3.1. Outcome Studies
Our search retrieved 496 articles related to silymarin or anti-TB/antipsychotic DILI. However, 370 duplicate articles were excluded. By reading the title and the abstract of articles, 109 articles were excluded because of being a review study, animal study, or doing an inappropriate intervention. After reading the full texts, eight articles did not meet the inclusion criteria (no available data, non-RCT, and observations or control groups of less than 100 patients in Chinese language literature), as shown in Table 1. In total, nine studies were included. RCTs were screened independently by two authors (SY and HY) through all databases, as shown in Figure 1.
Table 1.
Summary of Quality Evaluation by the Jadad Scale for Clinical Trials of Silymarin Anti-TB/Antipsychotic DILI
Trials | Random Sequence Generation | Allocation Concealment | Double Blinding | Description of Withdrawals and Drop-outs | Score |
---|
Luangchosiri et al. (22) | 2 | 2 | 2 | 1 | 7 |
Marjani et al. (16) | 1 | 2 | 2 | 1 | 6 |
Heo et al. (15) | 2 | 0 | 2 | 1 | 5 |
Gu et al. (18) | 2 | 1 | 0 | 1 | 4 |
Wu et al. (23) | 2 | 1 | 0 | 1 | 4 |
Ni (24) | 1 | 1 | 0 | 1 | 3 |
Zhang et al. (17) | 2 | 0 | 0 | 1 | 3 |
Duan (25) | 1 | 1 | 0 | 1 | 3 |
Zhang et al. (26) | 1 | 0 | 0 | 1 | 2 |
3.2. Basic Characteristics of the Study
Nine RCTs with 2,712 participants (1,351 cases in the silymarin group and 1,361 cases in the control group) were evaluated. The first author, study design, sample size, intervention measures, follow-up, dosage, and related outcome indicators are shown in Table 2.
Table 2.
Basic Characteristics of the Included Studiesa
First Author | Treatment | Control | Follow-up, wk | Dose, mg/d | T/C | Outcome |
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Wu (23) | Anti-TB+SM | Anti-TB | 8 | 210 | 118/114 | 1, 2, 3 |
Gu (18) | Anti-TB+SM | Anti-TB | 8 | 210 | 253/255 | 1, 2, 3 |
Marjani (16) | Anti-TB+SM | Anti-TB+placebo | 2 | 420 | 35/35 | 1, 2 |
Luangchosiri (22) | Anti-TB+SM | Anti-TB+placebo | 4 | 420 | 27/28 | 1, 2 |
Heo (15) | Anti-TB+SM | Anti-TB+placebo | 8 | 280 | 45/58 | 1 |
Zhang (17) | Anti-TB+SM | Anti-TB | 8 | 400 | 56/44 | 1, 2 |
Ni (24) | Anti-TB+SM | Anti-TB | 8 | 315 | 216/200 | 1, 3 |
Zhang (26) | Anti-TB+SM | Anti-TB | 8 | 315 | 312/309 | 1, 2, 3 |
Duan (25) | Anti-TB+SM | Antipsychotic | 8 | 210 | 110/108 | 1 |
aAnti-TB, 2HRZE/4HR; SM, Silymarin; 1, Incidence of liver injury; 2, Adverse event; 3, Liver function indicators.
3.3. Result of Data Analysis
Nine studies contributed to the occurrence of anti-TB/antipsychotic DILI analysis and participants were separated into five subgroups with different dosages and follow-up periods. Sensitivity analysis showed that silymarin at less than 300 mg/d significantly reduced the occurrence of anti-TB/antipsychotic DILI, whether it was applied for two weeks, four weeks, or eight weeks [subtotal OR: 0.78, 95% CI (0.41, 1.32), P = 0.56, I2 = 0% for two weeks; subtotal OR: 0.28, 95% CI (0.13, 0.60), P = 0.28, I2 = 22% for four weeks; subtotal OR: 0.65, 95% CI (0.31, 1.35), P = 0.60, I2 = 0% for eight weeks; pooled OR: 0.53, 95% CI (0.35, 0.78), P = 0.42, I2 = 3%] (Figure 2). Silymarin at 315 mg/d significantly reduced the occurrence of anti-TB/antipsychotic DILI [subtotal OR: 0.17, 95% CI (0.08, 0.39), P = 0.04, I2 = 76%] for eight weeks but no significant difference was found between the over 400 mg/d silymarin group and the control group [subtotal OR: 0.93, 95% CI (0.20, 4.39), P = 0.02, I2 = 76%] (Figure 2). No significant difference was found in the occurrence of adverse events between the control and silymarin groups [pooled OR: 0.94, 95% CI (0.71, 1.25), P = 0.46, I2 = 0%] (Figure 3).
Figure 2.
Effect of different dosages and treatment times of silymarin on the occurrence of anti-TB/antipsychotic DILI
Figure 3.
The occurrence of adverse events by silymarin
Compare to the control group, 315 mg/d silymarin significantly reduced serum liver enzymes AST, ALT, and TBIL in eight weeks [subtotal MD: -29.00, 95% CI (-31.57, -26.43) for AST; subtotal MD: -124.00, 95% CI (-126.76, -121.24) for ALT; subtotal MD: -12, 95% CI (-12.72, -11.28) for TBIL], all with low heterogeneity (P = 1.00, I2 = 0%). Silymarin at less than 300 mg/d significantly reduced serum liver enzymes AST and ALT in two weeks, four weeks, and eight weeks [AST subtotal MD: -2.89, 95% CI (-6.87, 1.09) for two weeks; AST subtotal MD: -5.74, 95% CI (-10.69, -0.80) for four weeks; AST subtotal MD: -5.22, 95% CI (-9.92, -0.51) for eight weeks, with low heterogeneity (P > 0.29, I2 < 10%); ALT subtotal MD: -3.30, 95% CI (-7.15, 0.56) for two weeks; ALT subtotal MD: -3.55, 95% CI (-10.91, 3.80), P = 0.07, I2 = 70% for four weeks; ALT subtotal MD: -3.48, 95% CI (-10.58, 3.62) for eight weeks, with low heterogeneity (P > 0.61, I2 = 0%)]. No significant difference was found between the silymarin and placebo groups in terms of TBIL change [TBIL subtotal MD: 0.02, 95% CI (-0.07, 0.11) for two weeks; TBIL subtotal MD: -0.12, 95% CI (-0.50, 0.25) for four weeks; TBIL subtotal MD: -0.02, 95% CI (-0.12, 0.08) for eight weeks, with low heterogeneity (P > 0.61, I2 = 0%)], as shown in Figure 4.
Figure 4.
Effect of silymarin on serum liver enzymes AST, ALT, and TBIL
The time of the occurrence of anti-TB/antipsychotic DILI in the silymarin group and control group was analyzed. The results showed that silymarin prolonged the occurrence time of DILI, which was 1.78 times that of the control group (Figure 5).
Figure 5.
Time of occurrence of anti-TB/antipsychotic DILI in silymarin group and control group
3.4. Evaluation of Publication Bias
Considering all nine RCTs, the funnel plot of the occurrence of liver injury in each subgroup was basically symmetrical (Figure 6) with no significant publication bias. However, heterogeneity was found in the subgroups of 315 mg/d for eight weeks and over 400 mg/d.
Figure 6.
Publication bias of RCTs
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