Expert's Picks: Silymarin for NAFLD
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ISSUE: MAY 2012 | VOLUME: 63:5
Expert's Picks: Silymarin for NAFLD
By David Wild
Gastroenterology & Endoscopy News
Silymarin commonly known as milk thistle, was used in classical Greece to treat hepatic and gallbladder diseases and to protect the liver from toxins. Somewhat more recently, there has been renewed interest in its potential efficacy in non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), particularly given the role that oxidative stress is thought to play in the pathogenesis of NAFLD and the anti-oxidant properties of the herb. This month, Gastroenterology & Endoscopy News Medical Advisory Board member Alan Cutler, MD, provides a snapshot of, and commentary on, some of the most noteworthy research on silymarin.
A Placebo-Controlled Trial of Silymarin in Patients With Nonalcoholic Fatty Liver Disease (Hashemi SJ et al. Hepatitis
Monthly 2009;9:265-270)
Researchers at the Qazvin University of Medical Sciences in Qazvin, Iran, prospectively enrolled 100 NAFLD patients they had treated between 2007 and 2008. The participants had laboratory-confirmed disease, with elevated levels of
alanine aminotransferase (ALT) and asparate aminotransferase (AST). None of the patients had viral or autoimmune hepatitis, or had a history of excessive alcohol consumption or relevant drug use.
The investigators randomized 50 subjects to receive 280 mg silymarin daily for 24 weeks and the same number of patients to a placebo arm. The two groups were similar in age and gender distribution and had similar mean levels of ALT and AST at study outset.
According to the findings, mean serum ALT levels in the treatment group dropped from 113.03 IU/L at baseline to 73.14 IU/L after 24 weeks of treatment (P=0.001). In contrast, mean ALT levels decreased in the placebo group from 104.54 IU/L at baseline to 89.92 IU/L after six months (P=0.237).
Similarly, mean AST levels among silymarin recipients fell from 71.02 IU/L at baseline to 49.66 IU/L after six months of treatment (P=0.006), while mean AST levels in the placebo group were 73.02 at baseline and 66.16 at six months (P=0.343).
A data analysis showed ALT levels normalized to below 40 IU/L in 52% of silymarin subjects and 18% of placebo patients at six months (P=0.001). AST levels similarly normalized to below 40 IU/L in 62% and 20% of treatment and
placebo patients, respectively (P=0.0001). There were no serious adverse events in either group, the researchers
reported.
As glucose metabolism, hyperlipidemia and body mass index (BMI) remained statistically unchanged before and after the study in both groups, the improvements in liver function were due to treatment with silymarin, the investigators concluded.
The Efficacy of Silymarin in DecreasingTransaminase Activities in Non-Alcoholic Fatty Liver Disease: A Randomized
Controlled Clinical Trial (Hajaghamohammadi A et al. Hepatitis Monthly 2008;8:191-195).
An Iranian team randomly assigned 50 patients with high AST and ALT levels and ultrasound-proven liver steatosis to receive either 140 mg silymarin daily for two months or a placebo for the same duration. Subjects included 32 men and
18 women. Participants were a mean 40 years old in either group and had mean BMIs of approximately 30 kg/m2. None of the patients had a history of diabetes, alcohol abuse or autoimmune or viral hepatitis.
According to the results, mean serum ALT levels in the treatment group dropped from 103.1 IU/L at baseline to 41.4 IU/L following treatment (P<0.001). In contrast, mean serum ALT in the placebo group dropped from 96.6 IU/L at baseline to 88.8 IU/L at two months (P=not significant). Similarly, mean serum AST levels dropped significantly in the silymarin group, from 53.07 IU/L to 29.1 IU/L at two months, but decreased from 56.3 IU/L at baseline to 54.1 IU/L after two months in the control group (P<0.001 for baseline vs. 2 months in silymarin group; P=not significant in placebo group).
The authors did not report any adverse events associated with use of silymarin.
In a discussion of their findings, they wrote that, “the duration and the recommended dosage [of silymarin] should be studied in future research.” Furthermore, they said, “in our study, the effect of silymarin on a patient’s prognosis was not [evaluated].” Effects on long-term disease progression should be studied in future research, they suggested.
Dr. Cutler’s comment:
The studies by Hashemi et al and Hajaghamohammadi et al were the first to utilize milk thistle as a solo agent in randomized controlled trials of patients with fatty liver disease. Both studies demonstrated statistically significant improvements in liver function tests in NAFLD patients treated with milk thistle. Previous studies of fatty liver disease and vitamin E in children were
complicated by weight loss in the control group and subsequent liver function test improvements in the placebo arm. Importantly, in the studies by Hashemi and Hajaghamohammadi, there was no change in mean weight or BMI in either treatment or control groups, allowing for a more accurate evaluation of the milk thistle treatment.
The Effect of Silybin-Vitamin E-Phospholipid Complex on Nonalcoholic Fatty Liver Disease: A Pilot Study (Loguercio C et al. Dig Dis Sci 2007;52:2387-2395)
This prospective, open-label Italian study examined the efficacy of silybin—the active ingredient in silymarin—in combination with vitamin E and phosphatidylcholine (Realsil, Instituto Biochimico Italiano, Lorenzini S.p.a., Italy). The trial included 85 consecutive patients with ultrasonography-proven NAFLD, including 26 patients with hepatitis C virus (HCV) genotype 1
infection.
The researchers randomized 39 patients with NAFLD and no HCV to receive the combination treatment for six months and assigned 20 similar patients to a control untreated arm. They also randomized 14 of the HCV-positive participants
to receive the active treatment for six months and 12 subjects to receive no treatment. Those in the non-HCV infection group had failed to respond to prior treatment with interferon and ribavirin and had discontinued those medications
approximately one year prior to study outset.
Non-HCV NAFLD patients were a median 44 years of age while HCV-positive patients were a median 51 years of age. None of the subjects had other possible underlying causes of chronic liver damage such as high daily alcohol consumption, drug use or associated autoimmune or genetic diseases. Participants were followed for one year from study outset.
Mean baseline ALT levels were higher in the treatment group than in the control group (79 IU/L in treated non-HCV vs. 54 IU/L in control non-HCV; 69 IU/L in treated HCV-positive vs. 47.8 IU/L in control HCV-positive). However, all other parameters were similar between the treatment and control groups.
The results showed a significant decrease in ALT levels in the treated non-HCV and HCV-positive patients after six months, with levels in the former group nearly halving, from 79 IU/L at baseline to 40 IU/L (P<0.01). ALT levels in the HCV-positive group fell from a mean 69 IU/L at baseline to 45 IU/L at six months (P<0.01). While ALT levels in the treated non-HCV
group rebounded six months following treatment discontinuation, they remained significantly lower than baseline levels, the researchers found.
Serum g-glutamyltranspeptidase (g-GT) levels also dropped significantly in the treated non-HCV and HCV-positive groups (for non-HCV: 75 IU/L at baseline vs. 59 IU/L and 60 IU/L at 6 and 12 months, respectively; P<0.01; for HCV-positive: 118 IU/L at baseline vs. 56 IU/L and 83 IU/L at 6 and 12 months; P<0.01 for 6 months vs. baseline). There were no significant
changes in ALT or g-GT levels in the untreated group, the investigators reported.
According to the findings, treated patients in both the non-HCV and HCV-positive groups experienced significant mprovements in insulinemia and homeostatic model assessment (HOMA) scores at six and 12 months, while there were no similar improvements in the control groups.
Silybin Combined with Phosphatidylcholine and Vitamin E in Patients with Nonalcoholic Fatty Liver Disease: A Randomized
Controlled Trial (Loguercio C et al. Free Radic Biol Med 2012;52:1658-1665)
In a follow-up to the above trial, Italian and Romanian researchers examined the efficacy of the same silybin/vitamin E acetate/phosphatidylcholine formulation in patients with non-HCV NAFLD and HCV-related NAFLD. They analyzed
prospectively-collected data from 108 patients with histologically-confirmed NAFLD and 30 HCV genotype-1 patients with NAFLD. Half the patients were randomized to receive the combination treatment twice daily for one year and
half received a placebo. None of the subjects were undergoing other NAFLD or HCV treatments or had other underlying causes of liver steatosis.
According to the investigators, many of the non-HCV patients had near-normal AST, ALT and g-GT levels at baseline. However, at one year, an additional 41% to 45% of treatment recipients achieved normalized AST, ALT and g-GT levels,
compared with an additional 5% to 19% of placebo patients who experienced the same normalization of liver function tests. There were no significant differences in absolute AST or ALT levels among treatment and placebo recipients
at one year.
A subgroup analysis of HCV-positive patients showed 54% and 20% of treatment and placebo subjects, respectively, experienced normalization of g-GT levels at one year (P=0.02 for treatment vs. placebo). Additionally, mean blood
glucose values were 48% lower at one year than at baseline among the HCV-positive treatment group patients, while there were no appreciable improvements in blood glucose in the placebo group. The silybin combination also significantly improved HOMA values in those with baseline scores greater than 2.7, the researchers found.
Liver fibrosis, lobular inflammation, ballooning and NAFLD activity scores (NAS) all significantly improved in the treatment group at one year but did not do so in the placebo group, the investigators reported. Although there were marked improvements in patients with moderate to severe steatosis who received the active treatment, overall liver steatosis grades were not statistically different between the two groups after one year.
Dr. Cutler’s comment:
The two studies by Loguercio et al used a unique combination of milk thistle, vitamin E and phospholipids in patients with NAFLD. The initial study demonstrated that the treatment improved liver enzymes, sonic evidence of steatosis and indices of liver fibrosis in patients with NAFLD. The follow-up study was a randomized, controlled trial that included liver histology. It
showed that active treatment with the combination agent caused significant improvements in liver enzymes, insulin resistance and liver histology in patients with NAFLD. The only issue in these two studies is that both evaluated only the combination product and did not include arms utilizing each treatment agent individually. It is therefore not possible to determine the importance of each element of the combination product and whether these elements work synergistically in fatty liver disease.
Certainly, the four studies reviewed support the use of milk thistle in patients with NAFLD, either alone or in combination with vitamin E.
Dr. Cutler has a financial interest in Cass Labs, which markets and distributes EThistile™, a combination of milk thistle and vitamin E to support liver wellness.
Alan Cutler, MD
Clinical
Associate Professor of Medicine
Wayne State University
Detroit, Michigan
http://www.gastroendonews.com/ViewArticle.aspx?d=Hepatology+in+Focus&d_id=481&i=May+2012&i_id=841&a_id=20796
Expert's Picks: Silymarin for NAFLD
By David Wild
Gastroenterology & Endoscopy News
Silymarin commonly known as milk thistle, was used in classical Greece to treat hepatic and gallbladder diseases and to protect the liver from toxins. Somewhat more recently, there has been renewed interest in its potential efficacy in non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), particularly given the role that oxidative stress is thought to play in the pathogenesis of NAFLD and the anti-oxidant properties of the herb. This month, Gastroenterology & Endoscopy News Medical Advisory Board member Alan Cutler, MD, provides a snapshot of, and commentary on, some of the most noteworthy research on silymarin.
A Placebo-Controlled Trial of Silymarin in Patients With Nonalcoholic Fatty Liver Disease (Hashemi SJ et al. Hepatitis
Monthly 2009;9:265-270)
Researchers at the Qazvin University of Medical Sciences in Qazvin, Iran, prospectively enrolled 100 NAFLD patients they had treated between 2007 and 2008. The participants had laboratory-confirmed disease, with elevated levels of
alanine aminotransferase (ALT) and asparate aminotransferase (AST). None of the patients had viral or autoimmune hepatitis, or had a history of excessive alcohol consumption or relevant drug use.
The investigators randomized 50 subjects to receive 280 mg silymarin daily for 24 weeks and the same number of patients to a placebo arm. The two groups were similar in age and gender distribution and had similar mean levels of ALT and AST at study outset.
According to the findings, mean serum ALT levels in the treatment group dropped from 113.03 IU/L at baseline to 73.14 IU/L after 24 weeks of treatment (P=0.001). In contrast, mean ALT levels decreased in the placebo group from 104.54 IU/L at baseline to 89.92 IU/L after six months (P=0.237).
Similarly, mean AST levels among silymarin recipients fell from 71.02 IU/L at baseline to 49.66 IU/L after six months of treatment (P=0.006), while mean AST levels in the placebo group were 73.02 at baseline and 66.16 at six months (P=0.343).
A data analysis showed ALT levels normalized to below 40 IU/L in 52% of silymarin subjects and 18% of placebo patients at six months (P=0.001). AST levels similarly normalized to below 40 IU/L in 62% and 20% of treatment and
placebo patients, respectively (P=0.0001). There were no serious adverse events in either group, the researchers
reported.
As glucose metabolism, hyperlipidemia and body mass index (BMI) remained statistically unchanged before and after the study in both groups, the improvements in liver function were due to treatment with silymarin, the investigators concluded.
The Efficacy of Silymarin in DecreasingTransaminase Activities in Non-Alcoholic Fatty Liver Disease: A Randomized
Controlled Clinical Trial (Hajaghamohammadi A et al. Hepatitis Monthly 2008;8:191-195).
An Iranian team randomly assigned 50 patients with high AST and ALT levels and ultrasound-proven liver steatosis to receive either 140 mg silymarin daily for two months or a placebo for the same duration. Subjects included 32 men and
18 women. Participants were a mean 40 years old in either group and had mean BMIs of approximately 30 kg/m2. None of the patients had a history of diabetes, alcohol abuse or autoimmune or viral hepatitis.
According to the results, mean serum ALT levels in the treatment group dropped from 103.1 IU/L at baseline to 41.4 IU/L following treatment (P<0.001). In contrast, mean serum ALT in the placebo group dropped from 96.6 IU/L at baseline to 88.8 IU/L at two months (P=not significant). Similarly, mean serum AST levels dropped significantly in the silymarin group, from 53.07 IU/L to 29.1 IU/L at two months, but decreased from 56.3 IU/L at baseline to 54.1 IU/L after two months in the control group (P<0.001 for baseline vs. 2 months in silymarin group; P=not significant in placebo group).
The authors did not report any adverse events associated with use of silymarin.
In a discussion of their findings, they wrote that, “the duration and the recommended dosage [of silymarin] should be studied in future research.” Furthermore, they said, “in our study, the effect of silymarin on a patient’s prognosis was not [evaluated].” Effects on long-term disease progression should be studied in future research, they suggested.
Dr. Cutler’s comment:
The studies by Hashemi et al and Hajaghamohammadi et al were the first to utilize milk thistle as a solo agent in randomized controlled trials of patients with fatty liver disease. Both studies demonstrated statistically significant improvements in liver function tests in NAFLD patients treated with milk thistle. Previous studies of fatty liver disease and vitamin E in children were
complicated by weight loss in the control group and subsequent liver function test improvements in the placebo arm. Importantly, in the studies by Hashemi and Hajaghamohammadi, there was no change in mean weight or BMI in either treatment or control groups, allowing for a more accurate evaluation of the milk thistle treatment.
The Effect of Silybin-Vitamin E-Phospholipid Complex on Nonalcoholic Fatty Liver Disease: A Pilot Study (Loguercio C et al. Dig Dis Sci 2007;52:2387-2395)
This prospective, open-label Italian study examined the efficacy of silybin—the active ingredient in silymarin—in combination with vitamin E and phosphatidylcholine (Realsil, Instituto Biochimico Italiano, Lorenzini S.p.a., Italy). The trial included 85 consecutive patients with ultrasonography-proven NAFLD, including 26 patients with hepatitis C virus (HCV) genotype 1
infection.
The researchers randomized 39 patients with NAFLD and no HCV to receive the combination treatment for six months and assigned 20 similar patients to a control untreated arm. They also randomized 14 of the HCV-positive participants
to receive the active treatment for six months and 12 subjects to receive no treatment. Those in the non-HCV infection group had failed to respond to prior treatment with interferon and ribavirin and had discontinued those medications
approximately one year prior to study outset.
Non-HCV NAFLD patients were a median 44 years of age while HCV-positive patients were a median 51 years of age. None of the subjects had other possible underlying causes of chronic liver damage such as high daily alcohol consumption, drug use or associated autoimmune or genetic diseases. Participants were followed for one year from study outset.
Mean baseline ALT levels were higher in the treatment group than in the control group (79 IU/L in treated non-HCV vs. 54 IU/L in control non-HCV; 69 IU/L in treated HCV-positive vs. 47.8 IU/L in control HCV-positive). However, all other parameters were similar between the treatment and control groups.
The results showed a significant decrease in ALT levels in the treated non-HCV and HCV-positive patients after six months, with levels in the former group nearly halving, from 79 IU/L at baseline to 40 IU/L (P<0.01). ALT levels in the HCV-positive group fell from a mean 69 IU/L at baseline to 45 IU/L at six months (P<0.01). While ALT levels in the treated non-HCV
group rebounded six months following treatment discontinuation, they remained significantly lower than baseline levels, the researchers found.
Serum g-glutamyltranspeptidase (g-GT) levels also dropped significantly in the treated non-HCV and HCV-positive groups (for non-HCV: 75 IU/L at baseline vs. 59 IU/L and 60 IU/L at 6 and 12 months, respectively; P<0.01; for HCV-positive: 118 IU/L at baseline vs. 56 IU/L and 83 IU/L at 6 and 12 months; P<0.01 for 6 months vs. baseline). There were no significant
changes in ALT or g-GT levels in the untreated group, the investigators reported.
According to the findings, treated patients in both the non-HCV and HCV-positive groups experienced significant mprovements in insulinemia and homeostatic model assessment (HOMA) scores at six and 12 months, while there were no similar improvements in the control groups.
Silybin Combined with Phosphatidylcholine and Vitamin E in Patients with Nonalcoholic Fatty Liver Disease: A Randomized
Controlled Trial (Loguercio C et al. Free Radic Biol Med 2012;52:1658-1665)
In a follow-up to the above trial, Italian and Romanian researchers examined the efficacy of the same silybin/vitamin E acetate/phosphatidylcholine formulation in patients with non-HCV NAFLD and HCV-related NAFLD. They analyzed
prospectively-collected data from 108 patients with histologically-confirmed NAFLD and 30 HCV genotype-1 patients with NAFLD. Half the patients were randomized to receive the combination treatment twice daily for one year and
half received a placebo. None of the subjects were undergoing other NAFLD or HCV treatments or had other underlying causes of liver steatosis.
According to the investigators, many of the non-HCV patients had near-normal AST, ALT and g-GT levels at baseline. However, at one year, an additional 41% to 45% of treatment recipients achieved normalized AST, ALT and g-GT levels,
compared with an additional 5% to 19% of placebo patients who experienced the same normalization of liver function tests. There were no significant differences in absolute AST or ALT levels among treatment and placebo recipients
at one year.
A subgroup analysis of HCV-positive patients showed 54% and 20% of treatment and placebo subjects, respectively, experienced normalization of g-GT levels at one year (P=0.02 for treatment vs. placebo). Additionally, mean blood
glucose values were 48% lower at one year than at baseline among the HCV-positive treatment group patients, while there were no appreciable improvements in blood glucose in the placebo group. The silybin combination also significantly improved HOMA values in those with baseline scores greater than 2.7, the researchers found.
Liver fibrosis, lobular inflammation, ballooning and NAFLD activity scores (NAS) all significantly improved in the treatment group at one year but did not do so in the placebo group, the investigators reported. Although there were marked improvements in patients with moderate to severe steatosis who received the active treatment, overall liver steatosis grades were not statistically different between the two groups after one year.
Dr. Cutler’s comment:
The two studies by Loguercio et al used a unique combination of milk thistle, vitamin E and phospholipids in patients with NAFLD. The initial study demonstrated that the treatment improved liver enzymes, sonic evidence of steatosis and indices of liver fibrosis in patients with NAFLD. The follow-up study was a randomized, controlled trial that included liver histology. It
showed that active treatment with the combination agent caused significant improvements in liver enzymes, insulin resistance and liver histology in patients with NAFLD. The only issue in these two studies is that both evaluated only the combination product and did not include arms utilizing each treatment agent individually. It is therefore not possible to determine the importance of each element of the combination product and whether these elements work synergistically in fatty liver disease.
Certainly, the four studies reviewed support the use of milk thistle in patients with NAFLD, either alone or in combination with vitamin E.
Dr. Cutler has a financial interest in Cass Labs, which markets and distributes EThistile™, a combination of milk thistle and vitamin E to support liver wellness.
Alan Cutler, MD
Clinical
Associate Professor of Medicine
Wayne State University
Detroit, Michigan
http://www.gastroendonews.com/ViewArticle.aspx?d=Hepatology+in+Focus&d_id=481&i=May+2012&i_id=841&a_id=20796