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Role of silymarin to treat fibrosis development in non‐alcoholic fatty liver disease

We read with great interest the recent review by Hojo and Watanabe on the various therapies available to treat non-alcoholic steatohepatitis (NASH), with particular emphasis on their efficacy for the improvement of liver fibrosis. The diagnosis of NASH is based on invasive liver biopsy. However, this technique to evaluate liver damage is inadequate to understand the pathogenetic mechanisms involved in the development of liver fibrosis. Reactive oxygen species (ROS), including the superoxide radical, hydroxyl radical, hydrogen peroxide and lipid peroxide radicals, were involved in the pathogenesis of liver diseases and in particular in the development of liver fibrosis. The mechanism of free radical damage included ROS-induced peroxidation of the polyunsaturated fatty acid in the bilayer cell membrane, which caused the chain reaction of lipid peroxidation, thus damaging the cellular membrane and causing further oxidation of membrane, lipids and proteins. Silybum marianum or milk thistle (MT) is the most wellresearched plant in the treatment of liver disease. The active complex of MT is a lipophilic extract from the seeds of the plant and is composed of four isomer flavonolignans, collectively known as silymarin. Silymarin acts as an antioxidant by reducing ROS production and lipid peroxidation, and is an anti-fibrotic agent by reducing the activation of hepatic stellate cells, inducing hepatic stellate cell apoptosis, or inducing degradation of collagen deposits. Particularly in liver steatosis, silymarin showed an improvement in glucose and lipid metabolism. Silymarin inhibits the activation of nuclear factor-kB and its related pathways in the liver. It is known that a relationship exists between body mass index, insulin and liver fibrosis and the activation and release of some growth factors, such as transforming growth factor. Published work has reported that silybin, when conjugated with phopholipids and vitamin E, improves bodyweight, insulin resistance, plasma markers of liver fibrosis and liver histology in experimental animals and in man. However, standardization of silymarin is still lacking in its various formulations and effective dosages. In addition, a relevant problem of most clinical trials on this topic has been the definition of end-points, such as progression of fibrosis, and such pitfalls may even have lead to missing true treatment effects. Well-designed, double-blind, placebocontrolled studies are necessary. In accordance with the authors, therapeutic targets of drug development are in early stages, but a multifaceted approach to oxidative stress and to mechanisms underlying ROS-related damage with several treatment options is probably in the years to come. Along the way, further studies to develop non-invasive biochemical tests for the diagnosis of different degrees of liver steatosis are mandatory.