Clinical effect and molecular mechanisms of action of s-adenosylmethionine (SAMe) in patients with primary sclerosing cholangitis (PSC)

Primary Sclerosing Cholangitis (PSC) is an increasingly recognized chronic liver disease, currently defined as one of the greatest challenges of modern hepatology. In its course, as a result of not fully understood mechanisms, the bile ducts are damaged. The disease may be accompanied by a number of troublesome ailments, including chronic fatigue, persistent itching of the skin, recurrent episodes of cholangitis threatening sepsis. The disease is associated with a significantly increased risk of an aggressive neoplasm such as bile duct cancer. The current pharmacological treatment options for PSC are significantly limited. The effectiveness of the only drug used, which is ursodeoxycholic acid (UDCA), remains controversial.
S-adenosylmethionine (SAMe) is a precursor of two very important metabolic pathways (transmethylation and transsulfuration) improving the elimination of toxic compounds from the body. The end product of SAMe metabolism is glutathione, one of the key antioxidant compounds. Chronic liver diseases lead to acquired SAMe deficiency, which can significantly aggravate the already impaired liver function. Unfortunately, in the world literature there are no well-planned, randomized trials with the use of SAMe in cholestatic diseases, therefore this preparation is still awaiting its place in the treatment of liver diseases.
Our previous studies have demonstrated the additive beneficial effect of SAMe in combination with UDCA in various experimental cholestasis models. In our recent MAESTRO research, conducted in patients with another cholestatic disease, which is Primary Biliary Cholangitis (PBC), we showed not only an improvement in the biochemical parameters of liver function, but, very importantly, a significant improvement in the quality of patients' lives. Our subsequent research, also within the MAESTRO project, has shown that SAMe can also inhibit the production of autoantibodies that lead to biliary damage.
The project is divided into two parts: clinical and laboratory.
In the clinical part, the effect of SAMe treatment will be assessed in a group of 60 patients with stable PSC. The study will be randomized and will last 6 months. SAMe and placebo will be purchased commercially. Patients will receive either UDCA + SAMe or UDCA + placebo for a period of 6 months. The influence of SAMe on clinical, biochemical and serological parameters as well as the result of the elastographic examination of the liver will be analyzed. The effects of SAMe therapy on quality of life, which is quite often severely impaired in PSC patients, will be analyzed in great detail. This is an area of great importance, but unfortunately neglected for years in the context of autoimmune liver diseases. The quality of life study will be carried out with the use of a series of well-verified questionnaires, assessing, among others, symptoms of chronic fatigue, itching, depression and anxiety. This issue has been the subject of our interest for many years, which is confirmed by numerous publications of our team in recent years. The results of the study will help to define the role of SAMe in the treatment of PSC and therefore could be directly translated into clinical practice.The aim of the laboratory part is to expand our knowledge about the mechanisms of hepatoprotective action of SAMe and it will be a continuation of our previous research, financed, among others, from the NCN MAESTRO grant. Using biochemical, molecular methods and tandem liquid chromatography in mass spectroscopy (LC-MS / MS), we will deepen the scope of our still incomplete knowledge of the antioxidant role of SAMe and its potential protective activities as a sulfone and methyl donor group. Both parts of the project are complementary and should significantly contribute to a better understanding of the protective mechanisms in the liver.