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Agency for Healthcare Research and Quality (US), Rockville (MD)
Lawrence V, Jacobs B, Dennehy C, et al. Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects. Rockville (MD): Agency for Healthcare Research and Quality (US); 2000 Oct. (Evidence Reports/Technology Assessments, No. 21.) Evidence Tables.
| Study | Design | Liver Disease | Subject Characteristics | Outcomes (favoring silymarin unless otherwise noted) | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Author: Benda76 Year: 1980 Country: Germany Language: German |
Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon ®)/420 mg daily/ Unclear Control: Placebo MVI Outcome measures a : Survival Followup interval: 4 years Assessment time points with results reported: 4 years |
Type: Alcoholic and nonalcoholic cirrhosis Include: Biopsy-proven cirrhosis Exclude: Moribund; poor compliance; immunosuppressive treatment in the past year; Prednisone in past 6 months; D-Penicillamine in past 3 months; primary biliary cirrhosis; Wilson's disease Acuity/severity: Chronic, cirrhosis, no other information Baseline group similarity: No information |
N: 172 Mean age: Not given Percent male: Not given Setting: Unclear |
Significant: + Trend: Survival Not significant: Note: Trend was assessed qualitatively only for this review. | ||||||||||||||||
|
Author: Bunout66 Year: 1992 Country: Chile Language: Spanish |
Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon®)/280 mg daily/446 days Control: Placebo Outcome measures a : AST, GGTP, alk phos, bilirubin, albumin, PT Followup interval: Monthly for an average of 15 months Assessment time points with results reported: Mean of 15 months |
Type: Alcoholic liver disease (inactive cirrhosis, active cirrhosis, cirrhosis with alcoholic hepatitis, alcoholic hepatitis, fibrosis) Include: Positive for alcohol history and symptoms of icterus edema, ascites, or encepholopathy or total bilirubin exceeding 2 mg/dL; PT exceeding 75 percent control; albumin less than 3 mg/dL Exclude: HBV antigen; renal failure; cardiac failure; terminal liver disease Acuity/severity: Chronic, cirrhosis, no other information Baseline group similarity: Demos, LFTs appear similar |
N: 59 Mean age: 50 Percent male: 86 Setting: Specialty clinic |
Significant: Albumin Not significant: Child's score, bilirubin, AST, GGTP, alk phos, PT | ||||||||||||||||
|
Author: Buzelli 79 Year: 1993 Country: Italy Language: English |
Study type: RCT/blind Intervention/dose/duration: Silipide ® /240 mg silybin equivalents daily/7 days Control: Placebo Outcome measures a : AST, ALT, GGTP, MDA, alk phos, bilirubin, albumin Followup interval: 7 days Assessment time points with results reported: 7 days |
Type: Chronic active hepatitis due to HBV and/or HCV Include: Biopsy-proven CAH, AST, and/or ALT greater than twice normal limits for more than 12 months; age 30 to 70 years old Exclude: Portal hypertension; hepatic encephalopathy, ascites, hepatocellular cancer, pruritus, icterus bilirubin, and alk phos more than two-fold reference values; drug addiction and ANA, AMA, and ASMA; alcohol exceeding 30 g/d; malabsorption syndromes; cardiovascular, renal, or endocrine disorders; pregnancy; any drug treatment 3 months before beginning trial Acuity/severity: Chronic, AST or ALT greater than twice normal limits Baseline group similarity: Demos, LFTs appear similar |
N: 20 Mean age: 53 Percent male: 30 Setting: Hospital |
Significant: AST, ALT, GGTP Not significant: Bilirubin, alk phos, MDA, albumin | ||||||||||||||||
|
Author: Feher 70 99 100 Year: 1989/1990 Country: Hungary Language: Hungarian |
Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon ® )/420 mg daily/180 days Control: Placebo Outcome measures a : AST, ALT, GGTP, alk phos, bilirubin, albumin Followup interval: 90 and 180 days Assessment time points with results reported: 90 and 180 days |
Type: Chronic alcoholic liver disease (cirrhosis, reactive fibrosis, fatty degeneration) Include: Alcohol intake exceeding 60 g/d in men and 30 g/d in women for 8 ± 4 years; chronic liver disease; no previous corticosteroid or immunosuppressive treatment Exclude: Not given Acuity/severity: Chronic, no other information Baseline group similarity: Demos, LFTs appear similar |
N: 36 Mean age: 46 Percent male: 75 Setting: Unclear |
Significant: AST, GGTP, MDA Not significant: (Assumed for all) ALT, alk phos, albumin, PT | ||||||||||||||||
|
Author: Ferenci 75 Year: 1989 Country: Austria Language: English |
Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon ® )/420 mg daily/ mean 41 months, range 2 to 6 years Control: Placebo Outcome measures a : AST, ALT, GGTP, alk phos, bilirubin, albumin, PT Followup interval: 4 years Assessment time points with results reported: 2 and 4 to 5.5 years for survival |
Type: Alcoholic and nonalcoholic cirrhosis; cirrhosis with alcoholic hepatitis Include: Diagnosis of cirrhosis within 2 years before entering study Exclude: End-stage liver disease; known malignancies; primary biliary cirrhosis; immunosuppressive therapy Acuity/severity: Chronic, cirrhosis, Child's score A/B/C 89/69/12 Baseline group similarity: Demos, LFTs appear similar |
N: 170 Mean age: 57 Percent male: 72 Setting: Primary care/community clinic, specialty clinic, hospital |
Significant: Survival (alcohol disease, Child's score A) Not significant: (No data given; reported only as not significant) AST, ALT, GGTP, bilirubin, survival (non-alcohol disease, Child's score B and C) Correspondence from Ferenci, October 10, 1999: Length of treatment was variable. All patients were treated for 2 years (original primary end point) and were continued on the same therapy until the last patient that entered completed 2 years of therapy. Mortality was 27/83 in placebo group and 20/83 in silymarin group. | ||||||||||||||||
|
Author: Fintelmann 73 Year: 1980 Country: Germany Language: German |
Study type: RCT/blind Intervention/dose/duration: Silymarin(Legalon ® )/not given/not given Control: Placebo Outcome measures a : AST, ALT, GGTP, alk phos, bilirubin Followup interval: Days 1, 3, 7, 10, 14, 21, 28 Assessment time points with results reported: Had to read off graphs, but all followups |
Type: Toxic liver disease, any etiology (usually alcohol) Include: Clinical and laboratory evidence of toxic liver damage Exclude: Not given Acuity/severity: No other information Baseline group similarity: No information except age and gender "similar" |
N: 66 Mean age: Not given Percent male: Not given Setting: Unclear |
Significant: ALT, GGTP Not significant: AST, bilirubin, alk phos | ||||||||||||||||
|
Author: Kiesewetter 80 Year: 1977 Country: Austria Language: German |
Study type: RCT/quasi Intervention/dose/duration: Silymarin (Legalon ® )/420 mg daily/365 days Control: Placebo Outcome measures a : Histologic findings Followup interval: 14, 30, 60 days then every 90 days to 1 year Assessment time points with results reported: One, combined/90 to 360 days |
Type: Viral hepatitis (CPH and CAH) Include: CPH or CAH for more than 6 months; other medications for liver discontinued for 2 weeks or more Exclude: Disease less than 6 months; previous treatment with silymarin, steroids, or other cytotoxic drugs; alcohol exceeding 80 g/d or exceeding alcohol intake by laboratory values than patients' statement; other comorbidities requiring medications Acuity/severity: Chronic, no other information Baseline group similarity: Demos, similar, no information on LFTs |
N: 24 Mean age: 53 Percent male: 50 Setting: Hospital |
Significant: + Trend: Improvement in liver biopsy Not significant: Note: Trend was assessed qualitatively only for this review. | ||||||||||||||||
|
Author: Lang 71 Year: 1990 Country: Hungary Language: English |
Study type: RCT/blind/three arms Interventions/dose/duration: Silymarin (Legalon ® )/420 mg daily/30 days AICA-P/600 mg daily/30 days Control: Placebo Outcome measures a : AST, ALT, GGTP, alk phos, albumin Followup interval: 28 days Assessment time points with results reported: Weekly for 1 month |
Type: Alcoholic cirrhosis Include: Alcohol intake exceeding 60 g/d in men and 30 g/d women for more than 6 years; histologic diagnosis of micronodular cirrhosis Exclude: Vascular and/or parenchymal decompensation; +HBsAg Acuity/severity: Chronic, cirrhosis, no other information Baseline group similarity: LFTs appear similar |
N: 60 Mean age: 45 Percent male: 68 Setting: Unclear |
Significant: AST, ALT, GGTP Not significant: Bilirubin | ||||||||||||||||
|
Author: Magliulo 78 Year: 1978 Country: Italy Language: German |
Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon ® )/420 mg daily/25 days Control: Placebo Outcome measures a : AST, ALT, GGTP, alk phos, bilirubin, PT Followup interval: 1, 3, 5, 7, 9, 14, 21, 28 days Assessment time points with results reported: All followup |
Type: Viral HAV and HBV Include: Acute HAV and HBV patients Exclude: Not given Acuity/severity: Acute, no other information Baseline group similarity: LFTs appear similar |
N: 59 Mean age: 37 Percent male: 22 Setting: Hospital |
Significant: AST, bilirubin + Trend: ALT Not significant: Alk phos Note: Trend was assessed qualitatively only for this review. | ||||||||||||||||
|
Author: Palasciano 81 Year: 1994 Country: Italy Language: English |
Study type: RCT/blind, factorial design Intervention/dose/duration: Silymarin and psychotropic drugs/800 mg silymarin daily/ 90 days Silymarin and psychotropic drugs discontinued/800 mg daily/90 days Control: Placebo and no psychotropic drugs discontinued Placebo and psychotropic drugs/ not given/90 days Outcome measures a : AST, ALT, MDA Followup interval: Day 15, 30, 60, 90, 120 Assessment time points with results reported: 30, 60, 90, and 120 days for MDA; 30 and 90 for AST and ALT |
Type: Drug-induced liver disease (some patients were HBV-positive) Include: Women 40 to 60 years old; hospitalized; phenothiazines and/or butyrophenones for 5 years; AST or ALT greater than twice normal limits Exclude: Current therapy with other drugs that could influence progress of hepatopathy; other hepatopathies (alcohol, viral, autoimmune, hemochromatosis, Wilson's disease, porphyria cutanea tarda, primary or secondary hepatic neoplasia); BUN exceeding 60 mg/dL and/or creatinine exceeding 2.5 mg/dL; cardiac and circulatory insufficiency; diabetes mellitus; other important extrahepatic diseases; verified or presumed pregnancy; alcohol (more than 30 g/d) or opiate abuse Acuity/severity: Chronic; AST or ALT greater than two times the normal limit Baseline group similarity: Demos similar; LFTs variable |
N: 60 Mean age: 52 Percent male: 0 Setting: Hospital |
Significant: MDA for psychotropic drugs with silymarin versus placebo Not significant: AST, ALT, MDA for psychotropic drugs discontinued, silymarin versus placebo | ||||||||||||||||
|
Author: Pares 68 Year: 1998 Country: Spain Language: English |
Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon ® )/450 mg daily/unclear Control: Placebo Outcome measures a : AST, ALT, GGTP, alk phos, bilirubin, albumin, PT Followup interval: Every 3 months for 2 years Assessment time points with results reported: Survival at 5 years; all others at 2 years (assumed) |
Type: Alcoholic cirrhosis (24 percent had superimposed alcohol hepatitis) Include: Chronic alcoholism defined as alcohol exceeding 80 g/d men and 60 g/d women for more than 5 years; biopsy or laparoscopic proven alcoholic cirrhosis Exclude: If ever received colchicine, malotilate, penicillamine, or corticosteroids; life expectancy less than 6 months; drug addicted or pregnant; other known etiologies for cirrhosis (i.e., HBV, autoimmunity, primary biliary cirrhosis, or cryptogenic cirrhosis) Acuity/severity: Chronic, all cirrhosis, Child's score A/B/C/ 63/114/14 Baseline group similarity: Demos, LFTs appear similar |
N: 200 Mean age: 50 Percent male: 79 Setting: Diagnosis in hospital then outpatient followup. |
Significant: + Trend: Encephalopathy, UGIB, survival for HCV-positive patients Not significant: AST, ALT, GGTP, PT, bilirubin, alk phos, hepatomegaly, splenomegaly, jaundice, ascites, survival Note: Trend was assessed qualitatively only for this review. | ||||||||||||||||
|
Author: Salmi 69 Year: 1982 Country: Finland Language: English |
Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon ® )/420 mg daily/28 days Control: Placebo Outcome measures a : AST, ALT, alk phos, bilirubin, histologic findings Followup interval: Day 28 Assessment time points with results reported: 28 days |
Type: Alcoholic liver disease Include: Increased AST and ALT for more than 1 month despite order to abstain from alcohol Exclude: Not given Acuity/severity: No other information Baseline group similarity: Aminotransferase levels reported as similar but lower in controls |
N: 97 Mean age: 37 Percent male: 86 Setting: Hospital |
Significant: AST, ALT, histology Not significant: Alk phos, bilirubin | ||||||||||||||||
|
Author: Tanasescu 74 Year: 1988 Country: Romania Language: English |
Study type: RCT, randomization stratified by type of disease: CPH, CAH, HCV/blind Intervention/dose/duration: Silymarin (Silimarina ® )/210 mg silybin equivalents daily/40 days Control: Placebo Outcome measures a : ALT, GGTP, bilirubin, alk phos, PT Followup interval: 40 days Assessment time points with results reported: 40 days |
Type: CPH, CAH, hepatic cirrhosis, etiology not given Include: Diagnosis based on hepatic biopsy; clinical and laboratory data on CAH and CPH patients; some hepatic cirrhosis patients did not have hepatic biopsy; medium forms of disease; both sexes; 20 to 60 years old; basic disease from 1 to 10 years Exclude: Not given Acuity/severity: Chronic, no other information Baseline group similarity: Age, LFTs appear similar |
N: 177 Mean age: 53 Percent male: 47 Setting: Hospital |
Note: Trend was assessed qualitatively only for this review. | ||||||||||||||||
|
Author: Trinchet 67 Year: 1989 Country: France Language: French |
Study type: RCT/blind Intervention/dose/duration: Silymarin (Legalon ® )/420 mg daily/90 days Control: Placebo Outcome measures a : AST, GGTP, bilirubin, albumin, PT, histology Followup interval: 90 days Assessment time points with results reported: 90 days |
Type: Alcoholic hepatitis (50 percent with cirrhosis) Include: Biopsy-proven alcoholic hepatitis with or without cirrhosis Exclude: Hepatic encephalopathy; contraindications to liver biopsy; hepatocellular cancer; ascites resistant to diuretics; platelets less than 100,000 per mm; PT less than 50 percent; other diseases limiting survival Acuity/severity: 58/116 with cirrhosis; no other information Baseline group similarity: Demos, LFTs appear similar |
N: 116 Mean age: 51 Percent male: 67% Setting: Unclear |
Significant: Both silymarin and placebo better with alcohol abstinence Not significant: PT, albumin, bilirubin, GGTP, AST, histologic findings (hepatitis, fibrosis) |
Results not necessarily reported for all.
Alk phos = alkaline phosphatase; ALT = alanine aminotranferase; AMA = antimitochondrial antibody; ANA = antinuclear antibody;
ASMA = antismooth muscle antibody; AST = aspartase aminotranferase; BUN = blood urea nitrogen; CAH = chronic active hepatitis;
CPH = chronic persistent hepatitis; demos = demographic variables; GGTP = gammaglutamyl transpeptidase; HAV = hepatitis A virus; HbsAg = Hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; LFT = liver function test; MDA = malondialdehyde; MVI = multivitamin; PT = prothrombin time;
RCT = randomized controlled trial; UGIB = upper gastrointestinal bleed.
| Study | Design | Liver Disease | Patient Characteristics | Outcomes (favoring silymarin unless otherwise noted) |
|---|---|---|---|---|
|
Author: Fintelmann 72 Year: 1970 Country: Germany Language: German |
Study type: Cohort with comparison group/blinding unclear Intervention/dose/duration: Silymarin (Legalon ® )/6 tablets daily/42 days Control: Placebo Outcome measures a : Bilirubin, alk phos, AST, ALT Followup interval: 42 days Assessment time points with results reported: 42 days |
Type: Alcoholic liver disease, also other causes of fatty liver (pure parenchymal fatty degeneration, fatty degeneration and reactive inflammation, cirrhosis transformation in progress) Include: Biopsy-proven fatty liver, including early cirrhosis without portal hypertension, assignment stratified by diabetes mellitus, obesity, alcohol intake Exclude: Not given Acuity/severity: All degrees of fatty liver including early cirrhosis without portal hypertension Baseline group similarity: LFTs appear similar |
N: 50 Mean age: Not given Percent male: Not given Setting: Unclear |
Significant: AST (categorical) Not significant: AST (continuous), ALT, alk phos |
|
Author: Marcelli 77 Year: 1992 Country: Italy Language: English |
Study type: RCT/blinding unclear Intervention/dose/duration: Silipide ®)/240 mg daily/90 days Control: Placebo Outcome measures a : AST, ALT, bilirubin, albumin, PT Followup interval: 90 days Assessment time points with results reported: 90 days |
Type: CPH, etiology unknown Include: Biopsy confirmed CPH, ALT, or AST 1.5 or greater than 2 times normal limits in past year Exclude: Other forms of liver disease (non-CPH) or decompensated disease; treatment with interferon antivirals, immunosuppressants, or immunomodulators within past 6 months Acuity/severity: Chronic, no other information Baseline group similarity: Demos appear similar; higher AST and ALT in Silipide ® group |
N: 65 Mean age: 48 Percent male: 71 Setting: Specialty clinic |
Significant: AST, ALT Not significant: Bilirubin, albumin, PT |
a Results not necessarily reported for all.
alk phos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartase aminotransferase; CPH = chronic persistent hepatitis; Demos = demographic variables; LFT = liver function test; PT = prothrombin time; RCT = randomized controlled trial.
| Study | Design | Liver Disease | Patient Characteristics | Outcomes (favoring silymarin unless otherwise noted) | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Author: Boari101 Year: 1981 Country: Italy Language: Italian |
Study type: RCT unclear/blinding unclear Intervention/dose/duration: Silymarin/420 mg daily/15 to 20 days Control: Vitamin B complex/not given/15 to 20 days Outcome measures a : AST, ALT, GGTP, alk phos, bilirubin Followup interval: 20 days Assessment time points with results reported: 20 days |
Type: Toxic hepatopathy caused by various substances (mostly solvents, paints, and glues); mostly suffering from chronic or subacute forms Include: Not given Exclude: Not given Acuity/severity: ? Chronic, 0 cirrhosis, 11 liver failure, 29 other, no other information |
N: 55 Mean age: 36 Percent male: 60 Setting: Hospital |
Significant: AST, ALT, GGTP, alk phos Not significant: Bilirubin | |||||||||||||||
|
Author: Bode102 Year: 1977 Country: Germany Language: German |
Study type: RCT (quasi/odd-even birthdate)/not blind Intervention/dose/duration: Silymarin (Legalon®)/420 mg daily/35 days Control: No treatment Outcome measuresa: AST, ALT, GGTP, alk phos, bilirubin, PT Followup interval: 10, 25, 35 days Assessment time points with results reported: 35 days |
Type: Viral hepatitis Include: Patients with viral hepatitis Exclude: Jaundice exceeding 8 days Acuity/severity: Acute, no other information |
N: 151 Mean age: Not given Percent male: 48 Setting: Unclear |
Significant: Not Significant: AST, bilirubin, ALT, alk phos | |||||||||||||||
|
Author: Cavalieri
103 Year: 1974 Country: Italy Language: Italian |
Study Type: RCT unclear/blinding unclear Intervention/dose/duration: Silymarin (Legalon ® )/ 420 mg daily/variable Control: "Traditional treatment": a 12-component cocktail including vitamin and steroids Outcome measures a : AST, ALT, GGTP, alk phos, bilirubin, PT Followup interval: 7, 14, 28 days Assessment time points with results reported: 7, 14, 28 days |
Type: Acute hepatitis (posttransfusion, contagious, presumably parenteral, and sporadic) Include: Not given Exclude: Not given Acuity/severity: Acute, no other information |
N: 40 Mean age: 29 Percent male: 45 Setting: Hospital |
Significant: AST at weeks 1, 2, and 3; ALT at week 2; alk phos at week 1; albumin at week 1 Not Significant: AST at week 4; ALT at weeks 1, 3, and 4; PT and albumin at weeks 2 and 3 | |||||||||||||||
|
Author: Del Dotto
104 Year: 1982 Country: Italy Language: Italian |
Study Type: RCT unclear/blinding unclear Intervention/dose/duration: Silymarin (Legalon ® )/420 mg daily/90 days Control: Vitamin B complex Outcome measures a : AST, ALT, GGTP, PT, bilirubin, albumin, alk phos Followup interval: 30, 60, 90 days Assessment time points with results reported: 30, 60, 90 days |
Type: Alcoholic liver disease Include: Patients with alcoholic liver disease Exclude: Not given Acuity/severity: Chronic, no other information |
N: 42 Mean age: 53 Percent male: 74 Setting: Specialty clinic |
Significant: Not Significant: AST, ALT, GGTP, PT, bilirubin, albumin, alk phos | |||||||||||||||
|
Author: DeMartiis
105 Year: 1980 Country: Italy Language: Italian |
Study Type: RCT unclear/blinding unclear
Intervention/dose/duration: Silymarin, traditional therapy, and diet/400 mg daily/45 to 90 days Control: Traditional therapy + diet Outcome measures a : Bilirubin Followup interval: 90 days Assessment time points with results reported: 90 days |
Type: Chronic hepatitis and cirrhosis Include: Macrocytic anemia and hemolytic syndrome Exclude: Lab values indicating the presence of cholestasis (alk phos, GGTP) dyslipidemia, or diabetes Acuity/severity: Chronic, no other information | .5pt; padding:0in 1.45pt 0in 1.45pt;height:139.0pt'>N: 45 Mean age: Not given Percent male: Not given Setting: Unclear |
Significant: Not Significant: Indirect bilirubin | |||||||||||||||
|
Author: DeMartiis106
Year: 1980 Country: Italy Language: Italian |
Study Type: RCT unclear/blinding unclear Intervention/dose/duration: Vitamin B12, folic acid, uridin-5, difosfoglucose, and silymarin/ 600 mg daily/not given Vitamin B12, folic acid, uridin-5, and difosfoglucose/not given/not given Control: Vitamin B12, folic acid, uridin-5, and difosfoglucose/not given/not given Outcome measures a : Alk phos, bilirubin Followup interval: Unclear Assessment time points with results reported: Unclear |
Type: Chronic hepatopathies (diagnoses include chronic hepatitis, hepatic cirrhosis, and hepatic neoplasm) Include: Hepatic disease Exclude: Not given Acuity/severity: 0 acute, 21 chronic, 61 cirrhosis, no other information |
N: 91 Mean age: 56 Percent male: 71 Setting: Not given |
| |||||||||||||||
|
Author: Fintelmann
107 Year: 1973 Country: Germany Language: German |
Study Type: RCT unclear/blinding unclear
Intervention/dose/duration: Silymarin (Legalon ® )/210 or 420 mg daily/preoperative and 8 days postoperative Control: No treatment Outcome measures a : AST, ALT, alk phos, bilirubin Followup interval: 1, 2, 3 days Assessment time points with results reported: 1, 2, 3 days |
Type: Cholestasis, not pregnancy related Include: Consecutive patients for cholecystectomy with cholelithiasis with or without cholecystitis Exclude: Obstructive jaundice Acuity/severity: Acute, no other information |
N: 63 Mean age: Not given Percent male: 6 Setting: Hospital |
Significant:
+ Trend: Less increase in AST, ALT on postoperative day 1 Not Significant: AST, ALT, bilirubin, alk phos Note: Trend was assessed qualitatively only for this review. | |||||||||||||||
|
Author: Flisiak
65 Year: 1997 Country: Poland Language: English |
Study Type: RCT/not blind
Intervention/dose/duration: Silymarin/210 mg daily/28 days Control: Misoprostol Outcome measures a : AST, ALT, GGTP, alk phos, bilirubin, jaundice, hepatomegaly Followup interval: 7, 14, 21, 28 days Assessment time points with results reported: 7, 14, 21, 28 days |
Type: Viral HBV Include: Viral HBV by HBsAg detection; male patients admitted; endoscopically confirmed stomach mucosal injury; comparable age and duration of jaundice (approximately 2 to 9 days); severe hepatocellular dysfunction with marked increases in bilirubin, AST, and ALT Exclude: Female patients; concomitant alcoholism, HCV or HDV infections and chronic diseases (e.g., diabetes) Acuity/severity: Acute |
N: 52 Mean age: 46 Percent male: 100 Setting: Hospital |
Significant: Misoprostol better than silymarin for hepatomegaly bilirubin, alk phos Not Significant: GGTP, AST, ALT Correspondence from Flisiak, November 2,1999: Study was not placebo controlled; subjects were blinded, but providers and outcome assessors were not blinded | |||||||||||||||
|
Author: Flisiak
65 Year: 1997 Country: Poland Language: English |
Study Type: Cohort with comparison group/not blind
Intervention/dose/duration: Silymarin/210 mg daily/28 days Control: No treatment Outcome measures a : AST, ALT, GGTP, alk phos, bilirubin, jaundice, hepatomegaly Followup interval: 7, 14, 21, 28 days Assessment time points with results reported: 7, 14, 21, 28 days |
Type: Viral HBV Include: Viral HBV by HBsAg; male patients admitted; endoscopically confirmed stomach mucosal injury; comparable age and duration of jaundice (approximately 2 to 9 days), severe hepatocellular dysfunction with marked increases in bilirubin, AST, and ALT Exclude: Female patients, concomitant alcoholism, HCV or HDV infections and chronic disease (e.g., diabetes) Acuity/severity: Acute, no other information |
N: 52 Mean age: 46 Percent male: 100 Setting: Hospital |
Significant: Alk phos Not Significant: AST, ALT, GGTP, bilirubin, hepatomegaly Correspondence from Flisiak, November 2, 1999: Study was not placebo controlled; subjects were blinded, but providers and outcome assessors were not blinded | |||||||||||||||
|
Author: Lirussi
108 Year: 1995 Country: Italy Language: English |
Study Type: RCT/blinding unclear
Intervention/dose/duration: UDCA/600 mg daily/180 days Silymarin (Legalon ® )/420 mg/180 days Combination therapy UDCA and silymarin/600 mg UDCA and 420 mg silymarin/6 months Outcome measures a : AST, ALT GGTP, alk phos, bilirubin Followup interval: 90, 180, 210, 300, 395 days Assessment time points with results reported: 90, 180 days |
Type: Compensated active cirrhosis (HCV, alcoholic with or without HCV, HBsAg) Include: Biopsy-proven compensated cirrhosis; AST and ALT 2 to 10 times normal limits Exclude: Not given Acuity/severity: No other information |
N: 23 Mean age: 58 Percent male: 36 Setting: Unclear Phase 1: Cross-over Phase 2: UDCA and silymarin versus no treatment |
Significant: Not Significant: AST, ALT, GGTP, bilirubin, alk phos | |||||||||||||||
|
Author: Roveda
109 Year: 1991 Country: Italy Language: Italian |
Study Type: RCT unclear/blinding unclear
Intervention/dose/duration: Silymarin/140 or 280 mg daily or silybin/70 or 140 mg daily/90 days Outcome measures a : AST, ALT, GGTP, alk phos, bilirubin Followup interval: 90 days Assessment time points with results reported: 90 days |
Type: Organic and functional diseases of liver parenchyma Include: Not given Exclude: Not given Acuity/severity: No other information |
N: 51 Mean age: 55 Percent male: 41 Setting: Not given |
Significant: Not Significant: Hepatomegaly, gastric burning, pain on palpation | |||||||||||||||
|
Author: Saba
110 Year: 1979 Country: Italy Language: Italian |
Study Type: RCT/blinding unclear
Intervention/dose/duration: Silymarin/420 mg daily/not given Control: MVI + choline + methionin Outcome measures a : AST, ALT, alk phos, bilirubin Followup interval: Unclear Assessment time points with results reported: Unclear |
Type: Acute viral hepatitis Include: Onset in 15 days or fewer; hospitalized 4 days or fewer of onset of jaundice; no previous episodes of jaundice Exclude: More than 100 g of alcohol per day for 15 days or fewer of disease onset Acuity/severity: Acute, no other information |
N: 38 Mean age: 36 Percent male: 53 Setting: Not given |
Significant: Time to normalization for direct bilirubin, AST, ALT, alk phos Not Significant: Time to normalization for total bilirubin | |||||||||||||||
|
Author: Schopen
111 Year: 1970 Country: Germany Language: German |
Study Type: RCT/blinding unclear
Intervention/dose/duration: Silymarin (Legalon ® )/1 tablet = 35 mg (dose varied from 6 tablets daily to 9 tablets daily and, in rare cases, 12 tablets daily/mean 45 days Control: Other hepatoprotective medicines but not silymarin Outcome measures a : AST, ALT, alk phos, bilirubin, albumin, PT Followup interval: 45 days Assessment time points with results reported: Mean 45 days |
Type: Alcoholic-, toxin-, and drug-induced liver disease and fatty liver secondary to diabetes mellitus; cholestasis (not pregnancy related) Include: Patients with microscopic changes of moderately severe to severe localized fatty deposits or diffuse steatosis; 51 toxic metabolic changes with fatty liver and some with cholestasis (patients with alcohol abuse, some diabetes mellitus); 13 diabetes mellitus; 8 poisoning; 2 aflatoxin; 1 mercury; 5 chronic barbiturate abuse Exclude: Not given Acuity/severity: No other information |
N: 72 Mean age: Not given Percent male: Not given Setting: Unclear |
Significant: AST, ALT Not Significant: | |||||||||||||||
|
Author: Szilard
112 Year: 1988 Country: Hungary Language: English |
Study Type: Cohort/not blind
Intervention/dose/duration: Silymarin (Legalon ® ) 420 mg daily/30 days Control: No treatment Outcome measures a : AST, ALT, GGTP Followup interval: 30 days Assessment time points with results reported: 28 days |
Type: Toxic hepatopathy caused by organic solvents (toluene and xylene) Include: Hepatomegaly, increased AST and ALT levels, lymphocytosis, decreased platelet counts attributable to toluene and/or xylene Exlcude: Alcoholics Acuity/severity: No other information Baseline group similarity: Demos, LFTs, appear similar except higher GGTP in treatment group |
N: 49 (Legalon
®
= 30; no treatment = 19) Mean age: Not given Percent male: 100 Setting: Workplace |
Significant: AST, ALT Not Significant: GGTP | |||||||||||||||
|
Author: Tkacz
113 Year: 1983 Country: Poland Language: Polish |
Study Type: RCT unclear/blinding unclear
Intervention/dose/duration: Silimarol ® (and vitamins B and C)/6 pills daily/21 days Control: Vitamins B and C and cocarboxylase Outcome measures a : ALT, alk phos, bilirubin, PT Followup interval: 21 days Assessment time points with results reported: 21 days |
Type: Viral hepatitis Include: Abnormal LFTs Exclude: Not given Acuity/severity: No other information |
N: 87 Mean age: Not given Percent male: Not given Setting: Unclear |
Significant: Not Significant: ALT, PT, bilirubin, length of stay | |||||||||||||||
|
Author: Vailati
85 Year: 1993 Country: Italy Language: English |
Study Type: RCT/not blind/phase 2 study
Intervention/dose/duration: Silymarin (Silipide ® )/160 mg silybin equivalents daily/14 days Silymarin (Silipide ® )/240 mg silybin equivalents daily/14days Silymarin (Silipide ® )/360 mg silybin equivalents daily/14 days Control: No treatment Outcome measures a : AST, GGTP, bilirubin Followup interval: 7, 14 days Assessment time points with results reported: 7, 14 days |
Type: Viral and alcoholic hepatitis Include: Biopsy-proven chronic hepatitis (viral or alcoholic); AST and ALT 1.5 or greater than 2 times normal limits and biopsy within 1 year Exclude: Other forms of liver disease; decompensated liver disease; treatment with interferon, antivirals, immunosuppressants, or immunodulators for 6 months or fewer Acuity/severity: Chronic, no other information |
N: 60 Mean age: 50 Percent male: 62 Setting: Outpatient clinic |
Significant: AST, GGTP, bilirubin for 240 or 360 mg versus 160 mg Not Significant: | |||||||||||||||
|
Author: Velussi
114
115 Year: 1993, 1997 Country: Italy Language: English |
Study Type: RCT/not blind
Intervention/dose/duration: Silymarin (Legalon ® )/600 mg daily/365 days Control: No treatment Outcome measures a : MDA, AST, ALT GGTP, alk phos, bilirubin Followup interval: 90, 180, 270, 365 days Assessment time points with results reported: 90, 180, 270, 365 days |
Type: Diabetics with alcoholic cirrhosis Include: Age 45 to 70 years; NIDDM with alcoholic liver cirrhosis; BMI more than 29 kg/m2; diabetes for 5 or more years treated with insulin only; stable insulin therapy for 2 or more years; increased endogenous insulin secretion; negative for HAV, HBV, and HCV; not addicted to alcohol for 2 or more years before study; no variceal esophagus bleeding; positive liver biopsy for cirrhosis 4 or fewer years before enrollment Exclude: Not given Acuity/severity: Chronic, no other information |
N: 60 Mean age: Not given Percent male: Not given Setting: Specialty clinic |
Significant: MDA Not Significant: GGTP, bilirubin, alk phos |
Results not necessarily reported for all.
alk phos = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartase aminotransferase; BMI = body mass index; CE = cirrosi epatica;
Demos = demographic variables; EC = epatite cronica; GGTP = gammaglutamyl transpeptidase; HAV = hepatitis A virus; HbsAg = hepatitis B surface antigen;
HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; LFT = liver function test; MDA = malondialdehyde; MVI = multivitamin;
NIDDM = noninsulin dependent diabetes; PT = prothrombin time; RCT = randomized controlled trial; UDCA = ursodeoxycholic acid.
| Author | Design | Liver Disease | Patient Characteristics | Outcomes (favoring silymarin unless otherwise noted) |
|---|---|---|---|---|
|
Author: Allain 83 Year: 1999 Country: France Language: English |
Study type: RCT/blind/prophylaxis Intervention/dose/duration: Silymarin/420 mg daily/84 days Control: Placebo Outcome measuresa: AST, ALT Followup interval: 8 times over 15 weeks Assessment time points with results reported: 8 times over 15 weeks |
Type: Drug- (Tacrine-)induced liver disease Include: Patient over 50 years old; mild to moderate Alzheimer's disease; Tacrine treatment Exclude: Past history hepatic disorder (cirrhosis, increased bilirubin, AST, and/or ALT) Acuity/severity: No disease at baseline |
N:
222 Mean age: Approximately 74 Percent male: 39 Setting: Specialty clinic |
Significant: Not significant: AST, ALT |
|
Author: Magula 82 Year: 1996 Country: Language: Slovak |
Study type: RCT/not blinded/prophylaxis Intervention/dose/duration: Tuberculosis treatment and Hepabene® (Silymarin and Fumaria officinalis alkaloids)/2 capsules daily/8 weeks Control: Tuberculosis medications alone Outcome measuresa: AST, ALT, bilirubin, "liver injury," interruption of tuberculosis medications Followup interval: Every 2 weeks for 8 weeks Assessment time points with results reported: 8 weeks (56 days) |
Type: Drug-induced liver disease Include: Patients requiring tuberculosis treatment; normal LFTs at baseline Exclude: Not given Acuity/severity: No disease at baseline |
N:
172 (92 tuberculosis medications alone; 29 tuberculosis medications plus silymarin) Mean age: 50 Percent male: 60 Setting: Unclear |
Significant:
AST, ALT Not significant: |
Results not necessarily reported for all.
ALT = alanine aminotransferase; AST = aspartase aminotransferase; LFT = liver function test; RCT = randomized controlled trial.
| Author, Year | Adverse Effect | Study N | Study Design | Milk Thistle Exposure | Questions | ||||
|---|---|---|---|---|---|---|---|---|---|
| Type | Amount | Improved after discontinued? | Rechallenged? | Alternative causes possible? | Dose-response? | ||||
| Bunout, 199266 |
Control: Pruritus Headache Treatment: Pruritus Headache | 11/34 4/34 4/25 3/24 | RCT | Placebo Silymarin (Legalon®) | 280 mg/d | Yes, in one patient Not discontinued | No No | Not given Not given | Not given Not given |
| Ferenci, 1989 75 |
Control: Nausea, epigastric discomfort Treatment: Nausea, epigastric discomfort | 2/83 2/87 | RCT | Placebo
Silymarin (Legalon®) | 420 mg/d | Yes Yes | No No | Not given
Not given | Not given
Not given |
| Pares, 1998 68 |
Control:
4 Urticaria, pruritus, arthralgia, headache Treatment:7 Urticaria, pruritus, arthralgia, headache | Total n: 11/200 | RCT | Placebo
Silymarin (Legalon®) | 450 mg/d | Yes, 2 patients in treatment and 1 patient in control | No | Not given | Not given |
| Vailati, 199385 |
Treatment:
Nausea, heartburn Dyspepsia Postprandial nausea, meteorism | 3/20
1/20 2/20 | RCT | Silipide® Silipide® | 160 mg/d 240 mg/d 360mg/d | Yes Yes | No No | Not given Not given | Not given Not given Not given |
| Andrade, 1998 87 |
Control: Treatment: Impotence | 0/31 1/29 | RCT | Silymarin | 450 mg/d | Not given | Not given | Not given | Not given |
| Marcelli, 1992 77 |
Control:
Nausea, dyspepsia, heartburn, skin rash
Treatment: Nausea, heartburn, transient headache | 5/34 3/31 | RCT | Placebo Silipide® | 240 mg/d | Not discontinued | Not given | Not given | Not given |
| Allain, 1999 83 |
Control: Frequency ADE occurred
b
: Diarrhea 5 (10.1%) Vomiting 10 (8.2%) Nausea 10 (6.3%) Anorexia 7 (5.7%) Irritability 6 (5.1%) Insomnia 6 (4.4%) Asthenia 5 (3.8%) Malaise 3 (3.2%) Bronchitis 7 (5.1%) Treatment: Frequency ADE occurred b : Diarrhea 8 (8.1%) Vomiting 6(4.8%) Nausea 10 (10.5%) Anorexia 9 (8.2%) Irritability 5 (4.8%) Insomnia 5 (4.8%) Bronchitis 7 (5.6%) | 112 110 | RCT | Placebo and Tacrine Silymarin and Tacrine | 420 mg/d | Not given Not given | Not given Not given | Not given Not given | Not given Not given |
| Studlar, 1985 90 | Temporary uneasiness of stomach | 2/34 | Prospective cohort | Silibene® (a silymarin-containing drug) | 280 mg/d | Not discontinued | Not given | Not given | Not given |
| Albrecht, a 1992 88 |
Treatment: (in 0.8% of patients): Mild diarrhea Nausea Upset stomach Itching Exanthem Headache Decreased energy and discomfort NOS | 4/2,637 3/2,637 2/2,637 2/2,637 1/2,637 1/2,637 7/2,637 | Prospective cohort | Silymarin (Legalon® ) 70 mg | 3.8±1.48 tablets per day 267.4±103.6 mg 1 to 9 tablets 55.2 percent 1 tablet tid 28.3 percent 2 tablets tid | Not given | Not given | Not given | Not given |
| Marena, 1991 93 | Gastrointestinal: Mostly upset stomach Control: Silipide® | 6/117 12/232 | Cohort c | Placebo Commercial extract Silipide® | 280 to 420 mg/d | Not given | Not given | Not given | Not given |
| Grungreiff, 1995 89 | Frequency ADE occurred
b
: Changes in BM 4 Diarrhea 4 Dizziness/circulatory problems 4 Nausea/vomiting 2 Itching 2 Eczemas 2 Indisposition 1 Flatulence 1 | 16/975 (12 patients reported 1 adverse effect and 4 patients reported 2 adverse effects) | Cohort c | Silymarin | 280 to 420 mg/d | Not given | Not given | Not given | Not given |
| Frerick, a 199091 | Frequency ADE occurred
b
: Mild diarrhea 4 Nausea 3 Gastric intolerance 2 Itching 2 Eczema 1 Diffuse headaches 1 Decreased energy/ restlessness 1 No specifics 7 | 2,169 | Cohort c | Silymarin | 1,210 patients received 210 mg/d 583 patients received 420 mg/d 376 patients received 70 to 630 mg/d | Not given | Not given | Not given | Not given |
| Schuppan, 1998 92 | 12 ADEs occurred, but not specifically noted; examples were diarrhea, flatulence, abdominal fullness or pain, nausea, vomiting, and dizziness | 20/998 | Cohort c | Silymarin | 280 to 420 mg/d | Not given | Not given | Not given | Not given |
| Anonymous, 1972 98 | Sweating, nausea, colicky abdominal pain, fluid diarrhea, weakness, and collapse | 1 | Case report | Microgenics Herbals M.T. Vegicaps® | 1 capsule | Yes | Yes | Yes, due to multiherbal capsule | Not given |
| Geier, 1990 94 | Anaphylactic shock: facial edema, oral mucosa swelling, marked respiratory distress, bronchospasm, and decrease blood pressure | 1 | Case report | Silybum marianum tea | Not given | Not given | Not given | Not given | Not given |
| Mironets, 1990 95 | Urticaria, fever, laryngeal edema | 1 | Case report | Carsil® | 3 pills per day, no dosage given | Yes, and Tx Prednisone | No | Not given | Not given |
| Wollemann, 1987 97 | Rhinoconjunctivitis | 1 | Case report | Silybum marianum | Contact with seeds | Not given | Yes | Not given | Not given |
| DeSmet, 199696 | Jaundice, increase LFTs | 1 | Case report | Multiherbal tablets with unknown amount of milk thistle | 6 to 15 tablets per day | Yes | Yes | Yes, due to multiherbal tablet | Not given |
The study by Albrecht is an extension of the study by Frerick and includes the same patients.19
Unit of reporting was ADE, not patient.
Unclear if cohort was prospective or retrospective.
ADE = adverse drug effects; BM = bowel movement; LFT = liver function test; NOS = not otherwise specified; RCT = randomized controlled trial; tid = three times daily.