4 | DISCUSSION
In this systematic review and meta-analysis, we summarized published
evidence from five RCTs that investigated effect of
BBR–silymarin on
liver enzymes (ALT and AST)
levels. To the best of our knowledge, this systematic review and
meta‐analysis is the first one that examined the effect of
BBR–silymarin supplementation on liver enzyme levels. The results of
the review showed that supplementation with BBR–silymarin had no
significant effect of on ALT and AST, in supplementation group compared
with placebo group in both sexes including men and women with liver
complications.
In the previous studies the effect of BBR and silymarin investigated
separately and observed beneficial effects to decrease liver enzymes
with BBR [31, 32]. Also studies represented that BBR was effective
to treat NAFLD [43]. The half-life of BBR in liver is longer than
that in other tissues, and these results may explain that liver is the
main target tissue of BBR [44]. BBR due to the presence of P-gp have
low oral bioavailability and low oral bioavailability can be improve by
P-gp inhibitors such as silymarin. recently trials are experimenting on
the nutraceutical combination of berberis aristata plus-silybum
marianum to treat NAFLD [45].
BBR has been previously shown that decreases transaminase levels,
reducing liver necrosis in hepatitis C infection [31] and has an
effectiveness in decreasing serum triglyceride and serum level of ALT
and AST within 48 hours in patients with NAFLD [32]. In case of
total cholesterol [9, 46, 47] it seems that the hypocholesterolemic
potential of BBR supplementation intensifies when is combined with
statin therapy [6, 48, 49].
There were also few studies that did not report
the effectiveness of silymarin on
liver enzymes. A clinical trial of silymarin treatment in patients with
cirrhosis of the liver showed liver function tests, such as
ALT, bilirubin and alkaline
phosphatase had no difference between the two study groups [50]. But
other studies have also reported different result; a double blind study
in 60 female patients were treated with antipsychotics (phenothiazines
or butyrophenones) drugs plus 800 mg/day silymarin represent serum
levels of AST or ALT decreased at least twice the normal values after 90
days, in receiving silymarin versus the placebo group, and no
significant change within the γGT levels [33]. Moreover, in another
trial 140 mg, Livergol capsule per day for 30 days reported a
statistically significant difference between the two groups in terms of
AST and ALT enzymes as the level of liver enzymes in the intervention
group was lower than that in the control one, at the end of the study
[34]; and a review article
which published in 2001 showed in person with chronic alcoholic liver,
silymarin treatment, normalized serum bilirubin, AST , ALT values, and
γ-GT activity levels decreased in the silymarin supplementation groups
[35, 36].
Dosage and duration are two important factors which may affect final
results of clinical trials. Included studies in this met-analysis used
different doses for their intervention. Silymarin; berberine
supplementation was used in a study [9] with a dose of 300 mg
silymarin compare to other study which its participants used 210 mg/day.
Studies have found that milk thistle, alone or in combination with
vitamin E, may help reduce insulin resistance, inflammation and liver
damage in people with NAFLD [4, 51-53] and the dosages of silymarin
utilized in these studies was 140–800 mg/day, so increase in silymarin
dosage may be helpful but further studies are needed to test to prove
it.
BBR
by regulation of hepatic lipids [19, 20], glucose metabolism
[20], and anti-inflammatory effect [21-25] play a role in
improving the NAFLD. BBR
significantly decreased Hepatic Fat Content (HFC) in the rats with high
fat diet induced NAFLD by decreasing methylation of the microsomal
triglyceride transfer protein (MTTP) promoter (13). Regulation of
AMP-activated protein kinase
(AMPK) independent mechanism for
BBR to suppress obesity-associated inflammation and alleviate hepatic
steatosis [21-23] decrease Cyclooxygenase-2 (COX-2), and mRNA levels
of proinflammatory cytokines, resulting in an anti-inflammation effect
[24, 25]. BBR also reduced rates of glucose appearance (Raglu),
gluconeogenesis (GNG) and hepatic lipogenesis [20] and alleviated
insulin sensitivity via activation of AMPK.
Silymarin is another component
used along with BBR may increase SOD, GSH, and GPx activity. Silymarin
is another component of berberol, increases Superoxide dismutase (SOD)
glutathione and glutathione
peroxidase (GPx) activity. Additionally Silymarin improved hepatic
fibrosis [26], decreased the hepatic levels of hydroxyproline and
connective tissue growth factor (CTGF) [28], and inhibition of the
5-lipoxygenase pathway particularly LTB4 are the major targets of
Silymarin in the treatment of NAFLD [29].
Despite the present study was the first to investigate the effects of
berberis aristate and Silybum marianum on liver enzymes, our
meta-analysis has some limitations. First, there were only a few
eligible RCTs in this meta-analysis, and most of them had a relatively
small population, thus performing further studies with a bigger
population is needed to determine whether BBR–silymarin is not
effective on controlling/lowering ALT and AST levels. Second, studies
that were included had heterogeneous patient characteristics.
Ultimately, the included studies enrolled only on adult subjects, so we
cannot directly infer our studies’ results to children and the elderly.