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The main direction in the treatment of chronic liver diseases is the etiological use of drugs that affect the cause of the pathological process. One of these drugs is considered to be silymarin, a hepatoprotector of plant origin, isolated from the fruits of milk thistle. The use of drugs with hepatoprotective activity is directly related to the requirements imposed by the modern concept of evidence-based medicine [1]. Silymarin preparations are widely used in clinical practice, especially in clinical hepatology, being the main or auxiliary treatment for alcoholic and viral liver damage, as well as for non-alcoholic steatohepatitis. This is facilitated by their multifactorial mechanism of action, relative cheapness, mild side effects and good tolerability.

Milk thistle is one of the most studied plants, the components of which have a hepatoprotective effect [2]. Its healing properties have been used in folk medicine for more than 2000 years, but its biochemical composition was discovered only in the 20th century. The main active principle of milk thistle is silymarin, which is a mixture of flavonoids: silibinin, silydianin and silicristin. According to pharmacological studies, after a single oral dose, silymarin is rapidly absorbed, reaching maximum concentration in the blood after 30–60 minutes. Silymarin accumulates mainly in the liver and kidneys. Most of it is found in the cytoplasm of hepatocytes, while in the nuclei its concentration is 100–200 times less. The flavonoid complex is metabolized in the liver by conjugation with glucuronic and sulfuric acids without affecting the microsomal system, which makes it possible to use silymarin in combination with other drugs without affecting their pharmacokinetics and pharmacodynamics. Silymarin is excreted mainly in bile and in small amounts in urine. Silymarin glucuronides and sulfates, entering the intestines, are broken down by enzymes of the intestinal microflora. The resulting silymarin is reabsorbed, which creates enterohepatic circulation of the drug, which persists for some time after completion of treatment. Preparations based on milk thistle seed juice are recognized as safe and well tolerated. The high safety and good tolerability of silymarin have been proven both experimentally and clinically [3]. The absence of silymarin toxicity has been shown even when used in high doses – more than 1500 mg/day [4]. In clinical studies, the laxative effect of the drug, associated with increased secretion and release of bile, as well as mild allergic reactions, was most often noted. However, the side effects did not reach a severity level requiring discontinuation of the drug [5]. Silymarin has found wide use in clinical practice; it is taken by up to 30–40% of patients with liver diseases [6]. Its composition depends on a number of factors: the geographical origin of the raw material, the characteristics of its extraction and further processing, methods for determining the active component. Silymarin preparations from different manufacturers used in the treatment of patients with alcoholic liver disease and non-alcoholic steatohepatitis have proven to be effective and safe [1, 7].

The mechanism of action of silymarin is well studied and is due to the following factors. Its antihepatotoxic effect is associated with the ability to prevent the penetration of toxins into hepatocytes, the membrane-stabilizing effect and the ability to directly interact with the components of the cell membrane, preventing the occurrence of disturbances in the lipid fractions responsible for maintaining normal membrane fluidity. Its antioxidant effect is associated with the ability to react with free radicals, suppress lipid peroxidation and reduce the consumption of glutathione reserves and stabilize the cell membrane [8]. Under conditions of experimental liver damage, especially when silymarin is administered in combination with phosphatidylcholine, the transmembrane potential is restored and cell death is prevented. The oxidized form of silibinin, dehydrosilibinin, has a much more powerful antioxidant effect. This substance has higher lipophilicity and the ability to penetrate membranes. The anti-inflammatory and antiallergic effects of silymarin consist of inhibition of lipoxygenase activity, which leads to suppression of the formation of leukotrienes, inhibition of the migration of neutrophil granulocytes, and suppression of histamine release from basophilic granulocytes [9]. The antifibrotic effect of silymarin is associated with its ability to inhibit the activation of hepatic stellate cells, reduce their proliferation and transformation into myofibroblasts [10]. Stimulation of liver tissue regeneration under the influence of silymarin is carried out by enhancing the synthesis of ribosomal RNA and stimulating the formation of mature ribosomes.

Silymarin is finding increasing use in clinical practice. To date, however, there have been relatively few high-quality clinical studies of silymarin. Its effect was mainly studied in alcoholic and viral liver damage. The Cochrane Collaboration Group analyzed studies of the effectiveness of silymarin in acute and chronic liver diseases, which showed that there was no significant effect of the drug on the course of the disease, but there was a 50% reduction in mortality in the group of patients with alcoholic liver disease compared to the placebo group [11] . A statistically significant reduction in mortality (p = 0.05) in the group of patients receiving silymarin for 4 years was shown in a study by P. Ferenci et al. (1989) [12]. Positive changes in the histological picture, proliferation of lymphocytes and indicators of lipid peroxidation in patients with verified chronic alcoholic hepatitis were noted by J. Feher, L. Lang (1988) [13]. Among patients in this group, a statistically significant positive effect of silymarin on bilirubin and gamma-glutamyl transpeptidase levels was noted [14], as well as an improvement in the morphological picture of the liver [15]. In a systematic review by R. Saller et al. (2001) summarized the results of 4 clinical studies studying the effects of silymarin in patients with alcoholic liver disease. In 2 of them, an improvement in the histological picture was found, and in 2, a significant improvement in prothrombin time, as well as a decrease in aminotransferase activity. Silymarin, according to the authors, can be used as an adjuvant treatment for alcoholic liver disease [16]. R. Saller et al. (2008) analyzed and pooled the results of 19 clinical studies. In the group of patients receiving silymarin, a significant decrease in the level of aspartate aminotransferase was detected (p = 0.01) compared to the placebo group. In liver cirrhosis (mainly alcohol etiology), overall mortality was 16.1% in the treatment with silymarin and 20.5% in the placebo group (differences are not significant); mortality in liver diseases of various etiologies when silymarin was included in therapy was 10.0, in the placebo group - 17.3% (p = 0.01). The authors consider it justified to use silymarin in combination with other drugs in the treatment of liver cirrhosis of alcoholic etiology [17].

The study of the possibilities of using silymarin in patients with acute viral hepatitis is reflected in a few works [18]. In the group of patients with acute viral hepatitis who took silymarin 140 mg 3 times a day, a more rapid resolution of the symptoms of the disease was noted, a decrease in the level of indirect bilirubin, but a weak effect on changes in the level of aminotransferases and direct bilirubin was noted. Despite this, the authors concluded that silymarin has potential therapeutic efficacy in acute viral hepatitis [19]. Chronic hepatitis HCV (Hepatitis C virus) etiology is the area of the most intensive research of silymarin, and there are prerequisites for this. The use of silymarin in patients with chronic hepatitis of HCV etiology who did not respond to standard antiviral therapy led to a decrease in the severity of symptoms of the disease in the absence of changes in liver function tests and viral load levels [20]. Its antiviral effect was also noted in patients who did not respond to standard therapy. The duration of taking the drug was 6 months at a dose of 160–360 mg/day [21, 22]. A number of long-term controlled studies in patients with hepatitis C virus have revealed a significantly lower incidence of liver cirrhosis and hepatocellular carcinoma with a sustained biochemical response to interferon therapy compared with patients in whom these indicators did not change under the influence of therapy [23]. In this case, doses of silymarin were used that were significantly higher than traditional ones (10, 280, 560 and 700 mg every 8 hours for 7 days). The drug was well tolerated, on the basis of which the authors concluded that the drug could be used in high doses – up to 2.1 g/day. Silymarin does not affect the replication of viruses, but its ability to inhibit some parts of the inflammatory and cytotoxic processes and improve regenerative processes in the liver makes its use in the treatment of viral hepatitis advisable [24]. A. Par et al. (2008) attempted to evaluate the effectiveness of the drug in patients with chronic hepatitis of HCV etiology receiving treatment with a combination of pegylated interferon and ribavirin. Silymarin was prescribed 166 mg 2 times a day for 3 months. Compared with the placebo group, there was an improvement in antioxidant protection, but alanine aminotransferase levels did not change [25]. The rationality of prescribing silymarin to patients with non-alcoholic steatohepatitis continues to be actively discussed. The complex use of silymarin, vitamin E and phospholipids in patients in this group led to a significant improvement in well-being, a decrease in the concentration of insulin in the blood, aminotransferase activity and the severity of hepatosis [26]. The mechanism of its influence on pathological processes in non-alcoholic steatohepatitis is associated with a decrease in the production of free radicals, leading to dysfunction of mitochondria, a decrease in ATP production, and disruption of the conformation of proteins and enzymes [27]. The use of silymarin by patients in this group (according to the results of a few studies) led to a persistent decrease in the level of aminotransferases, a decrease in hyperinsulinemia, and a significant decrease in the severity of fibrosis during ultrasound examination. The insufficient number of high-quality studies that meet the requirements of evidence-based medicine (in particular, the lack of histological examination data in a number of studies) does not currently allow us to draw a conclusion about the advisability of using silymarin for this pathology, although experimental work indicates its positive effect. The possibilities of using silymarin in primary biliary cirrhosis are not completely clear due to the small number of studies. A decrease in itching, a decrease in the frequency of complications and an improvement in the histological picture in patients with this disease when using silymarin are indicated [28]. A special place is occupied by the use of silymarin as a means of detoxification. During chemotherapy of tumors, when the likelihood of a hepatotoxic effect is high, milk thistle preparations are recommended to reduce the risk of liver damage, although large studies on this topic have not been conducted [29]. In case of severe poisoning with toadstool, the use of silymarin in the first 48 hours of poisoning can significantly reduce the severity of liver damage and increase survival [30]. For patients with acute poisoning, it is advisable to use the drug for intravenous administration. The US Food and Drug Administration has approved the use of milk thistle preparations for the risk of death from liver failure.

Indications for the use of silymarin are chronic liver diseases (fatty hepatosis, chronic hepatitis and cirrhosis of the liver), toxic liver damage (intoxication with halogenated hydrocarbons, toadstool poison, heavy metal compounds, certain drugs), lipid metabolism disorders. Silymarin is slowly absorbed from the gastrointestinal tract and participates in the enterohepatic circulation.

Given its safety, good bioavailability and proven positive treatment effects, silymarin can be used for a wide range of the above liver diseases.