ArticlePDF Available

A Placebo-Controlled Trial of Silymarin in Patients with Nonalcoholic Fatty Liver Disease

Authors:

Abstract

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition that is characterized by significant hepatic lipid deposition with or without necroinflammation and fibrosis. Researchers have proposed that oxidative stress may play a role in pathogenesis of NAFLD, and there is challenging evidence for the efficacy of antioxidant agents in its treatment. Therefore, we tried silymarin as an antioxidant in a randomized controlled trial for a group of patients with NAFLD.Methods: During an 18-month period, a placebo-controlled study was conducted among patients with nonalcoholic steatohepatitis (NASH) referred to the Ahvaz Jundishapour University Hospital (AJSUH) and Hepatitis Clinic from 2007 to 2008. Based on sonography findings and elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels or liver biopsy, we selected 100 NASH patients who were referred to our center for management of liver disease. Patients who had positive viral markers and other hepatic diseases and patients who had ingested ethanol or drugs known to produce fatty liver disease within the previous 6 months were excluded from the study. Patients were randomized to two groups: Group A received a placebo, and Group B received treatment with 280 mg of silymarin. Treatment was continued for 24 weeks, and cases were evaluated every 4 weeks in the outpatient clinic.Results: A total of 100 subjects who met the inclusion and exclusion criteria were included in the analysis. Group A (50 cases, 29 males and 21 females) and Group B (50 cases, 28 males and 22 females). The mean age was 39.0 ± 10.70 years for Group A and 39.28 ± 11.117 years for Group B. The age range for both groups was 20 to 50 years. The mean serum ALT levels in the silymarin group were 113.03 and 73.14 IU/mL before and after treatment, respectively (P = 0.001). ALT normalization (ALT < 40) was observed in 18% and 52% of patients in Groups A and B, respectively (P = 0.001). AST normalization (AST < 40) was observed in 20% of cases in the placebo group and 62% of cases in the silymarintreated group (P = 0.0001). No significant side effects were reported in our cases.Conclusions: Silymarin treatment appears to be significantly effective in biochemical improvement and decreasing transaminases levels in patients with NAFLD.
ORIGINAL
A RTICLE
Hepatitis Monthly 2009; 9(4): 265-270
A Placebo-Controlled Trial of Silymarin in Patients
with Nonalcoholic Fatty Liver Disease
Seyed Jalal Hashemi, Eskandar Hajiani*, Ebrahim Haidari Sardabi
* Division of Gastroenterology and Hepatology, Department of Internal Medicine, Emam Hospital,
Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
Introduction
Introduction
Nonalcoholic fatty liver disease (NAFLD)
is a spectrum of conditions ranging from
simple fatty infiltration of the liver to steatohepatitis,
fibrosis, and cirrhosis. Nonalcoholic steatohepatitis
(NASH) is histologically characterized by significant
accumulation of hepatic lipid and predominantly
lobular necroinflammation, with or without
centrilobular fibrosis. NASH is histologically similar
to alcoholic liver disease, but without a history of
ingesting significant amounts of ethanol (1). The
disorder may be progressive, causing chronic liver
*
Correspondence:
Correspondence:
Eskandar Hajiani, M.D.
Associate Professor of Gastroenterology and Hepatology,
Division of Gastroenterology and Hepatology, Department
of Internal Medicine, Emam Hospital, Ahvaz Jundishapur
University of Medical Sciences, Ahvaz, Iran.
Tel:
Tel:
+98 611 553 0222
Fax:
Fax:
+98 611 334 0074
E-mail:
E-mail:
ehajiani@ajums.ac.ir
Received:
Received:
26 Apr 2009
Revised:
Revised:
8 Nov 2009
Accepted:
Accepted:
9 Nov 2009
Hepat Mon 2009; 9 (4): 265-270
Background and Aims:
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition that is characterized by signifi-
cant hepatic lipid deposition with or without necroinflammation and fibrosis. Researchers have proposed that oxidative
stress may play a role in pathogenesis of NAFLD, and there is challenging evidence for the efficacy of antioxidant agents
in its treatment. Therefore, we tried silymarin as an antioxidant in a randomized controlled trial for a group of patients
with NAFLD.
Methods:
During an 18-month period, a placebo-controlled study was conducted among patients with nonalcoholic ste-
atohepatitis (NASH) referred to the Ahvaz Jundishapur University Hospital (AJSUH) and Hepatitis Clinic from 2007 to
2008. Based on sonography findings and elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
levels or liver biopsy, we selected 100 NASH patients who were referred to our center for management of liver disease.
Patients who had positive viral markers and other hepatic diseases and patients who had ingested ethanol or drugs
known to produce fatty liver disease within the previous 6 months were excluded from the study. Patients were random-
ized to two groups: Group A received a placebo, and Group B received treatment with 280 mg of silymarin. Treatment
was continued for 24 weeks, and cases were evaluated every 4 weeks in the outpatient clinic.
Results:
A total of 100 subjects who met the inclusion and exclusion criteria were included in the analysis. Group A (50
cases, 29 males and 21 females) and Group B (50 cases, 28 males and 22 females). The mean age was 39.0 ± 10.70 years
for Group A and 39.28 ± 11.117 years for Group B. The age range for both groups was 20 to 50 years. The mean serum
ALT levels in the silymarin group were 113.03 and 73.14 IU/mL before and after treatment, respectively (P = 0.001). ALT
normalization (ALT < 40) was observed in 18% and 52% of patients in Groups A and B, respectively (P = 0.001). AST
normalization (AST < 40) was observed in 20% of cases in the placebo group and 62% of cases in the silymarin-treated
group (P = 0.0001). No significant side effects were reported in our cases.
Conclusions:
Silymarin treatment appears to be significantly effective in biochemical improvement and decreasing
transaminases levels in patients with NAFLD.
Keywords:
Nonalcoholic Fatty Liver Disease, Milk Thistle, Vitamin E, Silymarin
Archive of SID
www.SID.ir
Hepatitis Monthly, Autumn 2009; 9(4): 265-270
Hepatitis Monthly, Autumn 2009; 9(4): 265-270
266
266 Trial of Silymarin in NAFLD
disease, including liver cirrhosis. Because of the
increase in the incidence of its predisposing conditions
such as obesity and type 2 diabetes mellitus, NASH
is a common disorder. NAFLD is the most common
liver disorder in developed countries, and it is
estimated that 20%-40% of the Western population
and 5%-35% of the population of Pacific and Asian
countries are afflicted with the disease (2, 3).
Insulin resistance plays an important role in
the pathogenesis of NASH, but oxidative stress is
also an important issue. Consequently, the exact
pathophysiology of the disease is not clear, and
because of that, the management of this condition
is empirical so various drug treatments have been
attempted with variable success, including vitamin
E, ursodeoxycholic acid, gemfibrozil, metformin
pioglitazone, and orlistat (4-7).
Because no single pharmacologic therapy has
completely proven to be effective for the treatment
of this disorder, weight loss is generally suggested as
the standard therapy; however, studies on the benefits
of weight loss have shown inconsistent results, and
there are some reports that weight loss may increase
inflammation (8) and worsen fibrosis (9, 10). Given
that a considerable number of patients with NAFLD
are not obese or would not benefit from weight
loss, use of medication that can directly reduce the
severity of liver damage independent of weight loss is
a reasonable alternative.
There are few challenging evidences for efficacy of
antioxidant agents such as vitamin E and silymarin
in the management of NASH.
Despite a proposed role of oxidant stress in the
pathogenesis of NAFLD, antioxidant approaches
have not been investigated sufficiently in NAFLD
therapy (11, 12).
Milk thistle (silybum marianum or silymarin), an
antioxidant and a regulator of immune functions
by modulating cytokine production, was used in
classical Greece to treat liver and gallbladder diseases
to protect the liver against toxins (13-15). There are
some challenging reports about silymarin efficacy
for treatment of NASH (16, 17) but few randomized,
placebo-controlled studies provide support for
silymarin, so we tried to evaluate the efficacy and
safety of oral silymarin in a placebo-controlled study
of subjects with NASH.
Materials and Methods
Materials and Methods
After approval of the ethics committee during an
18-month period, we conducted a random clinical
trial of patients with NAFLD referred to the Ahvaz
JundiShapur University Hospitals (AJSUH) and
Hepatitis Clinic from 2007 to 2008.
The study included 100 NASH patients who
attended our center for management of liver disease.
The criteria used for diagnosis of NASH include (a)
sonographic evidence of fatty liver, (b) elevated ALT
more than 1.2 times of the normal (c) excluding other
chronic liver conditions, (d) suggestive histological
evidence of NASH, or (e) the presence of strong risk
factors such as type 2 diabetes or obesity (BMI 30
kg/m2).
Patients were excluded if they had an intake of
ethanol (more than 20 g/day) or if they had ingested
drugs known to produce fatty liver disease, such as
steroids, estrogens, amiodarone, tamoxifen, or other
chemotherapeutic agents in the previous 6 months.
Patients were screened for viral hepatitis B and
C using HBsAg and anti-HCV antibody and for
other hepatic diseases including autoimmune
hepatitis, Wilsons disease, hemochromatosis, and
alpha-1 antitrypsin deficiency. Patients with severe
comorbid medical conditions (such as severe cardiac,
pulmonary, renal, or psychological problems) or
those not consenting to participate in the study
were also excluded. The patients were followed up
with a weight-reducing diet at least three months
by checking ALT levels. After this screening period,
liver biopsies were performed in nonresponders to
rule out other causes of liver diseases and to prove the
histologic diagnosis of NAFLD in patients without
obesity or diabetes. At the end of this period, the
patients having ALT levels of at least 1.2 times the
upper normal limit and risk factors of NAFLD or
histological evidence of the disease, were included in
the study.
Ultrasonographic evaluations of liver were
performed at the entry of the study and at the end of
the treatment. In the ultrasonographic examination,
fatty liver was diagnosed according to the modified
criteria (18). The four parameters used in this
criteria were brightness of the liver, attenuation of
echogenicity, blurred vessels, and the contrast ratio
of the liver-to-kidney in an ultrasonography (US;
General Electric LOGIQ 400 CL).
Patients were randomized to two groups, which
received a placebo (Group A, 50 patients) or silymarin
treatment (Group B, 50 patients).
In Group B, the patients were treated with
Livergol tablets containing 140 mg of silymarin active
extract. Group A served as a control group, and the
participants were treated with a placebo. Both drugs
were in the form of tablets. The placebo tablet had
the same shape, color, and packaging as the active
drug. Patients of each group took two tablets per day
for 6 months.
Treatment was continued for 24 weeks, and cases
Archive of SID
www.SID.ir
Hepatitis Monthly, Autumn 2009; 9(4): 265-270
Hepatitis Monthly, Autumn 2009; 9(4): 265-270
267
267
Seyed Jalal Hashemi et al.
were evaluated every 4 weeks in the outpatient clinic
for a 6-month period. Serum levels of ALT, aspartate
aminotransferase (AST), alkaline phosphatase
(ALP), gamma-glutamyl transpeptidase (GGT),
fasting plasma glucose (FPG), serum triglycerides,
and cholesterol were monitored at each visit during
treatment.
Statistical analysis
Sample size calculations were based on the
comparison of paired data. With a sample size of
71 subjects (36 cases for each arm), this study had
an 95% power to detect a difference in ALT levels
equivalent to one standard deviation with a two-
sided = 0.05. Considering the possibility of non-
adherent cases to therapy we included 100 patients
in the study. Statistical analysis was performed
using a repeat-measures analysis of variance and
Pearson’s correlation, with baseline and population
comparisons made using student’s t tests and chi-
squared tests for equal proportion where appropriate.
For all comparisons, a two sided = 0.05 was
considered statistically significant.
All calculations were made using SAS, version 8.2
(SAS Institute,Cary, NC, USA).
Results
Results
Basal characteristics were similar in the two
groups. Twenty-nine men (58%) and 21 women
(42%) in Group A and 28 men (56%) and 22 women
(44%) in Group B were studied (P = 0.8). The mean
age for Group A was 39.0 ± 10.70 and for Group B
was 39.28 ± 11.117 years. The age range for both
groups was 20 to 50 years. For Group A, the mean
BMI before administration of the drug was 27.80
kg/m2, which decreased to 27.42 after the treatment
(P = 0.99). For Group B, the mean BMI before drug
administration was 26.75 kg/m2, which decreased to
26.60 after the treatment (P = 0.609; see Table 1).
The mean serum ALT levels in Group B were
113.54 and 73.14 IU/mL before and after treatment
with silymarin, respectively (P = 0.001; see Fig. 1).
The mean serum ALT levels in Group A were 104.54
and 89.92 IU/mL before and after administration of
placebo, respectively (P = 0.237; see Fig. 1).
The percentage of patients with ALT normalization
(ALT < 40) in Group A was 12% (6 patients) after
3 months of therapy which increased to 18% (9
cases) after 6 months. In the sylimarin-treated group,
the figures were 32% (16 patients) after 3 months
and 52% (26 cases) after 6 months. The difference
between the two groups was significant (P = 0.001).
The mean serum AST level in Group A was
73.02 and 66.16 IU/mL before and after treatment
with the placebo, respectively (P = 0.343; see Fig. 2).
The mean serum AST level in Group B was 71.42
and 49.66 IU/mL before and after treatment with
silymarin, respectively (P = 0.006; see Fig. 2).
The percentage of patients with AST normalization
(AST < 40) was 22% (11cases) after 3 months and
20% (10 patients) after 6 month in Group A. The
figures were 46% (23 cases) after 3 month and 62%
(31 patients) after 6 month in the sylimarin-treated
group. The difference between the two groups at the
Variable
Placebo(n:50)
Before After
Treatment Treatment P-value
Sillymarin(n:50)
Before After
Treatment Treatment P-value
P-value
Sillymarin vs. Placebo
Baseline After Treatment
Age (yr) 39.0±10.70 39.28±11.117 NS
Sex (m/f) 29/21 28/22 0.8
BMI 27.80±3.75 27.42±3.35 0.99 26.75 ±2.65 26.60 ±2.53 0.609 0. 098 0.169
Fasting plasma glucose (mg/dl) 106.80±44.97 107.0±45.178 0.97 105.96±35.84 108.34±53.12 0.978 0.920 0.892
2hpp 158.92±64.56 165.60 ±60.63 0.087 161.32±63.72 165.78±64.24 0.986 0.852 0.989
Triglyceride (mg/dl) 261.32±102.02 268.52±102.68 0.66 281.48±116.66 260.16±102.18 0.915 0.360 0.694
Total Cholesterol (mg/dl) 216.18±52.12 220.82±53.79 0.196 235.18±59.25 238.42±59.94 0.999 0.092 0.126
LDL(mg/dl) 135.36±47.45 142.96±47.45 0.941 163.30±49.69 160.42±48.47 0.476 0.005 0.073
HDL(mg/dl) 41.06±6.00 39.40±5.33 0.458 40.58±5.19 40.90±5.75 0.589 0.670 0.179
ALT(U/liter) 104.54±41.82 89.92±41.83 0.237 113.54±50.92 73.14±62.44 0.001 0.363 0.118
AST (U/liter) 73.02±39.62 66.16±27.44 0.343 71.42±66.50 49.66±33.26 0.006 0.884 0.008
ALT<40 number`(%) 0.00 9 (18%) 0.00 26(52%) 0.001
AST<40 number`(%) 0.00 10 (20%) 0.00 31(62%) 0.0001
Table 1.
Table 1. Baseline characteristics of the subjects and outcome at 6 months.
Archive of SID
www.SID.ir
Hepatitis Monthly, Autumn 2009; 9(4): 265-270
Hepatitis Monthly, Autumn 2009; 9(4): 265-270
268
268 Trial of Silymarin in NAFLD
end of therapy was significant (P = 0.0001).
Discussion
Discussion
NAFLD is a disease with genetic, environmental,
metabolic, and stress-related components; the
prevalence of NAFLD has consistently increased
with changes in lifestyle. NAFLD is associated
with a potential risk of progression to cirrhosis,
hepatocarcinoma, and liver failure (19).
Therefore, treatment of NAFLD has drawn wide
attention. In recent studies, there has been increasing
evidence for considering NAFLD as part of a metabolic
syndrome including obesity, hyperinsulinemia,
insulin resistance, hypertriglyceridemia, and
hypertension (20).
However, the molecular mechanisms by which
obesity and diabetes can lead to NAFLD are still
not known. In a recent study, the presence of insulin
resistance and increases in free fatty acids, fatty acids
beta oxidation, and peroxidation of lipids in the liver
were observed in those with NAFLD (21).
There is no strong evidence supporting any
effective therapeutic agents for reducing inflammation
and fibrosis or preventing the progression of NASH.
Nonetheless, weight reduction and the drugs that
overcome oxidative stress may be appropriate to slow
the disease process.
Silybum marianum has been used as an anti-
Figure 1.
Figure 1. ALT levels before and after treatment with silymarin.
Figure 2.
Figure 2. AST levels before and after treatment with silymarin.
Archive of SID
www.SID.ir
Hepatitis Monthly, Autumn 2009; 9(4): 265-270
Hepatitis Monthly, Autumn 2009; 9(4): 265-270
269
269
Seyed Jalal Hashemi et al.
oxidant to protect the liver against toxin in several
studies. The substance has been investigated for
use as a cytoprotectant, an anticarcinogen, and a
supportive treatment for liver damage from Amanita
phalloides poisoning (22, 23).
The active component of the silymarin complex
is silybin, and the main mechanism of its action
is not completely understood, but a variety of
mechanisms have been proposed. For instance,
silymarin is reported to have antioxidant properties,
such as by increasing superoxide dismutase activity
in erythrocytes and lymphocytes (24).
Silymarin has also been reported to stabilize the
hepatocyte membrane structure, thereby preventing
toxins from entering the cell through entero-hepatic
recirculation, and to promote liver regeneration by
stimulating nucleolar polymerase A and increasing
ribosomal protein synthesis (25).
Silybin selectively inhibits leukotriene formation
by Kupffer cells and is a mild chelator of iron. It also
prevents glutathione depletion in human hepatocyte,
protecting cells from damage in vitro (26, 27).
There is a lack of studies about the treatment of
NAFLD in our area, so our trial was compared with
other drugs used in the treatment of NAFLD.
Previous studies that have suggested a therapeutic
role for silybum marianum in NAFLD have either
been uncontrolled and/or were conducted in a
heterogeneous group of patients with fatty livers.
In Caldwell et al. study (28), thiazolidindions were
used in 10 patients; in nine improvements in serum
transaminase level were detected.
In a recent double-blind, randomized controlled
study in Tehran, Merat et al. (29) compared a placebo
with Probucol, which is a lipid-lowering agent with
strong antioxidant properties. In this study liver
tests normalized or were significantly improved
after 6 months of treatment with Probucol. The
authors concluded that the antioxidant effect of
probucol regardless of its lipid-lowering effect was
the responsible mechanism for the normalization of
ALT levels.
In another study, treatment of NASH patients
with vitamin E resulted in significant improvement
in hepatic steatosis and ALP, ALT, and GGT levels
(4).
The effects of ursodeoxycholic acid (UDCA),
a hydrophilic bile acid with hepatoprotective
properties, on NASH were examined in a controlled
trial (5). Use of UDCA was associated with improved
liver enzyme levels and a decrease in hepatic steatosis.
However, the long-term effects and optimal dose of
UDCA have not been established.
Although promising results have been obtained
with silymarin in patients with alcoholic liver disease,
clinical trials have produced conflicting results.
Trails of silymarin in patients with NASH are
limited, but in one study, silymarin treatment
in patients affected by cirrhosis and diabetes was
associated with a reduction of insulin resistance
and a significant decrease in fasting insulin levels,
suggesting an improvement of the activity of
endogenous and exogenous insulin. Given these
findings, this substance presents an interesting option
for the treatment of NAFLD (6).
In one study of 85 consecutive cases of NAFLD
treated with 4 pieces per day of the complex
silymarin-vitamin E-phospholipids for 6 months
followed by another 6 months of follow-up, they
found an improvement in treated individuals,
including insulinaemia, liver enzyme levels, and
degree of steatosis (P < 0.01) (30).
Finally, in a recent study from Iran of 50 NAFLD
patients who were treated with 140 mg of silymarin
for 8 weeks followed by another 2 months of follow
up, the researchers found an improvement in the liver
enzyme levels of the treated individuals (17). In this
study, silymarin extract caused apparent improvement
in serum ALT levels (41% ). Additionally, serum
AST levels decreased from 53.07 to 29.1 IU/mL (P
< 0.001) (17).
In two groups of NAFLD patients with elevated
liver enzymes, we investigated the effects of a
placebo and silymarin on biochemical tests with
higher doses and longer durations of treatment than
previous studies. Although there were no significant
differences between silymarin and the placebo in
decreasing the mean ALT level after therapy, we
found a significantly greater number of patients with
normal ALT at the end of treatment with silymarin:
32% vs. 12 % after 3 months and 52% vs. 18% after
6 months (P = 0.001)
Compared to ALT, silymarin treatment had a
greater impact on the changes in AST level, not only
because AST normalization was more significant in
the silymarin group (62% vs. 20% in the placebo
group; P = 0.0001), but also the decrease in mean
AST level in the silymarin group was significantly
higher than the AST level of the placebo group
(P=0.008).
There were no significant changes in the variables
related to metabolic syndrome, including glucose
metabolism, hyperlipidemia, and BMI before and
after treatment with placebo or silymarin (Table1).
Another finding of the study was that treatment
with silybum marianum in subjects with NAFLD
was safe and well tolerated. Patient compliance with
medication was good in both groups, and all cases
completed the study.
We could not reach a conclusion about the
Archive of SID
www.SID.ir
Hepatitis Monthly, Autumn 2009; 9(4): 265-270
Hepatitis Monthly, Autumn 2009; 9(4): 265-270
270
270 Trial of Silymarin in NAFLD
histological change because we did not biopsy the
patients after the treatment period. In conclusion,
in terms of biochemical improvement, silymarin
treatment is effective in the treatment of NAFLD,
particularly when other drugs have failed or as a
complementary treatment associated with other
therapeutic modalities.
Treatment with silymarin costs less than any other
treatment, and there are negligible side effects. In
the future, our findings must be confirmed in larger
scale studies with pre- and post-treatment biopsies.
Fallow-up of cases to clarify persistent or temporary
effects of the drug on NASH is very important.
References
References
1. Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri
BA. Nonalcoholic steatohepatitis: an expanded clinical
entity. Gastroenterology. 1994;107(4):1103-9.
2. Kim HJ, Lee KE, Kim DJ, et al. Metabolic signicance of
nonalcoholic fatty liver disease in nonobese, nondiabetic
adults. Arch Intern Med. 2004;164(19):2169-75.
3. Noguchi H, Tazawa Y, Nishinomiya F, Takada G. The
relationship between serum transaminase activities and
fatty liver in children with simple obesity. Acta Paediatr
Jpn. 1995;37(5):621-5.
4. Lavine JE. Vitamin E treatment of nonalcoholic
steatohepatitis in children: a pilot study. J Pediatr.
2000;136(6):734-8.
5. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic
acid or clobrate in the treatment of non-alcohol-
induced steatohepatitis: a pilot study. Hepatology.
1996;23(6):1464-7.
6. Velussi M, Cernigoi AM, De Monte A, Dapas F, Caffau C,
Zilli M. Long-term (12 months) treatment with an anti-
oxidant drug (silymarin) is effective on hyperinsulinemia,
exogenous insulin need and malondialdehyde levels in
cirrhotic diabetic patients. J Hepatol. 1997;26(4):871-9.
7. Belfort R, Harrison SA, Brown K, et al. A placebo-
controlled trial of pioglitazone in subjects with nonalcoholic
steatohepatitis. N Engl J Med. 2006;355(22):2297-307.
8. Andersen T, Gluud C, Franzmann MB, Christoffersen P.
Hepatic effects of dietary weight loss in morbidly obese
subjects. J Hepatol. 1991;12(2):224-9.
9. Luyckx FH, Desaive C, Thiry A, et al. Liver abnormalities
in severely obese subjects: effect of drastic weight loss
after gastroplasty. Int J Obes Relat Metab Disord.
1998;22(3):222-6.
10. Palmer M, Schaffner F. Effect of weight reduction on hepatic
abnormalities in overweight patients. Gastroenterology.
1990;99(5):1408-13.
11. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med.
2002;346(16):1221-31.
12. Chitturi S, Farrell GC. Etiopathogenesis of nonalcoholic
steatohepatitis. Semin Liver Dis. 2001;21(1):27-41.
13. Valenzuela A, Garrido A. Biochemical bases of the
pharmacological action of the avonoid silymarin and of its
structural isomer silibinin. Biol Res. 1994;27(2):105-12.
14. Saller R, Meier R, Brignoli R. The use of silymarin in the
treatment of liver diseases. Drugs. 2001;61(14):2035-63.
15. Boerth J, Strong KM. The clinical utility of milk thistle
(Silybum marianum) in cirrhosis of the liver. J Herb
Pharmacother. 2002;2(2):11-7.
16. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker
S. Vitamin E and vitamin C treatment improves brosis
in patients with nonalcoholic steatohepatitis. Am J
Gastroenterol. 2003;98(11):2485-90.
17. Hajaghamohammadi AA, Ziaee A, Raei R. The Efcacy of
Silymarin in Decreasing Transaminase Activities in Non-
Alcoholic Fatty Liver Disease: A Randomized Controlled
Clinical Trial. Hepat Mon. 2008;8(3):191-5.
18. Saverymuttu SH, Joseph AE, Maxwell JD. Ultrasound
scanning in the detection of hepatic brosis and steatosis.
Br Med J (Clin Res Ed). 1986;292(6512):13-5.
19. Sanyal AJ. AGA technical review on nonalcoholic fatty liver
disease. Gastroenterology. 2002;123(5):1705-25.
20. Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty
liver disease: a feature of the metabolic syndrome. Diabetes.
2001;50(8):1844-50.
21. Day CP, James OF. Steatohepatitis: a tale of two “hits”?
Gastroenterology. 1998;114(4):842-5.
22. Jacobs BP, Dennehy C, Ramirez G, Sapp J, Lawrence VA.
Milk thistle for the treatment of liver disease: a systematic
review and meta-analysis. Am J Med. 2002;113(6):506-15.
23. Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ.
Cytokines and NASH: a pilot study of the effects of lifestyle
modication and vitamin E. Hepatology. 2003;38(2):413-9.
24. Feher J, Lang I, Nekam K, Muzes G, Deak G. Effect of
free radical scavengers on superoxide dismutase (SOD)
enzyme in patients with alcoholic cirrhosis. Acta Med Hung.
1988;45(3-4):265-76.
25. Blumenthal M, Goldberg A, Brinckmann J, editors. Herbal
Medicine: Expanded Commission E Monographs. Austin,
TX: American Botanical Council; Newton, MA: Integrative
Medicine Communications; 2000.
26. Masini A, Ceccarelli D, Giovannini F, Montosi G, Garuti
C, Pietrangelo A. Iron-induced oxidant stress leads to
irreversible mitochondrial dysfunctions and brosis in the
liver of chronic iron-dosed gerbils. The effect of silybin. J
Bioenerg Biomembr. 2000;32(2):175-82.
27. Neuman MG, Cameron RG, Haber JA, Katz GG, Malkiewicz
IM, Shear NH. Inducers of cytochrome P450 2E1 enhance
methotrexate-induced hepatocytoxicity. Clin Biochem.
1999;32(7):519-36.
28. Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle
EH, Sheppard BL. A pilot study of a thiazolidinedione,
troglitazone, in nonalcoholic steatohepatitis. Am J
Gastroenterol. 2001;96(2):519-25.
29. Merat S, Malekzadeh R, Sohrabi MR, et al. Probucol in the
treatment of non-alcoholic steatohepatitis: a double-blind
randomized controlled study. J Hepatol. 2003;38(4):414-8.
30. Federico A, Trappoliere M, Tuccillo C, et al. A new silybin-
vitamin E-phospholipid complex improves insulin resistance
and liver damage in patients with non-alcoholic fatty liver
disease: preliminary observations. Gut. 2006;55(6):901-2.
Archive of SID
www.SID.ir
... Similarly, Chahkandi et al. (2023) reported significant biochemical improvements in CLD patients treated with silymarin, specifically in liver enzymes [8]. Studies by Hashemi et al. (2009) and Wah Kheong et al. (2017) further underscored silymarin's efficacy in reducing serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and in achieving fibrosis reduction based on histology and liver stiffness measurements, suggesting its role in fibrosis management in non-alcoholic steatohepatitis (NASH) patients [9,10]. Conversely, another revealed no significant histological improvement in NASH compared to placebo [5]. ...
... Similarly, Chahkandi et al. (2023) reported significant biochemical improvements in CLD patients treated with silymarin, specifically in liver enzymes [8]. Studies by Hashemi et al. (2009) and Wah Kheong et al. (2017) further underscored silymarin's efficacy in reducing serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and in achieving fibrosis reduction based on histology and liver stiffness measurements, suggesting its role in fibrosis management in non-alcoholic steatohepatitis (NASH) patients [9,10]. Conversely, another revealed no significant histological improvement in NASH compared to placebo [5]. ...
... p = 0.038) and lower ALT levels in HCV (67. [9]. Similar results were reported by some of the previous RCTs [5,13,14]. ...
... Hesperidin supplementation demonstrated a considerable decrease in ALT and GGT but not AST [34,35]. Out of seven trials that used silybin and silymarin supplementation, five trials only showed a significant reduction over AST, ALT, and GGT [36,37,[40][41][42]. ...
... Of these 14 trials, seven studies showed significant improvement in blood lipid profile due to turmeric, curcumin, green tea extract, hesperidin, and silymarin [14][15][16]20,33,34,42]. The remaining seven studies involving the consumption of resveratrol [23,25,26], genistein [31], silybin [36], and silymarin [38,40] discovered non-significant amelioration for the whole lipid profile. ...
... In contrast, three studies on resveratrol [23,25,27] and one study on silybin [36] did not discover any significant improvement in TNF-α levels. Similarly, resveratrol and silybin failed to improve the serum levels of CRP [25,27,36], while green tea extract and hesperidin induced a significant amelioration, as shown in Table 1 [34,35,40]. IL-6 levels were reported to be controversial post-supplementation with resveratrol [25,27,28], but genistein supplementation significantly reduced IL-6 [31]. ...
Article
Full-text available
Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a challenging metabolic disorder with a strong emphasis on its prevention and management. Polyphenols, a group of naturally occurring plant compounds, have been associated with a decreased risk of various metabolic disorders related to NAFLD. The current systematic review aims to critically assess evidence about the ameliorative effect of polyphenol supplementation on NAFLD patients. A PRISMA systematic search appraisal was conducted in PubMed, Scopus, Web of Science Core Collection, and all relevant studies published prior to April 2024 and met the inclusion criteria were included. Twenty-nine randomized clinical trials (RCTs) comprised 1840 NAFLD patients. The studies primarily examined eleven phenolic compounds, including turmeric, curcumin, resveratrol, genistein, catechin, green tea extract, hesperidin, and silymarin. Turmeric and curcumin decreased liver enzymes, inflammatory cytokines, lipid profile, insulin resistance, and NAFLD score, while resveratrol did not present consistent results across all the studies. Most studies on silymarin showed a reduction in liver enzymes and lipid profile; however, no changes were observed in inflammatory cytokine levels. The dietary supplementation of hesperidin and naringenin or green tea extract caused improvements in liver enzyme, lipid profile, and inflammatory cytokine, while genistein supplementation did not modulate blood lipid profile. In conclusion, dietary supplementation of polyphenols could potentially prevent and ameliorate NAFLD. Still, the inconsistent results across the included RCTs require further clinical research to establish optimal dosage and duration.
... The mean age of the participants varied from 20 to 63 years old. The trials were performed in Iran [55,56,[59][60][61][62]64,65,[67][68][69][70]72,73,[75][76][77]79,81,82], Italy [52,53,84], the Czech Republic [54,58], Iraq [57,63,66], Malaysia [74], Egypt [71], Pakistan [80,83], and Australia [78]. They were conducted among healthy individuals [54,72,73,78], patients with cirrhosis [52,53], diabetic nephropathy [64], diabetes mellitus [55][56][57]59,63,65,67,70,71,75,77,79,80,83,84], metabolic syndrome [58], hyperlipidemia [66], β-thalassemia major (β-TM) [61], non-alcoholic fatty liver disease (NAFLD) [60,69,76,82], nonalcoholic steatohepatitis [62,68,74], and coronavirus disease 2019 (COVID-19) [81]. ...
... The trials were performed in Iran [55,56,[59][60][61][62]64,65,[67][68][69][70]72,73,[75][76][77]79,81,82], Italy [52,53,84], the Czech Republic [54,58], Iraq [57,63,66], Malaysia [74], Egypt [71], Pakistan [80,83], and Australia [78]. They were conducted among healthy individuals [54,72,73,78], patients with cirrhosis [52,53], diabetic nephropathy [64], diabetes mellitus [55][56][57]59,63,65,67,70,71,75,77,79,80,83,84], metabolic syndrome [58], hyperlipidemia [66], β-thalassemia major (β-TM) [61], non-alcoholic fatty liver disease (NAFLD) [60,69,76,82], nonalcoholic steatohepatitis [62,68,74], and coronavirus disease 2019 (COVID-19) [81]. One study was implemented among women [79] and five among men [54,72,73,77,78], whereas the majority of the trials comprised both sexes. ...
... The mean age of the participants varied from 20 to 63 years old. The trials were performed in Iran [55,56,[59][60][61][62]64,65,[67][68][69][70]72,73,[75][76][77]79,81,82], Italy [52,53,84], the Czech Republic [54,58], Iraq [57,63,66], Malaysia [74], Egypt [71], Pakistan [80,83], and Australia [78]. They were conducted among healthy individuals [54,72,73,78], patients with cirrhosis [52,53] ...
Article
Full-text available
It has been suggested that silymarin (SIL) supplementation has positive effects on cardio-vascular health and reduces the risk of cardiometabolic syndrome (CMS). This systematic review and dose-response meta-analysis assessed the impacts of SIL administration on cardiovascular risk factors. A systematic search of multiple databases was performed to identify eligible controlled trials published up to January 2023. The analysis used a random-effects model and included 33 trials with 1943 participants. It was revealed that SIL supplementation led to a notable reduction in serum levels of fasting blood glucose (FBG) (weighted mean difference (WMD): −21.68 mg/dL, 95% CI: −31.37, −11.99; p < 0.001), diastolic blood pressure (DBP) (WMD: −1.25 mmHg; 95% CI: −2.25, −0.26; p = 0.013), total cholesterol (TC) (WMD: −13.97 mg/dL, 95% CI: −23.09, −4.85; p = 0.003), triglycerides (TG) (WMD: −26.22 mg/dL, 95% CI: −40.32, −12.12; p < 0.001), fasting insulin (WMD: −3.76 mU/mL, 95% CI: −4.80, −2.72; p < 0.001), low-density lipoprotein (LDL) (WMD: −17.13 mg/dL, 95% CI: −25.63, −8.63; p < 0.001), and hemoglobin A1C (HbA1c) (WMD: −0.85%, 95% CI: −1.27, −0.43; p < 0.001) in the SIL-treated groups compared to their untreated counterparts. In addition, there were no substantial differences in body mass index (BMI), systolic blood pressure (SBP), C-reactive protein (CRP), body weight, and high-density lipoprotein (HDL) between the two groups. These outcomes suggest that SIL consumption reduces certain CMS risk factors and has favorable impacts on lipid and glycemic profiles with potential hypotensive effects. These findings should be supported by additional trials with larger sample sizes and longer durations.
... The primary search of the different databases generated 2178 potential records. A total of 571 studies were omitted owing to duplication ( Figure S1) Fried et al., 2012;Gharagozloo et al., 2009;Gordon et al., 2006;Hajaghamohammadi et al., 2008;Hashemi et al., 2009;Heo et al., 2017;Huseini et al., 2004Huseini et al., , 2006Kheong et al., 2017;Luangchosiri et al., 2015;Lucena et al., 2002;Masoodi et al., 2013;Mirhashemi et al., 2022;Mirnezami et al., 2020;Mirzaei et al., 2021;Moayedi et al., 2013;Moezian et al., 2022;Mohaghegh et al., 2015;Momeni et al., 2015;Palasciano et al., 1994;Parés et al., 1998;Ramezani et al., 2008;Razzaq et al., 2011;Rendina et al., 2014;Salmi & Sarna, 1982;Simanek et al., 2001;Solhi et al., 2014;Taghvaei et al., 2013;Valentová et al., 2008). Table S1 shows the RoB assessments of the eligible studies. ...
... Thirty RCTs with 2152 participants (SIL-treated group, n = 1084 and placebo group, n = 1068) were selected for the meta-analysis of AST values following SIL intake (Abbasirad et al., 2021;Ahmed et al., 2022;Anushiravani et al., 2019;Aryan et al., 2022;Di Pierro et al., 2013;Fallah Huseini et al., 2005;Gharagozloo et al., 2009;Hashemi et al., 2009;Heo et al., 2017;Huseini et al., 2004Huseini et al., , 2006Kheong et al., 2017;Luangchosiri et al., 2015;Lucena et al., 2002;Masoodi et al., 2013;Mirhashemi et al., 2022;Mirnezami et al., 2020;Mirzaei et al., 2021;Moayedi et al., 2013;Moezian et al., 2022;Mohaghegh et al., 2015;Palasciano et al., 1994;Parés et al., 1998;Ramezani et al., 2008;Razzaq et al., 2011;Salmi & Sarna, 1982;Simanek et al., 2001;Solhi et al., 2014;Taghvaei et al., 2013;Valentová et al., 2008) (Figure 1) ...
... Thirty-four studies (38 trial arms; 2393 participants) explored the impact of SIL supplementation on serum ALT levels (Abbasirad et al., 2021;Ahmed et al., 2022;Anushiravani et al., 2019;Aryan et al., 2022;Di Pierro et al., 2013;Fallah Huseini et al., 2005;Fried et al., 2012;Gharagozloo et al., 2009;Gordon et al., 2006;Hajaghamohammadi et al., 2008;Hashemi et al., 2009;Heo et al., 2017;Huseini et al., 2004Huseini et al., , 2006Kheong et al., 2017;Luangchosiri et al., 2015;Lucena et al., 2002;Masoodi et al., 2013;Mirhashemi et al., 2022;Mirnezami et al., 2020;Mirzaei et al., 2021;Moayedi et al., 2013;Moezian et al., 2022;Mohaghegh et al., 2015;Palasciano et al., 1994;Parés et al., 1998;Ramezani et al., 2008;Razzaq et al., 2011;Rendina et al., 2014;Salmi & Sarna, 1982;Simanek et al., 2001;Solhi et al., 2014;Taghvaei et al., 2013;Valentová et al., 2008). The pooled results showed that SIL effectively reduced serum ALT concentrations in SIL-treated groups (n = 1243) compared with their untreated counterparts (n = 1167) (WMD: À9.72 IU/L, 95% CI: À12.44, À7; ...
Article
Full-text available
It is suggested that supplementation with silymarin (SIL) has beneficial impacts on kidney and liver functions. This systematic review and dose-response meta-analysis assessed the impact of SIL administration on certain hepatic, renal, and oxidative stress markers. A systematic search was conducted in various databases to identify relevant trials published until January 2023. Randomized controlled trials (RCTs) that evaluated the effects of SIL on kidney and liver markers were included. A random-effects model was used for the analysis and 41 RCTs were included. The pooled results indicated that SIL supplementation led to a significant reduction in serum levels of alkaline phosphatase, alanine transaminase, creatinine, and aspartate amino-transferase, along with a substantial elevation in serum glutathione in the SIL-treated group compared to their untreated counterparts. In addition, there was a nonsignifi-cant decrease in serum levels of gamma-glutamyl transferase, malondialdehyde (MDA), total bilirubin, albumin (Alb), total antioxidant capacity, and blood urea nitrogen. Subgroup analyses revealed a considerable decline in MDA and Alb serum values among SIL-treated participants with liver disease in trials with a longer duration (≥12 weeks). These findings suggest that SIL may ameliorate certain liver markers with potential hepatoprotective effects, specifically with long-term and high-dose supplementation. However, its nephroprotective effects and impact on oxida-tive stress markers were not observed. Additional high-quality RCTs with longer durations are required to determine the clinical efficacy of SIL supplementation on renal and oxidative stress markers.
... All of which have anti-inflammatory, anti-fibrotic, and antioxidant effects [17][18][19]. Moreover, evidence from placebo-controlled randomized clinical trials (RCTs) showed that silymarin significantly reduced levels of liver transaminase enzymes (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) in NAFLD and NASH patients [20,21]. A 2017 meta-analysis that included eight RCTs involving 587 patients with NASH also reported that silymarin successfully reduced transaminases levels in this population [22]. ...
... Therefore, it was decided that the patient no longer needs to continue with our investigational product and will be referred to a dermatologist for treatment the treatment and control groups in terms of HDL, LDL, total cholesterol, and triglyceride levels change. A prior placebo-controlled trial (n = 100) showed no significant change in the lipid profile levels between the experimental and control groups [21]. Several studies revealed the same results [32,40]. ...
Article
Full-text available
Background Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) characterized by damage and inflammation of hepatocytes. Some medicinal plants have shown antioxidant and anti-inflammatory effects on liver cells. We aimed to investigate the hepatoprotective effect of Heptex® capsules containing 200 mg of Dukung Anak (a powdered extract from aerial parts of Phyllanthus niruri) and 100 mg of Milk Thistle (a powdered extract from fruits of Silybum marianum) in patients with an apparent risk factor for NASH. Methods This was a phase II, randomized, double-blind, placebo-controlled, three-arm, interventional clinical trial. Patients were randomized in a 1:1:1 ratio to receive placebo, low dose (one capsule) of Heptex®, or high dose (two capsules) of Heptex®. After 36 weeks, liver enzymes, Fib-4 score, lipid profile, CAP score, and kPa score were evaluated. Patients were monitored for safety throughout the treatment duration. Results A total of 146 patients were enrolled in the study. A significant decrease was observed in ALT levels in the low-dose group (57 IU/L to 40 IU/L, p = 0.026) and the high-dose group (61 IU/L to 47.5 IU/L, p < 0.0001) and in AST levels in the high-dose group (43.5 IU/L to 32 IU/L, p = 0.001), with no significant difference between the relative percent change in ALT (p = 0.465) or AST (p = 0.632) between the three groups. No significant difference was revealed between the three groups regarding the median change in Fib-4 score at the end of treatment (p = 0.985). No significant change in the lipid profile was observed in any of the three groups except for the total cholesterol level, which significantly decreased from 210 IU/L to 187 IU/L, p = 0.031 in the low-dose group. Conclusion Heptex® capsules were safe and well tolerated over a treatment period of 36 weeks. However, the hepatoprotective effect in patients at risk of NASH still needs further assessment using more accurate investigation tools, a larger sample size, and/ or higher doses of the combination. Trial registration Retrospectively registered (registration date: 25/04/2022; trial registration number: NCT05343780)
... Silymarin is a flavonolignan fraction of milk thistle (Silybum marianum (L.) Gaertner), comprising mainly silybin, silydianin, silychristin, and isosilybin. The seeds of milk thistle have a long history of use in liver disorders [53]. The use of milk thistle (silymarin) is believed to have several potential benefits in the field of hepatology. ...
... A total of 676 patients diagnosed with various liver conditions, including NAFLD, NASH, acute/chronic hepatitis, cirrhosis, and other liver disorders, were included in the studies (Table S7) to evaluate the impact of silymarin on liver health outcomes [53][54][55][56][57][58][59][60]. The patients ranged in age from 29 to 63 years old. ...
Article
Full-text available
The hepatoprotective effects of natural products have been a significant focus in recent decades due to the growing demand for the help in the treatment of hepatic impairments. This review specifically delves into the findings of clinical trials involving 13 selected natural products, namely plants and their derived compounds (e.g., artichoke, berberine, and turmeric), algae (e.g., spirulina), probiotics, and other products like phospholipids and vitamin D. A literature search was performed in the Scopus database, PubMed, and Google Scholar, covering all articles found up to June 2024. Artichoke, berberine, chlorella, chicory, green tea, probiotics, phospholipids, schisandra, silymarin, spirulina, and vitamin D caused a decrease in liver enzymes, while for cinnamon and turmeric such an effect was either not observed or not convincing. The presented results indicate that some natural products might satisfactorily improve hepatic outcomes in NAFLD, NASH, and other liver disorders; however, further studies and metanalyses are needed to clearly demonstrate their effectiveness.
... Silymarin is well-recognized for its therapeutic liver-protecting activity, which is attributed to its antioxidant, antifibrosis, detoxification, and hepatocyte-protection properties [2,3]. There have been many clinical studies that report the benefits of silymarin in treating various liver disorders [4], such as viral hepatitis [5,6], alcoholic liver disease [7], and nonalcoholic liver disease [8,9]. ...
Article
Full-text available
Backgroud/Objectives: Silymarin, an extract from milk thistle, is widely recognized for its therapeutic potential in treating liver disorders. However, its clinical utility is limited by the poor solubility and low bioavailability of its key active ingredient, Silybin. In this study, we sought to address this issue through the development of a novel cocrystal of Silyin. Methods: Silybin-L-proline cocrystal was synthesized and the physicochemical properties of the cocrystal were characterized by PXRD, TGA, DSC, and FTIR. Dissolution tests were conducted in various pH solutions, and the impact of precipitation inhibitors was evaluated. Furthermore, pharmacokinetic study in rats were performed to assess the bioavailability. Results: The dissolution studies demonstrated that the cocrystal has a significant improvement in dissolution performance, particularly in acidic environments. Furthermore, the use of precipitation inhibitors, such as PVP, prolonged the supersaturation period for adequate absorption. Pharmacokinetic studies in rats revealed that the cocrystal exhibited a 16-fold increase in bioavailability compared to the raw Silybin extract, outperforming the commercial Silybin–phosphatidylcholine complex. Conclusions: The Silybin–L-proline cocrystal significantly enhances dissolution and bioavailability, indicating its potential to improve the therapeutic efficacy of Silybin in clinical applications.
... The RCTs included in this study involved three polyphenols: curcumin, resveratrol, and silymarin. Twenty seven eligible studies met the inclusion and exclusion criteria and were included in the study (Anushiravani et al. 2019;Beheshti Namdar et al. 2023;Chachay et al. 2014;Chen et al. 2015;Cicero et al. 2020;Faghihzadeh et al. 2014;Farzin et al. 2020;Hashemi, Eskandar, and Sardabi 2009;Ghaffari et al. 2019;He et al. 2024;Heeboll et al. 2016;Jarhahzadeh et al. 2021;Jazayeri-Tehrani et al. 2019;Kalhori et al. 2022;Kantartzis et al. 2018;Loguercio et al. 2012;Masoodi, Panahian, and Vojdanian 2013;Mirhafez, Azimi-Nezhad, et al. 2021;Moradi Kelardeh et al. 2020;Navarro et al. 2019;Navekar et al. 2017;Panahi et al. 2017;Panahi et al. 2019;Rahmani et al. 2016;Saadati et al. 2019;Saberi-Karimian et al. 2020;Safari et al. 2023;Solhi et al. 2014;Wah Kheong, Nik Mustapha, and Mahadeva 2017). Some records are merged because they belong to the same RCTs. ...
Article
Full-text available
Polyphenols, known for their potent antioxidant and anti‐inflammatory properties, have emerged as promising, natural, and safe complementary treatment options for metabolic‐associated steatotic liver disease (MASLD). Among these, curcumin, resveratrol, and silymarin are the most extensively studied; however, their differential effects on MASLD outcomes remain inconclusive. This systematic review and meta‐analysis of RCTs aimed to evaluate the efficacy of curcumin, resveratrol, and silymarin in patients with MASLD. A comprehensive search of seven databases was conducted up to September 2024. Odds ratios (OR), mean differences (MD), and standardized MD (SMD) with 95% confidence intervals (CI) were used to assess treatment effects. Primary outcomes included improvement in hepatic steatosis and ALT activity, while secondary outcomes included changes in AST activity, blood lipids, glucose, BMI, blood pressure, and TNF‐α. Twenty‐seven studies involving 1691 participants were included. Curcumin significantly improved hepatic steatosis compared to placebo (OR: 4.39, 95% CI: 1.45 to 13.27, p = 0.009), followed by resveratrol (OR: 3.18, 95% CI: 1.20 to 8.42, p = 0.02). Silymarin exhibited the strongest effect in reducing ALT levels (MD: −6.44 U/L, 95% CI: −10.03 to −2.85, p = 0.0004), with curcumin (MD: −5.88 U/L, 95% CI: −9.05 to −2.72, p = 0.0003) also showing significant reductions. A marked reduction in AST was observed with silymarin (MD: −6.99 U/L, 95% CI: −8.56 to −5.42, p < 0.00001), followed by curcumin (MD: −3.36 U/L, 95% CI: −5.35 to −1.36, p = 0.001). Furthermore, curcumin intake significantly improved metabolic indicators (TG, FBG, HOMA‐IR, and BMI). Resveratrol reduced FBG and DBP. Curcumin had the strongest effect on hepatic steatosis and improved both transaminase levels and metabolic markers. Silymarin demonstrated the greatest reduction in transaminase levels, while resveratrol showed modest benefits in steatosis and metabolic improvements. The three polyphenols appear as promising therapeutics for the treatment of MASLD.
... Nonalcoholic steatohepatitis (NASH) is histologically characterized by significant accumulation of hepatic lipid and predominantly lobular necroinflammation, with or with out centrilobular fibrosis. NASH is histologically similar to alcoholic liver disease, but without a history of ingesting significant amounts of ethanol [7]. ...
Article
Full-text available
Non alcoholic steatohepatitis (NASH) is a pathological condition characterized by accumulation of lipids in the liver of non alcoholic individuals and consequent oxidative stress leading to cirrhosis of liver in the long run. Silymarin is a unique flavonoid complex extract isolated from seeds of the milk thistle plant (Silybum marianum) and has strong antioxidant and radical scavenging properties. The present research aimed to evaluate the therapeutic effects of silymarin (Slym) as natural antioxidant and anti-inflammatory on liver tissue of male rats exposed to experimental model of non alcoholic steatohepatitis (NASH) induced by supplementation of high fat diet (HFD) for 3 months, Through evaluation of serum Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP) and Gamma Glutamyl-Transferase (γ-GT) activities and Albumin, Total Protein, Total Bilirubin, Total Cholesterol and triglycerides concentrations. Levels of reduced glutathione (GSH) and activities of Superoxide Dismutase (SOD) and Catalase (CAT), were determined in liver tissues. Extent of oxidative stress was also assessed by hepatic lipid peroxides (MDA). HFD supplementation induced a significant increase in 1) serum ALT, AST, ALP and γ-GT activities, in addition to Total Bilirubin, Total Cholesterol and triglycerides concentrations. 2) Liver MDA concentration. On contrast, it exhibited a significant decrease in serum Albumin and Total Protein, also marked depletion in liver GSH, CAT and SOD, were observed after HFD supplementation. Silymarin treatment was able to mitigate and ameliorate hepatic NASH induced by HFD and showed pronounced curative effect against lipid peroxidation and deviated serum enzymatic variables as well as maintained glutathione status and antioxidant enzymes toward control levels. Silymarin treatment was highly effective against HFD induced NASH. The results of the present study suggest that silymarin has the potential to exert curative effects against liver NASH.
Article
Full-text available
Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition affecting a broad population. This review aimed to identify and summarize the current evidence on bioactive-substance-based interventions for adults with MASLD, formerly known as nonalcoholic fatty liver disease (NAFLD), covering publications from 2000 to 2023. Methods: A search was conducted across six databases (MEDLINE, CINAHL, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, Food Science Source, and SPORTDiscus) for randomized controlled trials and other study types (e.g., prospective cohort studies and systematic reviews), reflecting the scoping nature of this review. The search was limited to studies in adults (>18 years old), with an intervention of interest and at least one comparator group. Results: A total of 4572 articles were retrieved, with 201 full-text articles screened for eligibility. Of these, 131 primary studies and 49 systematic reviews were included in the scoping review. The most studied bioactive substances were Curcumin (Turmeric) (n = 25), Silymarin (Milk Thistle) (n = 17), Resveratrol (n = 10), Coffee (n = 7), Green Tea (n = 5), and Berberine (n = 5 each). Moreover, 46 studies reported on 36 other bioactive substances with 2 or fewer articles each. Among the included systematic reviews, 13 focused on Curcumin, 12 on Coffee or Tea, 10 on bioactive substance combinations, 6 on Resveratrol, and 2 each on Silymarin and Artichoke Leaf. The included studies showed substantial heterogeneity in reported outcomes, which primarily focused on hepatic health, body weight, adverse events, glycemic control, blood lipids, and body composition. Conclusions: This scoping review highlights a range of bioactive substances used in the treatment of MASLD. While evidence is abundant for bioactive substances like Curcumin and Silymarin, further research and synthesis of findings is necessary to establish the clinical efficacy of all bioactive substances.
Article
Full-text available
To examine the factors associated with liver steatosis in severely obese subjects and to test the potential reversibility of fatty liver after weight loss. Retrospective clinical study. 528 obese patients before bariatric surgery and 69 obese subjects of the initial cohort evaluated before and 27+/-15 months after gastroplasty. Fatty deposition (scored as mild, moderate or severe) and inflammatory changes were evaluated in liver biopsies; clinical (body mass index (BMI), age, gender, duration of obesity) and biological (glucose, triglycerides, liver enzymes) parameters were related to histological findings. 74% of the 528 biopsies showed fatty change, estimated as mild in 41% of cases, moderate in 32% and severe in 27%. The prevalence of steatosis was significantly higher in men than in women (91% vs 70%, P = 0.001) and in patients with impaired glucose tolerance or type 2 diabetes compared with nondiabetics (89% vs 69% P = 0.001). The severity of the steatosis was associated with BMI (P = 0.002) but not with the duration of obesity or the age of the patient. When compared with patients without fatty change, those with liver steatosis had significantly higher fasting plasma glucose (5.5 mmol/l vs 5.1 mmol/l, P = 0.007) and triglycerides (1.8 mmol/l vs 1.3 mmol/l, P = 0.002). Mean serum liver enzyme activities (alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl-transpeptidase (gammaGT) were significantly (P < 0.001) increased in patients with fatty change but remained within laboratory reference values. In the 69 patients who have been evaluated after a marked weight reduction (-32+/-19kg), 45% of the biopsies were considered as normal (vs 13% before, P < 0.001) while pure fatty change was still observed in 38% of the patients (vs 83% before, P = 0.001). However, the severity of the steatosis was significantly (P < 0.001) reduced (mild: 62% vs 21%; moderate: 23% vs 37%; severe: 15% vs 42%). In addition, a significant increase of hepatitis was observed in 26% of the biopsies (vs 14% before, P < 0.05). Liver steatosis in obese subjects is associated with men, diabetic status, BMI, higher fasting glucose and hypertriglyceridaemia. Postgastroplasty weight loss reduces liver steatosis, but seems to increase the incidence of inflammatory lobular hepatitis.
Conference Paper
Aim: To determine whether supplemental oral vitamin E is effective in lowering serum aminotransferase and alkaline phosphatase levels in children with nonalcoholic steatohepatitis (NASH) associated with obesity. Study design: Open-label pilot study enrolling all children <16 years old with chronically elevated serum am;notransferase (alanine aminotransferase and aspartate aminotransferase) levels for greater than 3 months, who demonstrated a diffusely echogenic liver on ultrasonography, had no demonstrable reason for abnormal serum chemistry values other than obesity, and therefore were diagnosed to have NASH. Patients were prescribed oral Vitamin E between 400 and 1200 IU per day. Serum chemistry values were monitored monthly during treatment. Results: Eleven subjects with a mean age of 12.4 years were enrolled; treated patients were followed up for 4 to 10 months. The body mass index did not change significantly before and after treatment (32.8 +/- 3.8 kg/m(2) vs 32.5 +/- 4.4 kg/m(2), respectively). Serum alanine aminotransferase decreased from 175 +/- 106 IU/L to 40 +/- 26 IU/L (P < 001, paired Student I test), serum aspartate aminotransferase decreased from 104 +/- 61 IU/L to 33 +/- 11 IU/L (P <.002, and alkaline phosphatase decreased from 279 +/- 42 IU/L to 202 +/- 66 IU/L (P <.003) during treatment. Serum aminotransferase levels remained normal during treatment but returned to abnormal in those electing to stop treatment. Serum alpha-tocopherol levels were within the normal range before the commencement of therapy and increased significantly with supplementation. The liver remained diffusely echogenic during therapy, at the time serum aminotransferase levels were reduced. Conclusions: Daily oral vitamin E administration normalized serum aminotransferase and alkaline phosphatase levels in children with NASH. Obese children with NASH should le encouraged to lose weight as part of a comprehensive weight reduction program and to consider taking supplemental alpha-tocopherol.
Article
Non-alcohol-induced steatohepatitis (NASH) is characterized by elevated serum aminotransferase activities with hepatic steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Our aim was to conduct a pilot study to evaluate the safety and estimate the efficacy of ursodeoxycholic acid (UDCA) and clofibrate in the treatment of NASH. Forty patients were diagnosed with NASH based on a compatible liver biopsy with other causes of liver disease, including alcohol abuse, excluded by history, serum tests, and use of ultrasound. Twenty-four patients received 13 to 15 mg/kg/d of UDCA for 12 months. Sixteen patients with hypertriglyceridemia were placed on clofibrate, 2 g/day for 12 months. Twenty-five women and 15 men entered the study. Six of 40 patients (15%) withdrew because of side effects. Four additional patients were withdrawn because of noncompliance; one of them later required liver transplantation. In the UDCA group, the decreases in mean serum levels of alkaline phosphatase, alanine transaminase (ALT), and gamma-glutamyl transpeptidase (GGT) as well as histological grade of steatosis were significant. Among the patients treated with clofibrate, no change from baseline was found in mean ALT, aspartate transaminase (AST), GGT, bilirubin, triglycerides, and cholesterol, or in histological grade of steatosis, inflammation, or fibrosis after 12 months of treatment as compared with entry. Alkaline phosphatase activities decreased significantly from baseline. Despite the known lipid-lowering effects of clofibrate, it did not appear to be of clinical benefit in the treatment of NASH in this 1-year pilot study. However, treatment of NASH with UDCA for 12 months resulted in significant improvement in alkaline phosphatase, ALT, GGT, and hepatic steatosis. The possible benefit of UDCA therapy should be further investigated in the context of a randomized, controlled trial. (Hepatology 1996 Jun;23(6):1464-7)
Article
PurposeMilk thistle, an herbal compound, is the dietary supplement taken most frequently by patients with chronic liver disease. We performed a systematic review of the literature to determine the efficacy and safety of this herb for the treatment of liver disease.
Chapter
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in North America, affecting approximately 30% of the population [1]. It is the hepatic manifestation of the metabolic syndrome, and is directly linked to the escalating prevalence of obesity and the associated insulin resistance. Histologically, NAFLD is characterized by a spectrum that ranges from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) which can progress to cirrhosis in 15–20% of subjects [2]. NASH is further distinguished from NAFL by the presence of inflammation and cytologic ballooning with or without Mallory hyaline or pericellular fibrosis in addition to steatosis [3]. Recently, studies have reported that NAFLD may predispose patients to hepatocellular carcinoma (HCC) in the absence of significant fibrosis or cirrhosis, and these subjects also seem to have more features of the metabolic syndrome [4].
Article
Hepatic iron toxicity because of iron overload seems to be mediated by lipid peroxidation ofbiological membranes and the associated organelle dysfunctions. However, the basicmechanisms underlying this process in vivo are still little understood. Gerbils were dosed with weeklyinjections of iron—dextran alone or in combination with sylibin, a well—known antioxidant,by gavage for 8 weeks. A strict correlation was found between lipid peroxidation and the levelof desferrioxamine chelatable iron pool. A consequent derangement in the mitochondrialenergy-transducing capability, resulting from a reduction in the respiratory chain enzymeactivities, occurred. These irreversible oxidative anomalies brought about a dramatic drop intissue ATP level. The mitochondrial oxidative derangement was associated with thedevelopment of fibrosis in the hepatic tissue. Silybin administration significantly reduced bothfunctional anomalies and the fibrotic process by chelating desferrioxamine chelatable iron.
Article
To study the effect of cytochrome P450 2E1-inducers on methotrexate (MTX)-induced cytotoxicity in human hepatocytes, and investigate the role of silymarin in preventing this toxicity. Cells were exposed to MTX in the presence of either ethanol (EtOH) or acetaminophen (APAP), or either combined with silymarin (S). Apoptosis and necrosis were measured by analyzing 6000 cells/sample using transmission electron microscopy, while cytokine release and apoptosis were quantitated by ELISA. Cytokine expression was measured by RT-PCR. Gluthatione (GSH) content was determined in cytosolic (c) and mitochondrial (m) fractions. MTX+EtOH and MTX+APAP increased MTX cytotoxicity 2.9-fold and 1.9-fold, respectively. S abolished this toxicity. MTX + EtOH increased the release of IL 6, IL 8 and TNF alpha by 1.0, 1.2, and 1.1 times, respectively. Cytokine expression was upregulated versus control for IL 6 (22%), IL 8 (38%), and TNF alpha (29%). Addition of 0.5 mmol/L S downregulated TNF alpha expression and reduced cytokine release. TNF alpha increased cytotoxicity by 22%, while anti-TNFalpha antibody eradicated it. MTX+EtOH depleted 45% mGSH (0 < 0.001) while S replenished it to 87% (p < 0.001), when both were compared to control levels. Cytochrome P450 2E1-inducers contribute to increase oxidative stress in MTX-exposed cells by increasing TNF alpha and depleting both cGSH and mGSH. This enhances MTX-cytotoxicity and promotes apoptosis.
Article
Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of increased liver enzymes. According to statistical reports, 20%-40% of Western population and 5%-30% of the population of Pacific and Asian countries are afflicted with this disease. The prevalence of NAFLD is higher in hyperlipidemic, diabetic and obese people. Considering the high prevalence of NAFLD and its complications and lack of consensus on its treatment, we were motivated to study the efficacy of silymarin on this disease. Methods: In this randomized clinical trial, 50 patients including 32 men (64%) and 18 women (36%) were divided into case and control groups. The mean age of case group was 40.3 and for control group was 39.9 years. All patients had elevated liver enzymes and had increased liver echogenicity (lipid accumulation) on sonography. The case group was treated with one tablet containing 140 mg silymarin per day for two months and the control group was treated in the same manner with placebo. Before and after the study, weight, body mass index (BMI) and liver transaminases levels were measured for each patient.Results: The difference between the mean weight and BMI measured before and after the study was not statistically significant in both case and control groups. But the mean ALT and AST levels deceased from 103.1 to 41.4 and 53.7 to 29.1 IU/mL, respectively in case group which was statistically significant (P<0.001 & P<0.001). In the control group, the decrease in mean ALT and AST, with decrease of 7.8 and 2.2 IU/mL, respectively, was not statistically significant.Conclusions: Considering the significant drop in liver enzymes following administration of silymarin, it seems that after conducting similar studies in order to determine the appropriate doses and treatment periods, this cheap and easy to access drug can be prescribed for treatment of NAFLD.