elevated blood pressure, and others. Additionally, the efficacy of the CG treatment was analyzed.

Types of research included

The experimental studies included in this meta-analysis were all completely randomized controlled trial studies, reporting relative risk (RR) values and their corresponding 95% confidence interval (CI), and weighted mean deviation (MD) values and their corresponding 95% CIs or counts of positive events. Additionally, the value of I2 was used to judge heterogeneity. Specifically, if I2 <50%, the heterogeneity was acceptable; if I2 >50%, subgroup analysis or heterogeneity source analysis was performed to determine whether to merge statistics.

Nonrandomized controlled trials (basic trials, case reports, etc.) were excluded from the analysis. The screening of the studies was conducted simultaneously by two statisticians; if they disagreed, they agreed, or the study was re-evaluated by a third party to determine whether it should be included. The studies included were published in Chinese or English.


 > Results Top


A total of 369 relevant studies were retrieved, 112 duplicate articles were excluded, 257 were further screened, and 183 articles that did not meet the inclusion criteria were excluded after reading the topics and abstracts. The remaining 74 articles were read in detail and then evaluated, and 56 articles were excluded because the subjects, interventions, control studies, outcome indicators, or design did not meet the inclusion requirements. The remaining 18 articles were eventually included [Figure 1],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22] with 1,355 subjects included in this meta-analysis.
Figure 1: The process by which articles were incorporated and retrieved

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Sixteen of the eighteen studies examined liver function,[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[20],[21] twelve reported adverse reactions,[5],[6],[7],[8],[11],[12],[13],[15],[16],[21],[22] and two reported the duration of adverse reactions.[5],[6] The therapeutic efficacy of remission or partial remission was reported in six studies.[13],[16],[19],[20],[21],[22] All the included studies were conducted in China and were published in Chinese journals, while most were published in Chinese core periodicals. The basic information in the included articles is given in [Table 2].
Table 2: Basic information in the included articles

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Methodological quality: Deviation risk assessment

Two statisticians assessed the risk of bias in the included studies, which were conducted following the Cochrane evaluation manual.[23] An experiment did not mention if it was conducted based on the random allocation principle and was then classified as having an unclear risk of bias.[17] The remaining 17 studies followed the principle of complete random allocation and were classified as having a low risk of bias. There was no mention of concealment in allocation during the experiments, and no reference was made using blinding methods; therefore, all trials were assessed as having an unclear risk of bias. All eighteen studies were published with complete outcome data, and no outcome data were lost, so they were all assigned to the low-risk group. The results of the quality assessment of the article are shown in [Figure 2].
Figure 2: Quality evaluation table. We assessed the risk of bias in the included studies following the Cochrane evaluation manual

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Outcome indicators

The outcome indicators included in the study were summarized. Only two studies did not record changes in ALT or AST after treatment.[19],[22] Twelve studies analyzed TBIL changes,[5],[6],[7],[9],[10],[12],[13],[14],[15],[18],[20],[21] nine studies counted ALB changes,[5],[6],[7],[8],[9],[10],[13],[17],[18] three studies counted changes in γ-GT in response to treatment,[8],[16],[17] and six studies reported the efficacy of the treatment.[13],[16],[19],[20],[21],[22] The studies also focused on adverse reactions, including nausea and vomiting, fever, the elevation of blood pressure, thrombocytopenia, leukocytopenia, diarrhea, edema, dizziness, and sweating. This meta-analysis extracted these data to describe the role of CG for treating liver cancer and its capability to protect the liver, enhancing the efficacy of treatment.

The data from the study were extracted and analyzed with ViewManager 5.4 (RevMan 5.4), data analysis software. The results are as follows:

ALT levels before and after treatment

The 16 studies that measured ALT levels showed that the observation group with CG treatment had significantly lower ALT values than the control group. Although the results showed considerable heterogeneity (P < 0.05, I2 = 93%), subgroup analysis was conducted to identify the source of heterogeneity. The patients with liver cancer were divided into two subgroups, namely the primary hepatic carcinoma group and the secondary liver cancer group, and the studies that led to heterogeneity were excluded [Figure 3]a. After dividing the subgroups, there was no heterogeneity, so a fixed-effect model was used. The results showed that the ALT level decreased significantly compared with that in the non-CG group with CG treatment. The combined effect in the metastatic liver cancer group (MD = −13.78, 95% CI = [−17.29, −10.27], I2 = 0) and in the primary group (I2 = 15%, MD = −32.15, 95% CI = [−35.48, −28.81]) showed that ALT was improved in the CG treatment group compared with the control group.
Figure 3: ALT (a) and AST (b) level changes after applying compound glycyrrhizin to treat liver cancer

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AST levels before and after treatment

A total of 16 studies reported statistics on AST levels before and after treatment.[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[20],[21] The combined statistics (CHI2 = 157.43, df = 15, I2 = 90%) revealed high heterogeneity, so we performed subgroup analysis, as well as sensitivity analysis, dividing the studies into two groups, namely those with a primary liver cancer group and those with a secondary liver cancer group, excluding the studies that caused the heterogeneity. The recombined statistics for the primary liver cancer group were CHI2 = 12.43, df = 9, and I2 = 28%, indicating no evident heterogeneity. Moreover, MD = −21.63, 95% CI = [−24.29, −18.96], and P < 0.05, the difference was statistically significant, indicating that CG treatment reduced the AST level in liver cancer patients. In the metastatic liver cancer group, CHI2 = 18.20, df = 1, and I2 = 95%, the heterogeneity was significant, but MD = −15.64 and 95% CI = [−19.08, −12.20], which were better than those of the control group [Figure 3]b.

ALB levels before and after treatment

Nine studies analyzed changes in ALB with treatment.[5],[6],[7],[8],[9],[10],[13],[17],[18] The combined statistics and results showed that CHI2 = 12.22, df = 8, and I2 = 35%, indicating low heterogeneity, so no subgroup division was imposed, and a fixed-effect model was used for analysis. Moreover, MD = 2.80, 95% CI = [1.85,3.74], and P < 0.05, showing that CG treatment of liver cancer maintained ALB levels in patients and was conducive to the recovery of liver function [Figure 4]a.
Figure 4: ALB (a) and TBIL (b) level changes after applying compound glycyrrhizin to treat liver cancer

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TBIL levels before and after treatment

Twelve studies reported the level of change in TBIL,[5],[6],[7],[9],[10],[12],[13],[14],[15],[18],[20],[21] and after combining the statistics, CHI2 = 222.71, df = 11, and I2 = 95%, indicating much heterogeneity. Eleven studies were combined after excluding one study that caused heterogeneity. MD = −1.61, 95% CI = [−2.71, −0.51], and P < 0.05 indicated that CG's use for treating liver cancer could improve patients' TBIL levels, which were better than those in the control group [Figure 4]b.

Therapeutic effect

Six studies reported the treatment efficacy.[13],[16],[19],[20],[21] The combined statistics showed that CHI2 = 27.16, df = 5, and I2 = 82%, indicating a significant degree of heterogeneity; therefore, sensitivity analysis was conducted. The study that led to heterogeneity was eliminated, resulting in I2 = 0%, indicating no heterogeneity. Using a fixed-effect model to combine statistics from five studies yielded RR = 1.66, 95% CI = [0.95–1.88], and P < 0.05, which indicated that the group with CG treatment of liver cancer had better outcomes [Figure 5]a.
Figure 5: The effect rate (a) and adverse reactions (b and c) after treatment

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Adverse fever reactions

Four studies reported statistics on adverse fever reactions in patients after taking the drug,[5],[6],[7],[8] showing CHI2 = 2.08, df = 3, and I2 = 0%, indicating no heterogeneity after combining the statistics of these studies. The fixed-effect model yielded RR = 1.13, 95% CI = [0.89–1.43], and P > 0.05, revealing no significant difference between the two groups. The results showed no significant difference in adverse reactions to fever between cancer patients taking CG and those taking the control drug. Consistent with the conclusions in the article, CG can cause fever but can be controlled [Figure 5]b.

Adverse nausea and vomiting reactions

Six studies reported statistics on adverse nausea and vomiting reactions,[5],[6],[7],[8],[12],[15] and after combining the statistics, CHI2 = 11.19, df = 5, and I2 = 55%, indicating heterogeneity; thus, the statistics were analyzed with random-effect models, yielding RR = 1.07, 95% CI = [0.68–1.69], and P > 0.05. There was no significant difference between the two groups; therefore, no significant difference between the CG treatment group and the control group in causing adverse nausea and vomiting reactions. In liver cancer patients treated with CG, nausea and vomiting are controllable with low-intensity reactions [Figure 5]c.

Although the difference in the number of people who developed adverse reactions of nausea, vomiting, or fever was not statistically significant between the two groups, analysis showed that the duration of adverse reactions in CG patients was shorter than that of the control group, and P < 0.05, indicating a statistically significant difference.

Other adverse reactions

Statistics on other adverse reactions, including edema, the elevation of blood pressure, thrombocytopenia, leukocytopenia, diarrhea, dizziness, and sweating, showed no significant differences between the CG treatment group and the control group. The adverse reactions were mild and controllable.

Publishing bias

The funnel plots of the changes in AST level and TBIL level were almost symmetrical, suggesting that the ALT funnel plot was not symmetrical [Figure 6]a, whereas there is no significant publishing bias among the included studies of AST and TBIL [Figure 6]b, [Figure 6]c. Fewer than 10 articles analyzed other indicators, such as ALB or adverse reactions, so we did not perform publishing bias analysis.
Figure 6: Funnel plots showing publication bias for the ALT (a), AST (b), and TBIL (c) indices

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 > Discussion Top


Liver cancer has been divided into primary liver cancer and metastatic hepatic carcinoma. Primary liver cancer also includes three categories: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, and mixed-type cancer hepatocarcinoma.[24] With the Barcelona clinic liver cancer (BCLC) staging system,[25] liver cancer can be divided into four stages and varying treatments. Ultra-early-stage tumors (stage 0) with diameters less than 2 cm or early-stage tumors (stage A) can be treated with curative treatment, such as resection or liver transplantation. For mid-stage (stage B) or stage C tumors, TACE technology and chemotherapeutics, such as sorafenib, can be used. Studies have shown that the combination of TACE and radiofrequency ablation (RFA) could provide a better outcome than RFA or TACE alone.[26] The drug-eluting beads transarterial chemoembolization (DEB-TACE), which is a modified procedure of TACE, could lower the incidence of complications in primary HCC than TACE. Patients in the end stage (stage D) can only receive systematic conservative treatment to maximize survival.[27] To alleviate the patient's pain and prolong their life span as long as possible, humans have been exploring the treatment of liver cancer constantly.

There is evidence from clinical studies that adding CG to the basic conventional treatment of liver cancer can protect liver function and improve treatment efficacy, thus prolonging the life span of patients and improving their quality of life. The main components of CG are glycyrrhizin and GA, which are extracts from the roots of herbal medicine licorice. Glycyrrhizin and GA are the most effective ingredients in licorice for protecting the liver and fighting against the hepatitis virus. The exoteric experiments on hepatoma carcinoma cells indicate that glycyrrhizin is cytotoxic to liver cancer cells but not normal hepatocytes. The administration of glycyrrhizin dramatically reduced viability and exhibited obvious inhibition of cell survival in a dose- and time-dependent manner, therefore inhibiting colony formation and migration of cancer cells. Supplementation with glycyrrhizin later triggers autophagy in HCC, with a mechanism associated with the suppression of the AKT/mammalian target of rapamycin (mTOR) pathways and the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathways.[28] In addition, the glycyrrhizin derivatives ME-GA (18β-glycyrrhetinic-30-methyl ester) and AKBA (3-acetyl-11-keto-β-boswellic acid) can effectively stop the spread or proliferation of HCC. ME-GA reduces the colony formation of the cluster by blocking the G2/M phase of the cell cycle, induces apoptosis of HCC cells via the extrinsic pathway, and increases p53 transactivation. The toxic effects of ME-GA are selective to HCC but not lethal to normal cells.[29] Another ingredient, GA, is an effective antitumor drug that induces apoptosis in HCC cells, gastric carcinoma cells, and promyelocytes. Glycyrrhetinic acid can be transformed into glycyrrhetinic acid monoglucuronide (GAMG) via biotransformation, while the 18a-GAMG inhibits telomere regeneration by inhibiting the expression of p65 telomerase reverse transcriptase, further blocking the proliferation of HCC.[30] SNMC (the trade name of CG) has been used to treat people who contracted the hepatitis C virus for decades in Japan. In a multicenter randomized, double-blind study, the ALT levels of hepatitis patients treated with SNMC decreased significantly compared to the placebo control group. ALT level is the most reliable indicator for assessing the dissolution level of liver cells. The ALT score can reflect the progression of liver cancer. CG therapy also significantly improved liver histology. Patients with chronic hepatitis taking SNMC for a long time had a lower risk of developing liver cancer than those in the control group.

This meta-analysis included 18 clinical studies where patients who developed liver cancer were given additional supplementation with CG after treatment with TACE, liver tumor removal surgery, or radiation therapy to protect liver function, enhance antitumor effectiveness, and reduce the time of adverse reactions or improve their quality of life. The results were statistically significant, showing that the application of CG could reduce the levels of ALT, AST, and TBIL in patients, improve the level of ALB, and protect liver function. The curative effect in the CG treatment group was significantly better than that in the control group. Patients treated with CG had elevated blood pressure, sodium water retention, hypokalemia, and other adverse reactions, which were consistent with the existing literature. Although the frequency of adverse reactions in the treatment group showed no significant differences between those in the control group, the duration of adverse reactions was significantly shortened, and the results were statistically significant. This guides the clinical study of CG, which should be supplemented in the future, and the sample size be expanded to ensure the credibility of these statistical results.


 > Conclusion Top


A meta-analysis of existing published clinical studies on the treatment of liver cancer with CG revealed that compound glycyrrhizin could improve liver function, decrease ALT, AST, and TBIL, increase ALB levels, and improve therapeutic efficacy. Treatment with CG may cause adverse reactions, such as fever, nausea, and vomiting, but these adverse reactions are mild and can be controlled. Related reports have also shown adverse effects, such as triggering elevated blood pressure, sodium storage, and elevated potassium in the blood. Conclusively, CG treatment of liver cancer has promising prospects.

Statement

The manuscript has been read and approved by all the authors, and each author believes that the manuscript represents honest work, if that information is not provided in another form.

Financial support and sponsorship

This study was funded by the Cultivation Fund of National Natural Science Foundation of China in Shandong Provincial Qianfoshan Hospital (No. QYPY2020NSFC1004), the Key Technology Research and Development Program of Shandong (No. 2017G006024), National Natural Science Foundation of China (No. 81400843), and Natural Science Foundation of Shandong Province (No. ZR2014HP033).

Conflicts of interest

There are no conflicts of interest.



 
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