TABLE 4.
Summary of main outcomes and the certainty of the evidence.
| Primary outcome/follow-up time | Results | No of participants/studies | Certainty of the evidence (GRADE) | Comments | |
|---|---|---|---|---|---|
| Active treatment | Control treatment | ||||
| ALT (mean ± SD; U/L)/28 days | Bicyclol 30.36 ± 17.41 | Polyene phosphatidylcholine 50.71 ± 27.13 | 168/1 RCT | Low a | A statistically significant difference was assessed at p <0.01 |
| Proportion of patients experienced (S)AEs (%)/90 days | Calmangafodipir + NAC | NAC | 24/phase 1 study | Very low b | Active treatment involved three patient’s group: 2, 5 or 10 μmol/kg |
| AEs: 100% (18/18) | AEs: 6/6 (100%) | ||||
| ≥1 SAES: 50% (9/18) | ≥1 SAES: 33.33% (2/6) | ||||
| ALT (nmol/L); AST (nmol/L); bilirubin (mcmol/l) average ± SD/3 days | Cytaphat | Essentiale | 142/1 clinical study | Very low c | Control treatment involved two patient’s groups. The statistically significant difference was observed between Cytaphat and placebo group (p <0.05) |
| ALT 248.9 ± 35.8 | ALT 232.2 ± 20.8 | ||||
| AST 109.1 ± 8.7 | AST 154.7 ± 19.6 | ||||
| Bilirubin 19.8 ± 1.7 | Bilirubin 24.6 ± 2.4 | ||||
| Placebo | |||||
| ALT 354.7 ± 45 | |||||
| AST 297.1 ± 33.6 | |||||
| Bilirubin 34.5 ± 3.7 | |||||
| Fraction of ingested paracetamol excreted as total oxidative metabolites/24-h urine | Fomepizole + paracetamol 80 mg/kg | paracetamol 80 mg/kg | 6/1 clinical crossover study | Very low d | All participants were healthy volunteers. Mean difference between groups was 3.97%, 95% CI 2.31–5.63%, p = 0.003) |
| 0.51% | 4.48% | ||||
| ALT (U/L); AST (U/L); Bilirubin, INR | Fomepizole + NAC | No control | 8/3 case studies | Very low e | All participants were paracetamol overdosed. Data were based on one case series (6 cases) and 2 case reports |
| ALT (IU/L); AST (IU/L); ALP (U/L); Bilirubin (mg/dl)/8 weeks | Livina | Placebo | 42/1 study | Very low f | All participants were treated for TBC. The statistically significant difference was observed for AST, ALT, ALP in placebo group compared to itself baseline (p <0.05) |
| ALT 28.7 ± 8.4 | ALT 52.5 ± 7.6 | ||||
| AST 30.1 ± 8.3 | AST 51.9 ± 10.5 | ||||
| ALP 239.1 ± 19.7 | ALP 386.2 ± 29.3 | ||||
| Bilirubin 0.95 ± 0.3 | Bilirubin 1.46 ± 0.5 | ||||
| Proportion of ALT normalization/28 days | MgIG 100 mg 85.71% (50/59 subjects) | Tiopronin 61.02% (36 subjects) | 174/1 RCT | Moderate g | The difference between MgIG 100 mg and tiopronin and between MgIG 200 mg and tiopronin were significant (p = 0.0111; p = 0.0087). Although, the results stayed significant, calculated proportions for active treatment in the originally publication were mixed: 85.71% corresponds to 48 out of 56 participants |
| MgIG 200 mg 84.75% (48/56 subjects) | |||||
| The number of patients who develop hepatotoxicity | Picroliv | Placebo | 182/1 study in abstract form only | Very low h | Results published in abstract significantly differ from those prespecified in protocol: there was no reported hepatotoxicity related to picroliv treatment |
| NA | NA | ||||
| Not prespecified: AST, ALT, bilirubin, INR. | PE | No control | 10/1 study in abstract form only | Very low i | The level of AST, ALT, bilirubin and INR have not been shown |
| There was significant improvement in aminotransferases (p < 0.05), direct bilirubin (p < 0.001), INR (p < 0.05) | |||||
| <20% reduction in serum bilirubin from baseline after 3 TPE sessions or reduction in serum bilirubin by < 5 mg and INR <1.5/28 days | PE | SMT | 30/1 study in abstract form only | Very low j | No measurement unit specified for bilirubin level; SMT not defined. Significant difference in bilirubin when compared to baseline levels, p <0.002 |
| bilirubin | Bilirubin | ||||
| 5.3 ± 7.6 | 10.4 ± 8.9 | ||||
| Different laboratory parameters and clinical symptoms of liver function | PE | No control | 19/4 case reports, one case series and two letter to the editors | Very low k | |
| Primary outcome not prespecified. AST (U/L), ALT, TBL (mg/dl), direct bilirubin (mg/dl), total bile acid (µmol/L), Child-Pugh and MELD scores; different clinical symptoms/3–6 months after RPR treatment | RPR | No control | 14/1 study abstract form only | Very low l | All laboratory parameters were statistically significantly decreased, p <0.05. The outcomes were compared before and after RPR treatment in the same patient |
| AST 113 ± 77 vs 49 ± 29 | |||||
| ALT 101 ± 91 vs. 38 ± 35 | |||||
| TBL 20.6 ± 6.1 vs. 4.9 ± 8.2 | |||||
| direct bilirubin 15.2 ± 5.3 vs. 3.2 ± 6.1 | |||||
| total bile acid 282 ± 134 vs. 50 ± 74 | |||||
| Child-Pugh 8.5 ± 1.1 vs. 6.3 ± 2.0 MELD score 25.0 ± 2.5 vs. 15.6 ± 6.6 | |||||
| jaundice (100 vs. 21%; p <0.001); fatigue (86 vs. 29%; p =0.006) | |||||
| AST, ALT, LDH, GGT, ALP, TBL/follow-up time not prespecified | SAMe | Placebo | 233/3 study | Very low m | Data from one study was available only in abstract as corresponding author did not reply to our email |
| The patient group (183) consisted of patients with colorectal cancer and treated with FOLFOX or B-XELOX chemotherapy regiments. Additional 50 patients had unspecified cancer and chemotherapy regimen was not described in abstract | |||||
| All prespecifed outcomes were found to be statistically significantly reduced in the SAMe group, p at least ≤0.04) | |||||
ALP, alkaline phosphatase; 4-MP, fomepizole or 4-Methylpyrazole; GGT, gammaglutamyltransferase; INR, international ratio; LDH, lactate dehydrogenase; MELD, model for end-stage liver disease; MgIG, magnesium isoglycyrrhizinate; NA, not applicable; NAC, N-acetylcistein; paracetamol (acetaminophen or N-Acetyl-p-Aminophenol); PE, plasma exchange; RCT, randomized control trial; RPR, Radix Paeoniae Rubra; (S)AEs, (serious) adverse events; SAMe, S-adenosylmethionine; SD, standard deviation; SMT, standard medical treatment; TBL, total bilirubin; U/L, unit per litre.
Downgraded twice for serious indirectness and imprecision (not representative sample: all participants had statin-induced liver injury and results are based on single study data included less than 400 patients.).
Downgraded three times for high risk of bias; not generalizable results (indirectness) and very sparse data (small sample size).
Downgraded three times for serious risk of bias, indirectness of the evidence (aetiology of acute toxic hepatitis included and only demonstrated statistically significant difference at the level p < 0.05 between Cytaphat and placebo) and very sparse data (small sample size).
Downgraded four times for serious risk of bias, serious indirectness of the evidence (only healthy volunteers included) and very serious imprecision (very sparse data).
Downgraded six times for very serious risk of bias (data based on case reports studies), serious inconsistency (heterogeneity between reports was remarkable in baseline characteristics, treatment administered and all work-up done), indirectness of the evidence (paracetamol overdosed all) and very serious imprecision (very sparse data).
Downgraded four times for serious risk of bias, indirectness of the evidence (TBC patients only included) and very serious imprecision (very sparse data).
Downgraded once for serious imprecision due to sparse data (small sample size, patients divided into three subgroup).
Downgraded four times for very serious risk of bias (outcomes were not reported as prespecified), indirectness of the evidence (TBC patients only) and publication bias (only abstract form published).
Downgraded six times for very serious risk of bias, serious inconsistency (heterogeneity could not be assessed due to lack of data), very serious imprecision (very sparse data) and publication bias.
Downgraded seven times for very serious risk of bias, very serious inconsistency (heterogeneity could not be assessed due to lack of data; prespecified outcome described in the Methods was not described in Results), and very serious imprecision (very sparse data) and publication bias (only abstract form published).
Downgraded six times for very serious risk of bias (case reports and series), very serious inconsistency (considerable heterogeneity within the patient group, treatment and follow-up), and very serious imprecision (very sparse data).
Downgraded seven times for very serious risk of bias, serious inconsistency and indirectness (heterogeneity and generalizability could not be assessed due to lack of data), very serious imprecision (very sparse data) and publication bias (only abstract form published).
Downgraded four times for very serious risk of bias, serious indirectness (only cancer patients included), and publication bias (only abstract available for one study).