Comparative Study Evaluating the Outcome of Obeticholic Acid Versus Vitamin E in Patients with Non-alcoholic Steatohepatitis Without Cirrhosis

Nonalcoholic fatty liver disease (NAFLD) is defined as the accumulation of excessive fat in the liver in the setting of no significant alcohol consumption and the absence of any secondary cause. NAFLD has reached epidemic proportions and currently affects 20-40% of the general population. In recent years, along with the increasing trend of obesity and type 2 diabetes, NAFLD has become one of the most common chronic liver diseases worldwide. The spectrum of the disease ranges from simple steatosis to hepatocellular injury with inflammatory infiltration characterized as nonalcoholic steatohepatitis (NASH) that may eventually progress to liver fibrosis, cirrhosis and hepatocellular carcinoma. Despite significant disease burden and mortality associated mainly with advanced disease, i.e., NASH and fibrosis, there is currently no approved medication for NASH, therefore, lifestyle modifications remain the mainstay of treatment. What is the pathogenesis of NAFLD? Although the proposal of "two hits" involving insulin resistance (IR) and oxidative stress has been well accepted, the mechanism of NAFLD was thought very complex and still remained unclearly.

Farnesoid X receptor (FXR) is a nuclear hormone receptor, which is expressed in various organs and tissues, mainly in the liver, intestine, kidney, and adrenal cortex. It is a ligand activated transcription factor, with bile acid being the natural ligand to these receptors. These receptors are involved in regulating various metabolic pathways such as bile acid, cholesterol, and lipid and glucose metabolism. The expression of FXR is reduced in the liver of NASH patients, and various FXR knockout animal models exhibit hepatic steatosis, bile acid accumulation, hyperlipidaemia, hyperglycaemia and fibrosis. Importantly, these conditions are improved by increasing FXR expression, indicating that the FXR agonist could be an effective therapeutic option for NASH patients.

FXR activation significantly impacts lipid synthesis, mainly by decreasing the expression of the sterol regulatory element binding protein 1c (SREBP-1c) and its enzymes which are the main regulator in lipogenesis. In addition, FXR activation increases the clearance of LDL, very low density lipoprotein (VLDL) and chylomicrons by activation of lipoprotein lipase. Furthermore, FXR activation results in the induction of the peroxisome proliferator activated-α receptor which increases fatty acid oxidation. Also it increases the secretion of Fibroblast Growth Factor-21 (FGF-21) which decreases lipogenesis by inhibition of SREBP-1c.

Obeticholic acid (OCA) is a semisynthetic derivative of the chenodeoxycholic acid. OCA was originally described as a selective and potent FXR ligand. OCA is currently approved for treatment of primary biliary cholangitis. Currently, OCA is investigated for its potential role in the treatment of NASH. Phase II and III ongoing trials have shown that OCA might attenuate the severity of liver fibrosis in patients with NASH. In summary, OCA has been the first-in-class of FXR ligands advanced to a clinical stage, highlighting the potential benefits linked to FXR-targeted therapies.

It is acknowledged that vitamin E is the major lipid-soluble chain-breaking antioxidant found in the human body. In addition to its anti-oxidative properties, molecules of vitamin E family exert anti-atherogenic and anti-inflammatory activities. According to American Association for the Study of Liver Diseases (AASLD) and National Institute for Health and Care Excellence (NICE) guidelines, vitamin E is approved at a dose of 800 IU/day in adults with biopsy-proven NASH.