Silymarin: Uses, Benefits, Composition, Side Effects and Mechanism of Action

It is the extract of Silybum marianum, or milk thistle, and its main active compound is silybin, which has a remarkable biological effect.

It is used in different liver disorders, particularly in chronic liver diseases , cirrhosis and hepatocellular carcinoma, due to its antioxidant, anti-inflammatory and antifibrotic power.

The most frequent liver diseases are inflammatory in nature, having different etiologies and characteristics.

The most common causes of chronic inflammatory liver diseases are viral infections (hepatitis B and C viruses), autoimmune diseases, alcoholic liver disease, and nonalcoholic fatty liver disease (NAFLD).

Other diseases also occur with inflammation, such as chronic biliary diseases, inherited metabolic diseases, and liver attacks by hepatotoxic substances.

Méndez-Sánches et al have estimated approximately two million cases of chronic liver disease by the year 2050.

Nutritional treatment comprises a fundamental step in the clinical treatment of these patients, as well as in:

The minimization and / or postponement of the common symptoms in these diseases and the prescription of herbal medicines can be a complementary tool to conventional dietary strategies.

In fact, the antioxidant and anti-inflammatory effect of Silymarin is geared towards reducing virus-related liver damage through cascade inflammatory softening and modulation of the immune system.

It also has a direct antiviral effect associated with its intravenous administration in hepatitis C virus infection. Regarding alcohol abuse, Silymarin can increase cell vitality and reduce lipid peroxidation and cell necrosis.

In addition, the use of Silymarin has important biological effects in nonalcoholic fatty liver disease.

These substances antagonize the progression of non-alcoholic fatty liver disease, intervening in several therapeutic targets: oxidative stress, insulin resistance, fat accumulation in the liver and mitochondrial dysfunction.

Silymarin is also used in liver cirrhosis and hepatocellular carcinoma, which represent common end stages of different liver diseases by modulating different molecular patterns.

Silymarin Ingredients

Silymarin is part of the group of flavonoids and is extracted from the plant Silybum marianum, a herbal remedy that has been extensively studied in various liver disorders.

It is composed of approximately 50% silibinin, which is considered the biologically active component of Silymarin.

Silybum marianum is one of the most widely used plants in liver disease treatments, as it is considered hepatoprotective and has been widely used in patients with cirrhosis, chronic hepatitis, and liver disease associated with alcohol consumption and exposure to environmental toxins.

Silybum marianum has other common names, such as cardus marianus, milk thistle, milk thistle, milk thistle, milk thistle, St. Mary’s thistle, Mediterranean milk thistle, variegated thistle, and Scottish thistle (though not to be confused with Onopordum acanthium).

This species is an annual or biennial plant of the Asteraceae family. This fairly typical thistle has red to purple flowers and glossy pale green leaves with white veins. Originally native to southern Europe through Asia, it is now found throughout the world.

Traditional milk thistle extract is made from seeds, which contain approximately 4-6% Silymarin. The extract consists of approximately 65–80% Silymarin (a flavonolignan complex) and 20–35% fatty acids, including linoleic acid.

Silymarin is a complex mixture of polyphenolic molecules, which includes seven closely related flavonolignans (silybin A, silybin B, isosilibin A, isosilibin B, siliquistin, isosilistristin, silidianin) and a flavonoid (taxifolin).

Silibinin, a semi-purified fraction of Silymarin, is primarily a mixture of 2 diastereoisomers, Silybin A and Silybin B, in a ratio of approximately 1: 1.

Currently, it is one of the most studied medicinal herbs for the treatment of nonalcoholic liver disease and nonalcoholic steatohepatitis (NASH) and its use has been shown to be safe, well tolerated, with limited adverse effects also for these groups of patients.

Uses and benefits of Silymarin

In chronic liver diseases caused by oxidative stress (alcoholic and non-alcoholic fatty liver diseases, drug- and chemical-induced liver toxicity), antioxidant medications such as Silymarin may have a beneficial effect.

Liver cirrhosis, nonalcoholic fatty liver, and steatohepatitis are risk factors for hepatocellular carcinoma (HCC).

Insulin resistance and oxidative stress are the main pathogenetic mechanisms that lead to liver cell damage in these patients.

Silymarin exerts antioxidant and membrane stabilizing activity, promotes the regeneration of hepatocytes; Furthermore, it reduces the inflammatory reaction and inhibits fibrogenesis in the liver.

These results have been established by experimental and clinical trials. According to open studies, long-term administration of Silymarin significantly increases the survival time of patients with alcohol-induced liver cirrhosis.

Based on the results of studies using molecular biology methods, Silymarin can significantly reduce tumor cell proliferation, angiogenesis, and insulin resistance.

Furthermore, it exerts an anti-atherosclerotic effect and suppresses tumor necrosis factor alpha-induced protein production and mRNA expression due to adhesion molecules.

The chemopreventive effect of Silymarin on hepatocellular carcinoma has been established in several studies using in vitro and in vivo methods; It can exert a beneficial effect on the balance of cell survival and apoptosis through the interference of cytokines.

In addition to this, anti-inflammatory activity and inhibitory effect of Silymarin have also been detected in the development of metastases. In some neoplastic diseases, Silymarin can also be administered as adjunctive therapy.

Serious Side Effects of Silymarin

Often considered a wonderful herb for liver health, Silymarin certainly has its share of side effects. Some of which you may not have expected.

Could cause abdominal problems

Research indicates that Silymarin can cause certain abdominal problems such as diarrhea, bloating, gas, and an upset stomach.

Oral ingestion of Silymarin has also been linked to abdominal fullness (or abdominal pain), anorexia (loss of appetite), and changes in bowel habits.

May cause allergic reactions

Silymarin can cause allergic reactions in people, especially those who are also allergic to ragweed, marigolds, daisies, and chrysanthemums.

Certain reports also state that Silymarin can cause skin rashes, hives, and eczema.

Silymarin rashes are due to IgE antibodies that raise histamine levels in the skin, leading to the condition.

As you ingest the herb, your immune system reacts to it as dangerous, creating a defense mechanism against the supplement.

If you develop an allergic reaction after taking Silymarin, stop using it and consult your doctor.

May interact with estrogen

Silymarin is known to have several estrogen-like properties, and certain sources say it could worsen some health conditions (such as endometriosis, where endometrial tissue appears outside the uterus and causes pain) sensitive to estrogen.

Silymarin may also lower hormone levels in the body. Taking it along with estrogen pills could reduce their effectiveness. Some of these estrogen pills include equine estrogens, ethinyl estradiol, estradiol, etc.

May interact with cholesterol medications

Silymarin may interact with statin drugs, which are known to lower cholesterol levels (lower lipids).

Some of these medications include Mevacor, Lescol, Zocor, Pravachol, and Baycol. This happens because both Silymarin and these drugs are broken down by the same liver enzymes.

Your blood sugar may drop too low

Silymarin is known to lower blood sugar levels. If you’re already taking blood sugar medications, taking the herb could lower your sugar levels too much.

May have interactions during lactation and pregnancy

Although milk thistle has historically been used to improve the flow of breast milk, in modern times there is limited research that speaks of the benefits of milk thistle during lactation and pregnancy. Therefore, keep safe and avoid its use.

May interact with other drugs

Certain medications are broken down in the liver, and Silymarin may decrease how quickly this happens. Taking Silymarin together with certain medications and medications can increase its effects or even side effects. Some of these medications include:

  • Elavil.
  • Valium.
  • Celebrex.
  • Voltaren.
  • cozaar.
  • Demadex.
  • Cumadin.
  • Zyflo.

Since Silymarin affects the way the liver breaks down these medications, it can affect how well these medications work.

May cause weakness

Some people may also experience weakness as one of the side effects of Silymarin. Other related symptoms include a tingling sensation in the muscles and muscle cramps.

Another case report from Australia had described reactions to the Silymarin extract that included sweating and weakness.

Research on the side effects of milk thistle is limited. An important part of the research says that it can only do more good than harm. But talk to your doctor once before using this herb.

Silymarin Mechanism of Action

Silymarin minimally, but without clinical relevance, reduces the serum levels of alanine aminotransferase and aspartate aminotransferase. It is necessary to carry out studies with more adequate methodological designs.

Silymarin acts mainly as an antioxidant, reducing the production of reactive oxygen species and lipid peroxidation, increasing endogenous concentrations of antioxidant enzymes such as glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase.

It exerts a significant anti-inflammatory effect, mainly due to the inhibition of the nuclear transcription factor NFκB and, consequently, the reduction of inflammatory cytokines in the liver parenchyma, in addition to the interaction with protein kinases and the negative regulation of cyclooxygenase 2.

It also acts as an immunomodulatory and antifibrotic agent, due to the reduction of the activation or stimulation of apoptosis of liver stellate cells, or increases the degradation of collagen deposits in the liver parenchyma.

In addition, it is considered a hepatoprotector due to its ability to stabilize the cell membranes of hepatocytes, preventing the entry of toxic chemicals into these cells.

Silymarin binds to the receptors present in these membranes, inhibiting the binding of toxins at these sites, reducing drug-induced hepatocellular damage.

It also stimulates the synthesis and activity of enzymes responsible for the liver biotransformation process, such as glutathione S-transferase.

Studies with Silymarin

Silymarin is commonly prescribed in the practice of many professionals and is taken as a self-medication for patients. Studies suggest the benefits of its use in liver disorders, discussing its mechanisms of action and potential as an adjunct in the treatment of these diseases.

Favorable clinical outcomes such as improved biochemical indicators and liver profile were seen in clinical trials.

However, other studies are controversial or have not reported statistical significance in the improvement of these indicators.

Studies have shown that Silymarin has a significant effect in reducing the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in liver diseases, which are considered beneficial in the treatment of these patients.

However, it is important to note that most of these studies present considerable methodological variations.

In addition to having used different doses with different concentrations of Silymarin and different formulations, which makes it difficult to carry out a comparative analysis of the studies and a consensus on the clinical use of this herbal medicine and its effects on biochemical indicators such as liver enzymes.

Biochemical and clinical indicators

Some intervention studies have observed an improvement in biochemical and clinical indicators evaluated in patients with nonalcoholic fatty liver disease, including hepatic steatosis and nonalcoholic steatohepatitis, after the use of Silymarin.

Although the results of the meta-analysis indicate that the use of Silymarin is associated with a reduction in serum levels of alanine aminotransferase and aspartate aminotransferase, the values ​​found are not clinically relevant.

The studies also showed limited adverse effects and good tolerance to the use of Silymarin as reported by other studies.

Some studies report that Silymarin is capable of improving biochemical indicators in patients with liver diseases of different etiologies, in addition to reducing alanine aminotransferase and aspartate aminotransferase levels are commonly described in other studies.

The hypothesis described by the researchers is that the antioxidant properties of Silymarin are capable of reducing reactive oxygen species, thus inhibiting cell damage.

Enzyme increase

In addition to the improvement in the antioxidant system, observed in experimental studies, due to the increase in enzymes such as glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase, all with antioxidant function and non-enzymatic antioxidants, through the modulation of transcription factors. associates.

On the other hand, there are reports of similar studies that, despite showing differences in the values ​​of these indicators, these were not statistically significant.

It is important to emphasize that there are some trials with rigorous methodologies that consider important topics such as:

  • The use of well-characterized products, evaluation of specific liver diseases, adequate sample size, representativeness of the study population, adequate intervention time, and adequate statistical analysis.

These factors are quite divergent between studies, which can directly interfere with both positive and controversial results, representing a major limitation to conclusions on this topic.

A clinical trial that found normal alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transferase values ​​at baseline, which is not surprising, since some patients may be carriers of nonalcoholic fatty liver disease and do not have alterations in liver enzyme levels.

Therefore, in the study mentioned above, there was no relevance in the results of these markers after the intervention, since in the baseline; the patients no longer presented alterations in these markers.

Significant reduction in γ-glutamyl transferase

It was also found that another clinical trial included in an analysis demonstrated a significant reduction in γ-glutamyl transferase in the control and intervention group, probably due to differences in the methodological design used.

In one study, both groups had prescriptions for a hypocaloric diet and physical activity, which probably influenced the clinical and biochemical parameters of patients with NAFLD.

Studies have associated high levels of alanine aminotransferase or aspartate aminotransferase: alanine aminotransferase> 1 in patients with non-alcoholic fatty liver disease and with disease progression and presence of hepatocellular fibrosis.

Changes in lifestyle

It has been considered that several publications change lifestyle with dietary intervention and the practice of physical activity, as strategies with an impact on the improvement of markers and liver function in individuals with non-alcoholic fatty liver disease.

Despite this, it has been observed that there is still more data available in the literature regarding the pattern of adherence of this patient profile to changes in lifestyle and nutritional guidelines provided by health professionals.

It is also important to consider the increasing increase in the prevalence of nonalcoholic fatty liver disease in recent years and it is even considered a global public health problem.

Taking this scenario into account, researchers have developed adjuvant therapeutic strategies, such as herbal medicine, and have considered the use of Silymarin as a possibility to improve the biochemical indicators of these patients.

However, the available studies have low methodological quality and the positive results found have no clinical relevance.

Therefore, there is still insufficient scientific evidence for the recommendation of Silymarin as a possibility of complementary therapeutic alternatives for the reduction of biochemical indicators in patients with liver disease.

It is important to highlight that the inconsistency tests carried out show that the evaluated studies presented a high degree of heterogeneity, which is generally present in meta-analyzes involving clinical trials, especially when specific topics are evaluated and few studies are presented.

The case of herbal medicine and specifically

The use of Silymarin. Furthermore, the details of the intervention, the blinding, the selection and recruitment of the population and the absence of adjustments in the statistical analyzes may be factors that interfere with the final results, as well as the high and medium risk of bias observed in the studies.

Trials with small samples and therefore low population representativeness were identified, which may have favored high heterogeneity, as studies with larger samples provide greater precision in association.

The absence of intention-to-treat analysis in the studies can also be considered factors that interfered with the final results and conclusions.

Another relevant methodological factor refers to the blinding of the evaluated studies: only one is double blind, which represents another inconsistency in the evaluated studies.

Although the meta-regression did not identify the interference with the sample size, the treatment time and the type of intervention in the results, it is considered that these results could have been strongly influenced by the low methodological quality, observed in all the studies, in general, depending on the methods used.

The results demonstrate that the use of Silymarin minimally, but without clinical relevance, reduces the serum levels of alanine aminotransferase and aspartate aminotransferase in patients with non-alcoholic fatty liver disease.

Although the observed reductions do not translate into clinical relevance, they may indicate a possible additional therapeutic strategy in the control of NAFLD.

When analyzing the data found, it is important to consider the great variability and methodological fragility of these studies, a very common finding in publications evaluating herbal medicines.

Therefore, it is necessary to carry out new studies with more adequate methodological designs, with special attention to complying with the planning and execution stages of clinical trials.

This will provide more consolidated scientific evidence and may contribute to greater safety in the indication or not of the doses of Silymarin that should be prescribed by qualified health professionals.

Despite the fact that the use of Silymarin in liver diseases is described as ancient and prescribed by many professionals, there is still controversy in the literature about its real effects on biochemical indicators in patients with liver diseases.