Effect of silymarin on biochemical indicators in patients with liver disease: Systematic review with meta-analysis

Table 1 Summary of clinical trial characteristics

Study	Year	Origin	Population	Silymarin dose	Intervention	Inclusion criteria	Follow-up	Outcomes
Loguercio et al[19]	2007	Italy	59 adult patients with NAFLD	4 × 94 mg silibin + 194 mg phosphatidylcholine + 90 mg vitamin E (Reasil®) daily	Silymarin	NAFLD with no chronic liver disease	6 mo and 12 mo	ALT, gGT, insulin and HOMA
					Control untreated (diet + physical activity)
Hashemi et al[38]	2009	Iran	100 adult patients with NAFLD (NASH)	2 × 140 mg silymarin (Livergol®) daily	Silymarin	USG evidencing steatosis, ALT elevation in more than 1.2 of the normal value, exclusion of conical diseases of the liver, histological evidence of NASH or presence of risk factor such as MD or obesity	6 mo	ALT, AST, gGT, FA, glycemia, triglycerides and cholesterol
					Control
Massodi et al[39]	2013	Iran	100 adult patients with NAFLD (NASH)	2 × 140 mg silymarin daily	Silymarin	NASH confirmada por USG e níveis elevados de AST e ALT	3 mo	AST and ALT
					Control
Solhi et al[28]	2014	Iran	64 adult patients with NAFLD (NASH)	3 × 70 mg silymarin (Livergol®) daily	Silymarin	NASH confirmada por USG abdominal e elevação persistente de AST e ALT mais de 1,2 acima do valor normal nos últimos 6 meses	8 wk	ALT and AST
					Control
Aller et al[34]	2015	Spain	36 adult patients with NAFLD	2 × Silybum marianum 540.3 mg + vitamin E - 36 mg (Eurosil 85®) daily	Silymarin	NAFLD confirmed by liver biopsy	3 mo	Glycemia, triglycerides, AST, ALT, gGT and HOMA IR
					Control untreated (diet + physical activity)
Sorrentino et al[35]	2015	Italy	78 adults with MS and NAFLD	2 × silymarin 210 mg+ 30 IU vitamin E (Eurosil 85®) daily	Silymarin	MS and NAFD confirmed by USG	3 mo	Hepatic steatosis, lipid accumulation index, ALT, AST, gGT, triglycerides, cholesterol, LDL, HDL, glycated Hb and Glycemia
					Control untreated (diet)
Abenavoli et al[36]	2015	Italy	30 overweight Caucasian adults with NAFLD	2 × Silibin 94 mg + phosphatidylcholine 194 mg + vitamin E 89.28 mg daily	Group A: Hypochloric diet	Overweight and NAFLD confirmed by USG	6 mo	BMI, weight, waist circumference, blood pressure, AST, ALT, gGT, bilirubin, glycemia, HOMA-IR, insulin, triglycerides, total cholesterol, HDL, LDL, creatinine, azotemia, hepatic steatosis index
					Group B: Diet + silymarin
					Group C: control
Luangchosiri et al[40]	2015	Thailand	55 adults and elderly with pulmonary tuberculosis	3 × silymarin 140 mg daily	Silymarin	Diagnosis of pulmonary tuberculosis, > 18 yr, treatment with anti-tuberculosis drugs	4 wk	ALT, AST, alkaline phosphatase, gGT, total proteins, albumin, bilirubin, SOD, glutathione, malonyldialdehyde, risk of hepatic injury by anti-tuberculosis drug, adverse events
					Control
El-Kamary et al[42]	2009	Egypt	105 adults with acute hepatitis of varied etiologies	3 × silymarin 140 mg daily (Legalon®)	Silymarin	ALT > 100 IU/L with jaundice and 3 or more symptoms of acute hepatitis	8 wk	ALT, AST, bilirubin, acute hepatitis symptoms, adverse events
					Control (multivitamin)
Fried et al[45]	2012	United States	154 adults with HCV	5 × silymarin 140 mg daily (Legalon®) - 700 mg	Group 1: silymarin 420 mg	HCV and ALT > 65 U/L or unsuccessful patients on interferon therapy	24 wk	ALT, RNA HCV
				3 × silymarin 140mg daily (Legalon®) - 420 mg	Group 2: silymarin 700 mg
					Group 3: control
Hajaghamohammadi et al[27]	2008	Iran	50 adults with NAFLD	1 × 140 mg silymarin (Livergol®) daily		NAFLD confirmed by USG and elevated levels of ALT and AST	2 mo	Weight, BMI, AST, ALT
Stiuso et al[37]	2014	Italy	30 adults with NASH	2 × 94 mg silibin + 194 mg phosphatidylcholine + 89.28 mg vitamin E (Reasil®) daily	Silymarin	NASH histologically confirmed	12 mo	Levels of substances that react with thiobarbituric acid, nitric oxide, SOD, catalase, BMI, glycemia, insulin, HOMA, AST, ALT, gGT, score for NAFLD
					Control
Velussi et al[26]	1997	Italy	60 diabetic adults and elderly with alcoholic cirrhosis	600 mg siymarin daily	Silymarin	Diabetics treated with insulin with alcoholic cirrhosis (biopsy), aged between 45 and 70 years old	12 mo	Glycemia, postprandial glycemia, glycated hemoglobin and malonildialdehyde
					Control
Yakoot et al[43]	2012	Egypt	66 adult and elderly patients with HCV genotype 4	3 × silymarin 140mg daily	Group 1: spirulina 500 mg	HCV genotype 4, elevated liver enzymes, virgin antiviral therapy	6 mo	Virological response, ALT, quality of life score, adverse events
					Group 2: silymarin
					Group 3: control
Zhang et al[41]	2015	China	370 adult patients with tuberculosis on antituberculosis therapy	2 × S. marianum 200 mg	Silymarin	> 12 yr with tuberculosis and in anti-tuberculosis therapy	8 wk	ALT, AST, bilirubin, gGT, alkaline phosphatase
					Control
Tanamly et al[44]	2004	Egypt	141 adults and elderly with HCV	3 × silymarin 140 mg daily (Legalon®)	Silynarin	HCV	12 mo	RNA HCV, ALT, fibrosis, adverse events
					Control (multivitamin)
Palasciano et al[8]	1994	Italy	60 adult women using psychotic drugs	2 × 400 mg sliymarin daily	Group 1A: drugs + silymarin	Women between 40 and 60 yr of age, treated with phenothiazines and/or butyrenes for at least 5 yr, AST or ALT with values 2 × higher than the regular range	3 mo	AST, ALT, gGT, malonildialdehyde, bilirubin
					Group 1B: drugs + control
					Group 2A: no drugs and with silymarin
					Group 2B: no drugs but control

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; γGT: Gamma glutamyl transpeptidase; NAFLD: Non-alcoholic fatty liver disease; HCV: Hepatitis C virus.

Table 2 Results of selected studies for meta-analysis

Ref.	Used Indicators	Results
Loguercio et al[19], 2007	ALT, γGT	There were no adverse events in either group. The intervention group presented a significant reduction of hepatic steatosis in the ultrasonography score (change from 2-3 to 1-2) after 6 mo and 12 mo (P < 0.01). Significant reduction of ALT and γGT after 6 mo and 12 mo only in the intervention group (P < 0.01). Treatment affected the levels of ALT and γGT Range independent of changes in BMI of the participants. We did not evaluate data from the group with HCV patients
Hashemi et al[38], 2009	ALT, AST	There was a significant reduction in the average of ALT levels only in the intervention group (113.54 IU/mL vs 73.14 IU/mL) (P < 0.001). The percentage of patients with normalization (ALT < 40) was 32% after 3 mo and 52% after 6 mo in the intervention group and the difference in these percentage between control and intervention group was significant (P = 0.001). There was also a significant reduction in AST averages only in the intervention group (71.42 IU/mL vs 49.66 IU/mL) (P = 0.006). The percentage of patients with normalization (AST < 40) was 46% after 3 mo and 62% after 6 mo in the intervention group and the difference in these percentages between control group and intervention was also significant (P = 0.0001)
Massodi et al[39], 2013	ALT, AST	There were no serious adverse events and the side effects were similar in frequency and uncommon in both groups. There was a significant reduction in the average of ALT levels only in the intervention group (84.06 IU/mL vs 68.54 IU/mL) (P < 0.001) and in the average AST levels only in the intervention group (71.94 IU/mL vs 54.70 IU/mL) (P < 0.001)
Solhi et al[28], 2014	ALT, AST	There was a significant difference in the mean values of ALT levels only in the intervention group (91.3 IU/mL vs 38.4 IU/mL) (P = 0.026) and in the AST levels only in the intervention group (62.8 IU/mL vs 30.5 IU/mL) (P = 0.038).
Aller et al[34], 2015	ALT, AST, γGT	There were no adverse events in both groups. There was a significant improvement in the fibrosis score in both groups (P < 0.05). There was a significant difference in the reduction of the average γGT levels (81.5 IU/L vs 46.2 IU/L) (P < 0.05) in the intervention group and also in the control group (80.5 IU/L vs 50.3 IU/L) (P < 0.05). There was a significant reduction only in the average of ALT levels (70.8 IU/L vs 54.7 IU/L) (P < 0.05) and AST (41.6 IU/L vs 36 IU/L) (P < 0.05) in the control group.
Sorrentino et al[35], 2015	ALT, AST, γGT	No adverse events were reported in both groups. Mean levels of ALT, AST and γGT were within normal limits at the baseline. There was a significant reduction only in the average values of right lobe size of the liver by the USG (17.24 cm vs -0.96 cm) (P = 0.044)

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; γGT: Gamma glutamyl transpeptidase.