A New Combination of 2 Nutraceuticals and 1 Probiotic (Epatrex) for Non-Alcoholic Fatty Liver Disease (NAFLD): Results from a Multi-Centre, Randomized, Single-Blind, Parallel, Cross-Over Study: the “REVEAL” Study
Keywords:
Probiotics, NAFLD, Reveal study, EpatrexAbstract
No pharmaceutical or nutraceutical treatments for non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) are currently available on the market, although there are different molecules in clinical trials (Phases 2 and 3). All guidelines suggest only lifestyle changes. In this article, the authors report a single-blind cross-over pilot study of the effect of a new nutraceutical, Epatrex. The primary outcomes were the in vivo safety and effects on gamma glutamyl transferase (GGT) levels and fatty liver index (FLI) values of a new 3-layer tablet containing the active ingredients. After 2 months of treatment with Epatrex or the placebo, the new product was found to be safe, although no significant differences in the absolute values of the fatty liver index (FLI) or GGT and triglyceride (TG) levels were observed. However, the percentage reductions in GGT and TG levels in patients treated with Epatrex were significantly greater (p<0.005) than those in patients treated with the placebo at 60, 90 and 150 days after the beginning of the study. Several studies have reported microbiota changes involving Lactobacillus Casei after 1- 3 weeks of daily administration, and for this reason we chose 8 weeks of treatment to obtain clinical results. We concluded that 2 months of treatment with Epatrex, a three-layer nutraceutical composed of Lactobacillus casei LC-XCAL + silymarin/silybin + chromium picolinate, was safe, albeit unable to significantly different doses and treatment periods are needed to confirm that Epatrex is a useful treatment for NAFLD.
References
Bellentani, S., Saccoccio, G., Masutti, F., Crocè, LS., Brandi, G., Sasso, F.,et al. (2000) Prevalence of and risk factors for hepatic steatosis in Northern Italy. Annals of Internal Medicine, 132(2): 112-117.
Bedogni, G., Bellentani, S. (2004) Fatty liver: how frequent is it and why? Annals of Hepatology, 3(2): 63-65.
Bedogni, G., Miglioli, L., Masutti, F., Castiglione, A., Crocè, LS., Tiribelli, C., et al. (2007) Incidence and natural course of fatty liver in the general population: the Dionysos study. Hepatology, 46(5): 1387-1391.
Scaglioni, F., Ciccia, S., Marino, M., Bedogni, G., Bellentani, S. (2011) ASH and NASH. Dig Dis, 29(2): 202-210.
Bedogni, G., Miglioli, L., Masutti, F., Tiribelli, C., Marchesini, G., Bellentani, S. (2005) Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology, 42(1): 44-52.
Bellentani, S., Marino, M. (2009) Epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD). Annals of Hepatology, 8 Suppl 1, S4-S8.
Bellentani, S., Scaglioni, F., Marino, M., Bedogni, G. (2010) Epidemiology of non-alcoholic fatty liver disease. Dig Dis, 28(1): 155-161.
Loomba, R., Sanyal, AJ. (2013) The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol, 10(11): 686-690.
Townsend, SA., Newsome, PN. (2016) Non-alcoholic fatty liver disease in 2016. British Medical Bulletin, 119(1): 143-156.
Asgari-Taee, F., Zerafati-Shoae, N., Dehghani, M., Sadeghi, M., Baradaran, HR., Jazayeri, S. (2019) Association of sugar sweetened beverages consumption with non-alcoholic fatty liver disease: a systematic review and meta-analysis. European Journal of Nutrition, 58(5): 1759-1769.
Wijarnpreecha, K., Thongprayoon, C., Edmonds, PJ., Cheungpasitporn, W. (2016) Associations of sugar- and artificially sweetened soda with nonalcoholic fatty liver disease: a systematic review and meta-analysis. QJM, 109(7): 461-466.
Wijarnpreecha, K., Thongprayoon, C., Panjawatanan, P., Ungprasert, P. (2017) Insomnia and risk of nonalcoholic fatty liver disease: a systematic review and meta-analysis. J Postgrad Med, 63(4): 226-231.
He, W., An, X., Li, L., Shao, X., Li, Q., Yao, Q., et al. (2017) Relationship between hypothyroidism and non-alcoholic fatty liver disease: a systematic review and meta-analysis. Front Endocrinol (Lausanne), 8: 335.
Mahfood Haddad, T., Hamdeh, S., Kanmanthareddy, A., Alla, VM. (2017) Nonalcoholic fatty liver disease and the risk of clinical cardiovascular events: a systematic review and meta-analysis. Diabetes Metab Syndr, 11 Suppl 1: S209-S216.
Calzadilla Bertot, L., Adams, LA. (2016) The natural course of non-alcoholic fatty liver disease. Int J Mol Sci, 17(5): 774.
Mantovani, A., Zaza, G., Byrne, CD., Lonardo, A., Zoppini, G., Bonora, E., et al. (2018) Nonalcoholic fatty liver disease increases risk of incident chronic kidney disease: a systematic review and meta-analysis. Metabolism, 79: 64-76.
Araújo, AR., Rosso, N., Bedogni, G., Tiribelli, C., Bellentani, S. (2018) Global epidemiology of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: what we need in the future. Liver Int, 38 Suppl 1: 47-51.
Piscaglia, F., Svegliati-Baroni, G., Barchetti, A., Pecorelli, A., Marinelli, S., Tiribelli, C., et al. (2016) Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology, 63(3): 827-838.
Chalasani, N., Younossi, Z., Lavine, JE., Diehl, AM., Brunt, EM., Cusi, K., et al. (2012) The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology, 55(6): 2005-2023.
Ratziu, V., Bellentani, S., Cortez-Pinto, H., Day, C., Marchesini, G. (2010) A position statement on NAFLD/ NASH based on the EASL 2009 special conference. J Hepatol, 53(2): 372-384.
Loria, P., Adinolfi, LE., Bellentani, S., Bugianesi, E., Grieco, A., Fargion, S., et al. (2010) Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease: a decalogue from the Italian Association for the Study of the Liver (AISF) expert committee. Dig Liver Dis, 42(4): 272-282.
Nascimbeni, F., Pais, R., Bellentani, S., Day, CP., Ratziu, V., Loria, P., et al. (2013) From NAFLD in clinical practice to answers from guidelines. J Hepatol, 59(4): 859-871.
Bellentani, S., Dalle Grave, R., Suppini, A., Marchesini, G. (2008) Behavior therapy for nonalcoholic fatty liver disease: the need for a multidisciplinary approach. Hepatology, 47(2): 746-754.
Centis, E., Moscatiello, S., Bugianesi, E., Bellentani, S., Fracanzani, AL., Calugi, S.,et al. (2013) Stage of change and motivation to healthier lifestyle in non-alcoholic fatty liver disease. J Hepatol, 58(4): 771-777.
European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). (2016) EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol, 64(6): 1388-1402.
Chalasani, N., Younossi, Z., Lavine, JE., Diehl, AM., Brunt, EM., Cusi, K., et al. (2012) The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology, 142(7): 1592-1609.
Cicero, AFG., Colletti, A., Bellentani, S. (2018) Nutraceutical approach to non-alcoholic fatty liver disease (NAFLD): the available clinical evidence. Nutrients, 10(9): 1153-1171.
Samimi, M., Dadkhah, A., Haddad Kashani, H., Tajabadi- Ebrahimi, M., Seyed Hosseini, E., Asemi, Z. (2019) The effects of synbiotic supplementation on metabolic status in women with polycystic ovary syndrome: a randomized double-blind clinical trial. Probiotics and Antimicrob Proteins, 11(4): 1355-1361.
Babadi, M., Khorshidi, A., Aghadavood, E., Samimi, M., Kavossian, E., Bahmani, F., et al. (2019) The effects of probiotic supplementation on genetic and metabolic profiles in patients with gestational diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Probiotics and Antimicrobial Proteins, 11(4): 1227-1235.
Wa, Y., Yin, B., He, Y., Xi, W., Huang, Y., Wang, C., et al. (2019) Effects of single probiotic- and combined probioticfermented milk on lipid metabolism in hyperlipidemic rats. Front Microbiol, 10: 1312.
Qian, Y., Li, M., Wang, W., Wang, H., Zhang, Y., Hu, Q., et al. (2019) Effects of Lactobacillus casei YBJ02 on lipid metabolism in hyperlipidemic mice. Journal of Food Science, 84(12): 3793-3803.
Aktas, B., De Wolfe, TJ., Safdar, N., Darien, BJ., Steele, JL. (2016) The impact of Lactobacillus casei on the composition of the cecal microbiota and innate immune system is strain specific. PLoS One, 11(5): e0156374.
Lü, M., Yu, S., Deng, J., Yan, Q., Yang, C., Xia, G., et al. (2016) Efficacy of probiotic supplementation therapy for Helicobacter pylori eradication: a meta-analysis of randomized controlled trials. PLoS One, 11(10): e0163743.
Cui, CX., Deng, JN., Yan, L., Liu, YY., Fan, JY., Mu, HN., et al. (2017) Silibinin capsules improves high fat diet-induced nonalcoholic fatty liver disease in hamsters through modifying hepatic de novo lipogenesis and fatty acid oxidation. J Ethnopharmacol, 208: 24-35.
Wah Kheong, C., Nik Mustapha, NR., Mahadeva, S. (2017) A randomized trial of silymarin for the treatment ofnonalcoholic steatohepatitis. Clin Gastroenterol Hepatol, 15(12): 1940-1949.e8.
Chen, WY., Chen, CJ., Liu, CH., Mao, FC. (2010) Chromium attenuates high-fat diet-induced nonalcoholic fatty liver disease in KK/HlJ mice. Biochemical and Biophysical Research Communications, 397(3): 459-464.
Hua, Y., Clark, S., Ren, J., Sreejayan, N. (2012) Molecular mechanisms of chromium in alleviating insulin resistance. J Nutri Biochem, 23(4): 313-319.
Anderson, RA. (2003) Chromium and insulin resistance. Nutrition Research Reviews, 16(2): 267-275.
Bedogni, G., Bellentani, S., Miglioli, L., Masutti, F., Passalacqua, M., Castiglione, A., et al. (2006) The fatty liver index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol, 6: 33. Supplementary Material Table S1: List of abbreviations used in the paper. Abbreviation Definition AE Adverse event LSM Least square mean IMP Investigation medical product NAFLD Non-alcoholic fatty liver disease AFLD Alcoholic fatty liver disease BMI Body mass index WC Waist circumference FLI Fatty liver index MS Metabolic syndrome GEE Generalized estimating equation AST Aspartate transferase ALT Alanine transferase GGT Gamma glutamyl transferase TG Triglyceride
Angulo, P., Hui, JM., Marchesini, G., Bugianesi, E., George, J., Farrell, GC., et al. (2007) The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology, 45(4): 846-854.
Stephen, S. (1993) Cross-over trials in clinical research. Statistics in practice. Chichester, England: John Wiley & Sons Ltd.
Diggle, PJ., Liang, KY., Zeger, SL. (1994) Analysis of longitudinal data. Oxford Statistical Science Series.
