Prophylactic Therapy of Silymarin (Milk Thistle) on Antituberculosis Drug-Induced Liver Injury: A Meta-Analysis of Randomized Controlled Trials
Canadian Journal of Gastroenterology and Hepatology
Prophylactic Therapy of Silymarin (Milk Thistle) on Antituberculosis Drug-Induced Liver Injury: A Meta-Analysis of Randomized Controlled Trials
Lina Tao 0 1
Xiaoyu Qu 0 1
Yue Zhang 0 1
Yanqing Song 0 1
Si-xi Zhang 0 1
Kevork M. Peltekian
0 Department of Pharmacy
1 e First Hospital of Jilin University , Changchun
Background. Prophylactic therapy with silymarin to prevent the development of antituberculosis drug-induced liver injury (antiTB DILI) has been under debate. We aimed to evaluate the effect of silymarin in the prevention of anti-TB DILI. Methods. We searched MEDLINE, PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) up to 30th November 2018. Randomized controlled trials (RCTs) that compared silymarin and placebo to prevent anti-TB DILI were included. All statistical analyses were conducted using STATA 12.0 software. Standardized mean difference (SMD) and risk ratio (RR) with 95% confidence intervals (CIs) were used to evaluate the effect of silymarin. The quality of included studies was assessed according to Cochrane handbook. Funnel plots and Egger's tests were carried out to evaluate publication bias. Sensitivity analysis was conducted to assess the influence of each study. Results. A total of 1198 patients from five RCTs (585 with silymarin and 613 with placebo groups) were included. Overall, silymarin significantly reduced the occurrence of anti-TB DILI at week 4 [RR: 0.33, 95% CI (0.15, 0.75)]. In addition, silymarin exerted protective effect on liver function in patients undergoing anti-TB drugs [SMD = ? 0.15, 95% CI (?0.24, ?0.07), P < 0.001 (ALT); SMD =?0.14, 95% CI (?0.23, ?0.06), P = 0.001(AST); SMD =?0.12, 95% CI (?0.20, ?0.03), P = 0.008 (ALP)]. Silymarin led to similar AEs in placebo groups [OR: 1.09, 95% CI (0.86, 1.39), P = 0.47]. Conclusion. Prophylactic therapy of silymarin is contributed to a noticeably reduced risk of development of anti-TB DILI four weeks after the initiation. In addition, silymarin significantly improved the liver function in patients who are receiving anti-TB drugs.
Tuberculosis (TB) is a major worldwide health threat and is
one of the top 10 causes of death. In 2016, the World Health
Organization (WHO) estimated that there were 10.4 million
incident TB cases and 1.7 million deaths . The standard
combined treatment regimen of anti-TB drugs consists of
isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and
ethambutol (EMB) [
Hepatotoxicity, one of the common adverse reactions of
anti-TB drugs, varies from asymptomatic elevation of liver
enzymes to fulminant hepatic failure. Anti-TB drug-induced
liver injury (anti-TB DILI) leads to increased morbidity and
mortality. Therefore, it may result in treatment withdrawal,
drug interruption and substitution, dosage regimen
adjustment, nonadherence, and drug resistance [
]. The overall
incidence of anti-TB DILI has been reported to be from 5% to
33%, depending on the definition of DILI and the population
The mechanism of anti-TB DILI remains unclear. INH
causes DILI through diverse mechanisms, i.e., by the
pathways of toxic metabolites, escalating oxidative stress,
generation of reactive oxygen species (ROS), and lipid peroxidation
]. RIF, an inducer of drug metabolic enzymes, triggers
unconjugated hyperbilirubinemia [
]. Previous studies have
reported that certain herbal drugs, phytochemicals, and food
supplements can prevent and reduce the hepatotoxicity of
anti-TB drugs [
Silymarin, a traditional herbal medicine extracted from
milk thistle (Silybum marianum L. Gaertn) fruits, has been
used as a remedy for hepatoprotection [
]. Silymarin is
the collective name of flavonolignans comprised of silybin
or silibinin, isosilybin, silydianin, and silychristin [
Silymarin manifests hepatoprotection by scavenging free
radicals, raising the glutathione content, inhibiting lipid
peroxidation, and restoring the function of enzymes, thereby
generating membrane stabilization and preventing toxic
metabolic liver injury [
To date, silymarin has demonstrated significant
hepatoprotective effects on anti-TB DILI in animal and vitro
]. However, the effectiveness of silymarin
is under debate [
]. Some clinical studies have shown that
silymarin possesses positive hepatoprotective effects . In
contract, other studies have observed no or limited preventive
effect of silymarin [
3, 20, 21
]. Therefore, we performed
this meta-analysis to evaluate the effect of silymarin in the
prevention of anti-TB DILI. We hypothesized that use of
silymarin would prevent the occurrence of anti-TB DILI in
patients with TB receiving anti-TB treatment.
We followed the PRISMA (Preferred Reporting Items for
Systematic Reviews and Meta-Analysis) guidelines
during the preparation of this meta-analysis (Supplementary
Table 1) [
]. All steps were carried out according to the
Cochrane Handbook for Systematic Reviews of
]. The present meta-analysis was not prospectively
. . Search Strategy. To identify relevant randomized trials,
we searched the literature through MEDLINE, PubMed,
Embase, and Cochrane Central Register of Controlled Trials
(CENTRAL) up to 30th November 2018 with the following
search strategies: ( ?silymarin? or ?silibinin? or ?silybum? or
?silybin? or ?silydianin? or ?silychristin? or ?milk thistle?) and
(?tuberculosis? or ?tubercul?? or ?antitubercul?? or ?tb?).
The search was restricted to English language articles. To
identify relevant unpublised studies, we searched ?ISRCTN
Register? and ?ClinicalTrials.gov? with the same search
strategies up to 30th November 2018. In addition, we searched
all references in the relevant articles, abstracts, presentations
or posters presented in scientific conferences, and previously
published reviews for additional eligible studies.
. . Inclusion and Exclusion Criteria. Two reviewers (Qu and
Zhang) independently searched for and examined the
relevant studies, and discrepancies were resolved by discussion
with a third author (Song). Individual studies of the RCTs on
the preventive effect of silymarin on anti-TB drugs induced
hepatotoxicity were included for analysis. We excluded the
following articles: experimental trials researched in animals,
articles focusing on pharmacokinetic or pharmacodynamic
variables, and trials focusing on the in vitro activity of
. . Data Extraction. The following data were extracted from
each study: year of publication, type of trial design, number of
patients, patient characteristics, treatment protocol, outcome
measures, and adverse effects. Two reviewers (Qu and Zhang)
independently extracted the relevant data. Disagreements
were resolved by discussion with a third author (Song).
. . Quality Assessment. The methodological quality of the
RCTs was evaluated according to the Cochrane Handbook
for Systematic Reviews of Interventions Version 5.1.0 [
The assessment included the following items: sequence
generation, allocation concealment, blinding of participants,
personnel and outcome assessors, incomplete outcome data,
selective outcome reporting, and other sources of bias.
Two reviewers (Qu and Zhang) independently evaluated the
quality by classifying as ?high?, ?low?, or ?unclear? risk of
bias, and disagreements were resolved by discussion with a
third author (Song).
. . Outcome Measures. Outcomes were measured for the
following: (1) the primary efficacy outcome was the
occurrence of anti-TB DILI, which was defined by serum AST or
ALT > 2 ? upper normal limit (UNL); (2) the key secondary
efficacy outcomes were changes in the liver enzymes,
including alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin
(TBIL); (3) the safety outcome was adverse events.
. . Statistical Analysis. The meta-analysis was performed
using STATA 12.0 (Stata Corporation, College Station, TX,
USA). Effect size was calculated as follows: measure at the
end of follow-up ? measure at baseline. Standard
deviations (SDs) of the mean difference were calculated using
the following formula: SD = square root [(SDbaseline)2 +
SDfollow-up)2 ? 2R ? SDbaseline ? SDfollow-up], assuming
a correlation coefficient (R) = 0.5. Mean and SD values were
estimated using the methods described by Wan et al. [
provided the outcome measures were reported in median
and interquartile range. We assessed heterogeneity with Q
statistics generated from the 2 test and inconsistency using
the I2 measure. Significant heterogeneity was judged with
P-values less than 0.10 or I2 more than 50%. We chose
to adopt a Mantel-Haenszel fixed-effect model (FEM) for
pooling the risk ratio (RR) or standardized mean difference
(SMD) and 95% confidence interval (CI) for outcomes when
heterogeneity was not significant. We chose a DerSimonian
and Laird random-effects model (REM) when heterogeneity
was obvious. Subgroup analyses were conducted according
to inconsistent follow-up period and different study design.
Sensitivity analysis was performed to test the influence of a
single study on the overall effect size by the leave-one-out
method. Possible publication bias in the meta-analysis was
explored using Egger?s test.
. . Study Selection Outcomes. The trial flow chart in Figure 1
shows the details of the study selection process. A total of 34
studies were identified, 17 of which were excluded based on
title and abstracts, and 10 full-texts were retrieved. However,
] was not an RCT, seven were duplicate publications
of the same study, nine [
] were animal studies, four
14, 16, 33, 34
] were in vitro research studies, three [
] were irrelevant to this study, one  was a conference
summary without available results, one [
] was a clinical
34 citations identified by electronic database searching
(1) 22 from MEDLINE
(2) 10 from CENTRAL
(3) 2 from ISRCTN Register and ClinicalTrials.gov
27 selected articles
10 articles reading full-text
7 excluded by duplication
17 excluded after reading title and abstracts
(1) 9 animal studies
(2) 4 vitro studies
(3) 3 articles irrelevant to the study
(4) 1 review
5 articles excluded
(1) 2 conference summaries without
(2) 1 non-randomized controlled study
(3) 1 clinical trial with unknown recruitment
(4) 1 data cannot be used
5 articles included in Meta-analysis
trial with unknown recruitment status, one [
] study?s data
could not be used, and one [
] was a review. Therefore, finally
five RCTs [
19?21, 42, 43
] were included in the meta-analysis.
. . Study Characteristics and Quality Assessment. A total of
585 and 613 patients were randomly treated with silymarin
and placebo, respectively. Table 1 shows the main
characteristics of the studies included in the meta-analysis.
All of the studies included in this meta-analysis were
described as randomized. In two studies [
], the method
of randomization was not clearly described, but
randomization was appropriate in other studies [
19, 21, 43
were described as computerized-based. The studies by Gu
et al. in 2015  and Zhang et al. in 2016 [
] were open
control studies with a high risk of detection and performance
bias, while the other three studies [
19, 20, 43
] used adequate
methods to blind the intervention. All of the included
studies had a low risk of incomplete outcome data. Selective
reporting was low risk in the included studies because the
main outcomes stated in the protocol were all reported in the
final manuscript. Any other potential biases were unclear in
the included studies (Table 2).
. . e Occurrence of Anti-TB DILI. All the included studies
contributed to this analysis and participants were divided into
three subgroups with different follow-up periods. Silymarin
administration was associated with a significant reduction in
the occurrence of anti-TB DILI [RR: 0.33, 95% CI (0.15, 0.75),
P = 0.008] with low heterogeneity (P = 0.22, I2 = 33%) at week
4. No significant differences were obtained between the two
groups at week 2 (P = 0.64, I2 = 0% ) and week 8 (P = 0.06,
I2 = 0%) (Figure 2).
. . Changes in Liver Enzymes (ALT, AST, ALP, and TBIL).
Three studies [
19, 42, 43
] reported the effect of silymarin on
liver function enzymes. Significant differences were found
with respect to change in ALT between silymarin and placebo
groups [SMD: ? 0.15, 95% CI (?0.24, ?0.07), P < 0.001]
(Figure 3(a)). In view of different follow-up durations, a
subgroup analysis was performed which showed that there
was no significant difference in the change in ALT level after
8 weeks of treatment [SMD: ? 0.08, 95% CI (?0.23, 0.07), P =
0.30]; however, silymarin significantly decreased ALT levels
compared with placebo groups after 2 weeks of treatment
[SMD: ? 0.16, 95% CI (?0.31, ?0.01), P = 0.04] and after 4
Luangchosiri et al.
silymarin, 140 mg,
week 2, 4
Values are presented as number (%) or mean?SD.
A: the occurrence of anti-TB treatment related DILI; B: liver function tests (ALT, AST, ALP, and TBIL); C: the occurrence of interruption of anti-TB treatment
or taking the second-line TB drugs; D: adverse events.
Criteria defined for quality assessment are based on the Cochrane guidelines.
H: high risk of bias; L: low risk of bias; U: unclear risk of bias.
weeks of treatment [SMD: ? 0.22, 95% CI (?0.37, ?0.07), P =
There was a significant difference between silymarin and
placebo groups in terms of AST change [SMD: ?0.14, 95% CI
(?0.23, ?0.06), P = 0.001] (Figure 3(b)). Because of different
follow-up durations, we performed a subgroup which showed
that there was no significant difference in the change in AST
level after 2 weeks of treatment [SMD: ? 0.06, 95% CI (?0.22,
0.09), P = 0.40]; however, silymarin noticeably decreased AST
levels compared with placebo groups after 4 weeks [SMD: ?
0.20, 95% CI (?0.34, ?0.05), P = 0.008] and after 8 weeks of
treatment [SMD: ? 0.16, 95% CI (?0.32, ?0.01), P = 0.034].
There was a significant difference between silymarin and
placebo groups in terms of ALP change [SMD: ?0.12, 95% CI
(?0.20, ?0.03), P = 0.008] (Figure 4(a)). Because of different
follow-up durations, we performed a subgroup analysis
which showed that there were no significant differences in
the change in ALP level after 2 weeks of treatment [SMD: ?
0.08, 95% CI (?0.23, 0.07), P = 0.288] and after 4 weeks of
treatment [SMD: ? 0.06, 95% CI (?0.21, ?0.08), P = 0.40];
however, silymarin noticeably decreased ALP level compared
with placebo group after 8 weeks of treatment [SMD: ? 0.21,
95% CI (?0.36, ?0.06), P = 0.007].
There was no significant difference between silymarin and
placebo groups in terms of TBIL change [SMD: ?0.03, 95% CI
(?0.12, 0.05), P = 0.441] (Figure 4(b)).
. . Adverse Event Analysis. Adverse events were reported
in four studies [
]. Nausea/vomiting was the most
frequently reported adverse event [
distension/pain and anorexia were also commonly reported
]. Rash/exanthema was observed in two studies [
]. Dizziness and pruritus were also observed in two studies
]. There was no significant difference in the proportion
of patients with adverse events in both groups [RR: 1.09, 95%
CI (0.86, 1.39), P = 0.47] and with no heterogeneity (P = 0.91,
I2 = 0%) (Figure 5).
. . Subgroup Analysis. Stratified analysis was also
performed based on blinded or open-labelled study designs to
explore potential sources of heterogeneity among studies that
considered the occurrence of anti-TB DILI as an example. No
?0.14 (?0.23, ?0.06)
?0.03 (?0.12, 0.05)
heterogeneity was found, and the open-labelled study design
did not alter the direction of the pooled effect (Supplementary
Figure 1(a), Supplementary Figure 1(b)).
. . Sensitivity Analysis and Publication Bias. In the
sensitivity analysis, we successively eliminated studies one-by-one to
recalculate RR, which showed one obvious fluctuation
(Supplementary Figure 2(a)). No significant publication bias was
detected with Egger?s test (P=0.093). The funnel plot showed
symmetry on visual inspection (Supplementary Figure 2(b)).
Anti-TB DILI is an important and pivotal adverse effect that
can occur during the initial two months when combination
therapy with three to four anti-TB drugs is required [
Any effective measure that can prevent anti-TB DILI is of
significance. Therefore, we conducted this meta-analysis to
evaluate the ef fect of silymarin on prevention of anti-TB DILI.
In this meta-analysis, the efficacy of silymarin was
assessed by comparing the incidence of anti-TB DILI and
changes in the liver enzymes. Fortunately, silymarin reduced
the occurrence of anti-TB DILI at week 4 [OR: 0.33, 95% CI
(0.15, 0.75), P = 0.008]. Additionally, it reduced ALT levels at
weeks 2 and 4, and AST levels at weeks 4 and 8. Moreover,
reduction in ALP level at week 8 was significant. However,
the effect of silymarin on TBIL level was similar to that of
A previous study indicated the median interval from
treatment initiation of anti-TB drugs to development of
clinical symptoms to be 16 weeks (range 6 weeks to 6
]. According to a recent Korean cohort study
focusing on the time of onset of anti-TB DILI that included
1031 TB patients, the majority (67.6%) hepatotoxic events
appeared within the first 30 days of anti-TB treatment [
This meta-analysis suggested that silymarin showed efficacy
in the prevention of anti-TB DILI. Interestingly, silymarin
administration significantly reduced the incidence of
antiTB DILI at week 4; however there was no beneficial effect
on the incidence at week 8. This showed that silymarin
shows hepatoprotective effect during short-term treatment of
anti-TB drugs. Previous research studies reported that
antiTB drugs result in oxidative stress, lipid peroxidation, and
exhaustion of glutathione reserves [
]. Recent studies
supported that INH-induced hepatotoxicity has also been
attributed to a reactive metabolite and an immune mediated
]. These intricate mechanisms responsible for
anti-TB DILI may be partly neutralized by the mechanism
of hepatoprotection of silymarin. Furthermore, there may be
a compensatory or adaptive response against anti-TB DILI,
representing immune tolerance that prevents further liver
injury, which could interpret delayed onset of DILI [
general, silymarin significantly reduced the incidence of
antiTB DILI at week 4.
Silymarin administration significantly lowers serum AST
and ALP levels. Despite silymarin presenting beneficial
effects on lowering the serum AST and ALP levels at week 8,
it could not reduce the incidence of anti-TB DILI at week 8.
This proved that silymarin has no promising hepatoprotective
effect in the long-term duration treatment with anti-TB
Considering the safety of silymarin, only minor adverse
effects such as nausea/vomiting, abdominal distension/pain,
anorexia, rash/exanthema, and dizziness were reported. All
of these reported adverse events were mild and tolerable.
Moreover, it showed no significant difference with placebo
There were some limitations to our study. First, the
sample size was relatively small with only 585 patients in the
silymarin group and 613 in the placebo group. Second, we
included two open-labelled studies [
], which may give
rise to information bias for the lack of blinding. However, the
outcomes were not affected by the absence of blinding. Third,
one study  chose vitamin C, a potential hepatoprotector
], as the control instead of a placebo, which may lower the
preventive effect of silymarin in anti-TB DILI. In addition,
silymarin is a multi-ingredient product, and its effect may
vary due to differences in cultivars, active ingredients, and
methods of improving low bioavailability [
further large-scale, well-designed clinical trials are required
to confirm and validate the preventive effect of silymarin on
Drug-induced liver injury associated with antituberculosis
drugs is a common adverse event. It is essential to prevent
the occurrence of anti-TB DILI, because anti-TB DILI may
affect treatment compliance and therapeutic effectiveness in
patients with tuberculosis. This meta-analysis suggested that
silymarin showed moderate efficacy in the prevention of
antiTB DILI, as it significantly reduced risk of development of
anti-TB DILI at week 4, and decreased serum ALT levels
at weeks 2 and 4, serum AST levels at weeks 4 and 8,
and ALP level at week 8. In addition, silymarin was
welltolerated. The intricate mechanisms of anti-TB DILI have
been poorly understood. Moreover, further studies on the
effect of silymarin on the prevention of anti-TB DILI are
needed with respect to consensus definition of anti-TB DILI
and homogeneous follow-up period.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
All authors have revised the final manuscript and confirmed
that it is never published anywhere.
The research was supported by National Natural Science
Foundation of China (no. 81803608) and the 8th Youth
Foundation of the First Hospital of Jilin University (no.
Supplementary Figure 1: subgroup analysis of the occurrence
of anti-TB DILI based on blinded or open-labelled study
designs. (a) Follow-up at week 4. (b) Follow-up at week 8.
Supplementary Figure 2: (a) forest plot of sensitivity analysis
in the meta-analysis; (b) funnel plot for the effect of silymarin
on the occurrence of anti-TB DILI. Supplementary Table 1:
PRISMA 2009 Checklist. (Supplementary Materials)
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