Clomethiazole improves alcoholic fatty liver in patients admitted to the hospital for alcohol detoxification therapy

Chronic alcohol consumption primarily results in alcoholic fatty liver (AFL). Various pathogenetic mechanisms contribute to AFL. The pathophysiology of AFL includes, among others, oxidative stress with the generation of reactive oxygen species (ROS). ROS leads to lipidperoxidation, protein alterations and DNA injury. One important source for ROS is microsomal ethanol metabolism catalyzed by Cytochrome P4502E1 (CYP2E1). Chronic ethanol consumption induces CYP2E1 primarily in the liver, and it has been shown that this induction increases fatty liver by preventing up-regulation of PPARα due to oxidative stress. On the other hand, inhibition of CYP2E1 by clomethiazole (CMZ), a CYP2E1 inhibitor, decreases oxidative stress in cell cultures and improves ALD in animal studies. To study whether CYP2E1 inhibition also improves AFL in humans, we performed a randomized controlled clinical trial in alcohol-dependent patients who were admitted to the hospital for alcohol detoxification therapy (ADT). All patients were non-cirrhotics identified by transient elastography with a liver stiffness of less than 12 kPa and all had serum AST activities of more than twice normal. The patients were randomly assigned for ADT either with CMZ or chlorazepate (CZP) for 7 to 10 days. CMZ almost completely inhibited CYP2E1 already 24 hours after its administration. At admission, controlled attenuation parameter (CAP) was comparable between the two groups (313 ± 11 vs. 310 ± 10 dB/m). At discharge, CAP in the CMZ group was significantly lower as compared to admission (252 ± 11 dB/m; p < 0.05), but not in the CZP group (273 ± 8 dB/m; p = 0.081). With CMZ, a significant correlation was found between hepatic fat at admission and the difference of fat between admission and discharge (r = 0.64; p < 0.001). This study proves, for the first time in humans, that CMZ, most likely through the inhibition of CYP2E1, improves AFL more than abstinence alone. Since CMZ can only be given for a short period of time because of its addictive potency, it is mandatory to search for non-toxic CYP2E1 inhibitors to treat AFL.