Non-alcoholic fatty liver disease in adults: clinic, diagnostics, treatment. Guidelines for therapists, third version

metabolic syndrome, non-alcoholic fatty liver disease, metabolically associated fatty liver disease, liver steatosis, steatohepatitis, comorbidity

1. Rotonya M. Carr, Amanke Oranu, and Vandana Khungar. Non-alcoholic fatty liver disease: Pathophysiology and management. MScGastroenterol Clin North Am. 2016 Dec; 45(4): 639–652. doi: 10.1016/j.gtc.2016.07.003

2. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388–1402.

3. ICD-11 Implementation or Transition Guide, Geneva: World Health Organization; 2019; License: CCBY-NCSA3.0IGO.

4. Eslam M, Newsome PN, Anstee QM, et al. A new defi nition for metabolic associated fatty liver disease: an international expert consensus statement. Journal of Hepatology. (2020), doi: 10.1016/j.jhep.2020.03.039.

5. Eslam M, Sanyal AJ, George J. MAFLD: a consensus driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology. 2020 Feb 8. Doi:10.1053/j.gastro.2019.11.312.

6. Yasser Fouad, et al. What’s in a name? Renaming ‘NAFLD’ to ‘MAFLD’. Liver International. 2020;00:1–8.

7. Shi Z., Tuomilehto J., et al. Th e circadian syndrome predicts cardiovascular disease better than metabolic syndrome in Chinese adults. J Intern Med. 2020 Dec 19. PMID: 31081577. PMCID: PMC6851668. DOI: 10.1111 / joim.12924

8. Ribeiro A., Igual‐Perez M.‐J., Santos Silva E., Sokal E. M. Childhood fructoholism and fructoholic liver disease. Hepatol Commun. 2019;3:44–51. doi:10.1002/hep4.1291

9. DiStefano J.K., Shaibi G. Q. Th e relationship between excessive dietary fructose consumption and paediatric fatty liver disease. Pediatr Obes. 2020 Dec 11: e12759. doi: 10.1111/ijpo.12759

10. Jegatheesan P, De Bandt J. P. Fructose and NAFLD: the multifaceted aspects of fructose metabolism. Nutrients. 2017;9(3):230. doi: 10.3390/nu9030230

11. Jensen T., Abdelmalek M. F., Sullivan S., et al. Fructose and sugar: a major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018;68(5):1063–1075. doi: 10.1016/j.jhep.2018.01.019

12. Byrne C.D., Targher G. NAFLD: a multisystem disease. J Hepatol. 2015 Apr;62(1 Suppl): S47–64. doi: 10.1016/j.jhep.2014.12.012. PMID: 25920090.

13. Day C.P., James O. F. Steatohepatitis: a tale of two ‘hits’? Gastroenterology. 1998;114:842–845.

14. Sharma M., Mitnala S., Vishnubhotla R. K., et al. Th e Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis. Journal of Clinical and Experimental Hepatology. 2015 Jun;5(2):147–158. DOI: 10.1016/j.jceh.2015.02.002

15. Tilg H., Moschen A. R. Evolution of infl ammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–1846.

16. Buzzetti E., Pinzani M., Tsochatzis E. A. Th e multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD) Metabolism: Clinical and Experimental. 2016, 65(8):1038–1048. DOI: 10.1016/j.metabol.2015.12.012

17. Chelakkot C., Ghim J., Ryu S. H. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp Mol Med. 50, 103 (2018). Doi: 10.1038/s12276–018–0126-x

18. Nier A., et al. Markers of intestinal permeability are already altered in early stages of non-alcoholic fatty liver disease: Studies in children. PLoS One. 2017 Sep 7;12(9): e0183282.

19. Kapil S. et al. Small intestinal bacterial overgrowth and toll-like receptor signaling in patients with non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 2016;31:213–221.

20. Philips C.A., Augustine P., Yerol P. K., et al. Modulating the Intestinal Microbiota: Th erapeutic Opportunities in Liver Disease. J Clin Transl Hepatol. 2020;8(1):87–99. doi:10.14218/JCTH.2019.00035

21. Wijarnpreecha Karn А. et al. Small intestinal bacterial overgrowth and nonalcoholic fatty liver disease: a systematic review and meta-analysis. European Journal of Gastroenterology & Hepatology. May 2020, Vol. 32, Issue 5, pp. 601–608 doi: 10.1097/MEG.0000000000001541

22. de Faria Ghetti F., et al. Infl uence of gut microbiota on the development and progression of nonalcoholic steatohepatitis. Eur J Nutr. 2018;57(3):861–876.

23. Seliverstov P.V., Sitkin S. I., Radchenko V. G., et al. Saccharomyces boulardii modulates the composition of the gut microbiota in patients with non-alcoholic fatty liver disease, thus preventing the progression of the disease. Experimental and Clinical Gastroenterology. 2018;(2):4–18. (In Russ.)

24. Jiang W., et al. Dysbiosis gut microbiota associated with infl ammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. Sci Rep. 2015;5:8096.

25. Shen F., et al. Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease. Hepatobiliary Pancreat Dis Int. 2017;16(4):375–381.

26. Boursier J, et al. Th e severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology. 2016;63(3):764–775.

27. Elizabeth K. Speliotes et al. Genome- Wide Association Analysis Identifi es Variants Associated with Nonalcoholic Fatty Liver Disease Th at Have Distinct Eff ects on Metabolic Traits. PLoS Genet. 2011 Mar; 7(3): e1001324.

28. Anstee Q.M., Darlay R., Cockell S., Meroni M., et al. Genomewide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort. Journal of Hepatology. 2020, Vol. 73, Issue 3, pp. 505–515.

29. Pang, J, Xu, W, Zhang, X, et al. Significant positive association of endotoxemia with histological severity in 237 patients with non‐alcoholic fatty liver disease. Aliment Pharmacol Th er. 2017; 46: 175–182. Doi:10.1111/apt.14119

30. Kurtanov K. A., Sydykova L. A., Pavlova N. I., et al. Polymorphism of the adiponutrin gene (PNPLA3) in the indigenous inhabitants of the Republic of Sakha (Yakutia) with type 2 diabetes mellitus. Almanac of Clinical Medicine. 2018;46(3):258–263. (In Russ.) doi: 10.18786/2072–0505–2018–46–3–258–263

31. Krolevets T. S., Livzan M. A., Akhmedov V. A., Novikov D. G. Study of PNPLA3 gene polymorphism in patients with non-alcoholic fatty liver disease and various stages of fi brosis. Experimental and Clinical Gastroenterology. 2018;159(11): 24–32. (In Russ.) DOI: 10.31146/1682–8658-ecg-159–11–24–32

32. Raikhelson K. L., Kovyazina V. P., Sidorenko D. V. et al. PNPLA gene polymorphism impact on the nonalcoholic fatty liver disease course. RMJ. 2019;12:85–88.

33. Dyakonova A. T., Kurtanov K. A., Pavlova N. I., et al. Polymorphism rs58542926 of the TM6SF2 gene in chronic non-infectious liver diseases in the yakut population. Modern problems of science and education. 2019, no. 6 (in Russ) Avalible at: http://www.science education.ru/ru/article/view?id=29334

34. Vajro P., Lenta S., Socha P., Dhawan A., et al. Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr. 2012. Vol.54, pp. 700–713.

35. Vos M.B., Abrams S. H., Barlow S. E., et al. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr. 2017 Feb;64(2):319–334. doi: 10.1097/MPG.0000000000001482. PMID: 28107283; PMCID: PMC5413933.

36. ICD-11 for Mortality and Morbidity Statistics (Version: 09/2020) Available from: https://icd11.ru/ (in Russ.)

37. Kleiner D.E, Brunt E.M, Natta M. Van, Behling C., Contos M.J, Oscar, et al. Nonalcoholic Steatohepatitis Clinical Research Network Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005 Jun;41(6):1313–21. doi: 10.1002/hep.20701.

38. Sorbi D., Boynton J., Lindor K. D. Th e ratio of aspartate aminotransferase to alanine aminotransferase: potential value in diff erentiating non-alcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol. 1999; 94: 1018–22.

39. Cerović I., et al. Alcoholic liver disease/nonalcoholic fatty liver disease index: distinguishing alcoholic from nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2013 Aug;25(8):899–904.

40. Lazebnik L. B., Golovanova E. V., Eremina E. Yu., et al. Clinical recommendations: alcoholic liver disease in adult. Th erapy. 2020, Vol. 6, No. 4 (38), pp. 10–35. (in Russ) doi: 10.18565/therapy.2020.4.10–35

41. Maev I.V., Samsonov A. A., Lazebnik L. B. et al. A New, Non- Invasive Scale for Steatosis Developed Using Real- World Data From Russian Outpatients to Aid in the Diagnosis of Non- Alcoholic Fatty Liver Disease. Adv Th er. 2020, no.37, pp. 4627–4640. Doi: 10.1007/s12325–020–01493-w

42. Chalasani N., Younossi Z., Lavine J. E., Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal A. J. Th e diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Jan; 67(1):328–357

43. Simona Leoni, Francesco Tovoli, Lucia Napoli, Ilaria Serio, Silvia Ferri, and Luigi Bolondi Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis. World J Gastroenterol. 2018 Aug 14; 24(30): 3361–3373. doi: 10.3748/wjg.v24.i30.3361

44. Raj Vuppalanchi, Robert J. Gould, Laura A. Wilson, Aynur Unalp- Arida, Oscar W. Cummings,1 Naga Chalasani, Kris V. Kowdley Clinical Signifi cance of Serum Autoantibodies in Patients With NAFLD: Results From The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) / Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Hepatol Int. 2012 Jan; 6(1): 379–385. doi: 10.1007/s12072–011–9277–8

45. Elke M. Hennes, Mikio Zeniya, Albert J. Czaja, Albert Parés, George N. Dalekos, et al. Simplifi ed criteria for the diagnosis of autoimmune hepatitis. International Autoimmune Hepatitis Group. Hepatology. 2008 Jul;48(1):169–76. doi: 10.1002/hep.22322.

46. Karlas T., Petroff D., Sasso M., Fan J. G., Mi Y. Q. Individual patient data meta-analysis of controlled attenuation parameter (cap) technology for assessing steatosis. Hepatol. 2017;66(5):1022–1030. doi: 10.1016/j.jhep.2016.12.022

47. Angulo P., et al. Liver Fibrosis, but no Other Histologic Features, Associates with Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2015 Aug; 149(2): 389–397.e10. doi: 10.1053/j.gastro.2015.04.043

48. Sterling R.K., Lissen E., Clumeck N., et. al. Development of a simple noninvasive index to predict significant fibrosis patients with HIV/HCV co-infection. Hepatology. 2006;43:1317–1325.

49. Sun W., et al. Comparison of FIB-4 index, NAFLD fi brosis score and BARD score for prediction of advanced fi brosis in adult patients with non-alcoholic fatty liver disease: A meta-analysis study. Hepatol Res. 2016 Aug;46(9):862–70.

50. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. Journal of Hepatology. 2015, vol. 63, j 237–264. DOI: 10.1016/j.jhep.2015.04.006

51. Zhang X., Wong G. L.H., Wong V. W. S. Application of transient elastography in nonalcoholic fatty liver disease. Clin Mol Hepatol. 2020;26(2):128–141.

52. Karolina Grąt, Michał Grąt, Olgierd Rowiński. Usefulness of Diff erent Imaging Modalities in Evaluation of Patients with Non Alcoholic Fatty Liver Disease. Biomedicines. 2020;8(9):298. doi: 10.3390/biomedicines8090298.,

53. Zobair M. Younossi, Rohit Loomba, Quentin M. Anstee, Mary E. Rinella. Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fi brosis. Hepatology. 2018;68(1):349–360. doi: 10.1002/hep.29721

54. Diomidova V. N., Petrova O. V. Comparative Analysis of Shear Wave Elastography and Transient Elastography in Diagnosis of Diff use Liver Disease. Ultrasound and functional diagnostics. 2013, no.5, pp. 17–23. (in Russ)

55. Morozova T. G., Borsukov A. V. Th e comprehensive elastography in diff erential diagnostic of diff use liver disease. Scientific notes of Orel State University. 2015, Vol. 4, no. 67, pp. 378–382. (in Russ)

56. Morozova T. G., Borsukov A. V., Bueverov A. O. Multiparametric elastography – principles of individual selection in the diff use liver diseases. Meditsinskiy sovet = Medical Council. 2017;(15):148–152. (In Russ.) doi: 10.21518/2079–701X-2017–15–148–152

57. Yangurazova A. E., Tukhbatullin M. G., Galeyeva Z. M. Complex ultrasound diagnostics in the evaluation of the liver state in patients with nonalcoholic fatty liver disease during treatment. Practical medicine. 2016;9(101):74–77. (in Russ)

58. Diomidova V. N., Tarasova L. V., Trukhan D. I., et al. Informational con-tent of shear wave elastography with elastometry in non-alcoholic fatty liver disease. Practical medicine. 2018;1(112):81–85. (in Russ)

59. Diomidova V. N., Tarasova L. V., Tsyganova Yu.V., Valeeva O. V., Ivanova A. L. Ultrasound hepatic elastography with decaying signal technology allows assessing the degree of steatosis and dynamic monitoring of the eff ectiveness of NAFLD treatment. Experimental and Clinical Gastroenterology. 2020;181(9): 45–54. (In Russ.) DOI: 10.31146/1682–8658-ecg-181–9–45–54

60. Katrich A. N., Okhotina A. V., Shamakhyan K. A., Ryabin N. S. Ultrasound shear wave elastography in the diagnosis of liver fi brosis stage. Ultrasound and Functional Diagnostics. 2017, no. 3, pp. 10–21. (in Russ)

61. Adams L.A., Lymp J. F., St. Sauver J., et al. Th e natural history of nonalcoholic fatty liver disease: a population based cohort study. Gastroenterol. 2005;129 (1);113–121.

62. Hashimoto E., Yatsuji S., Tobari M., et al. Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. J Gastroenterol. 2009;44 (19):89–95.

63. Ascha M.S., Hanouneh I. A., Lopez R., et al. Th e incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatol. 2010;51 (6):1972–1978.

64. Singal A., Volk M. L., Waljee A., Salgia R., Higgins P., Rogers M. A.M., Marrero J. A. Meta-analysis: surveillance with ultrasound for early stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Th er. 2009, no.30, pp.37–47.

65. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018 Jul;69(1):182–236. doi: 10.1016/j.jhep.2018.03.019.

66. Bedogni G., Bellentani S., Miglioli L., et al. Th e fatty liver index: a simple and accurate predictor of hepatic steatosis. BMC Gastroenterol. 2006; 6:33.

67. Barrera F., George J. Clin Liver Dis. 2014;18:91–112

68. Gepner Y., et al. Th e benefi cial eff ects of Mediterranean diet over low-fat diet may be mediated by decreasing hepatic fat content. J Hepatol. 2019 Aug;71(2):379–388. doi: 10.1016/j.jhep.2019.04.013.

69. Suarez M., Boque N., Del Bas J. M., Mayneris Perxachs J., Arola L., Caimari A. Mediterranean diet and multi ingredient- based interventions for the management of non-alcoholic fatty liver disease. Nutrients. 2017; 9 (10), pii: E1052. DOI: 10.3390/nu9101052

70. Romero Gomez M, Zelber Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67(4):829–46.

71. Berzigotti A., Saran U., Dufour J. F. Physical activity and liver diseases. Hepatology. 2016 Mar;63(3):1026–40. doi: 10.1002/hep.28132. Epub 2015 Dec 18. PMID: 26313307.

72. Ryuki Hashida, et al. Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: A systematic review. Journal of Hepatology. 2017, vol. 66, j 142–152,

73. Boström, Pontus, Jun Wu, Mark P. Jedrychowski, Anisha Korde, Li Ye, James C. Lo, Kyle A. Rasbach, et al. 2012. A PGC1-α-dependent myokine that drives brown-fatlike development of white fat and thermogenesis. Nature. 481(7382): 463–468.

74. Kechagias S. Fast-food-based hyperalimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects. Gut. 2008; 57: 649–654.

75. Sun. Meta-analysis on shift work and risks of specifi c obesity types. Obes Rev. 2018 Jan;19(1):28–40.

76. Andrade. Eating Slowly Led to Decreases in Energy Intake within Meals in Healthy Women. Journal of the American Dietetic Association. 2008, Vol.108, Issue 7, pp. 1186–1191.

77. Yuki Fujii, et al. Outcome of Living Donor Liver Transplantation Using Graft s from Donors Treated for Fatty Liver. Ann Transplant. 2020; 25: e920677.

78. Loomba R. Lim J. K. Patton H. El Serag H. B. AGA Clinical Practice Update on Screening and Surveillance for Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease: Expert Review Gastroenterol. Gastroenterology. 2020, Vol. 158, Issue 6, pp. 1822–1830. DOI: 10.1053/j.gastro.2019.12.053

79. Loomba R., Yang H. I., Su J., et al. Synergism between obesity and alcohol in increasing the risk of hepatocellular carcinoma: a prospective cohort study. Am J Epidemiol. 2013; 177: 333–342.

80. Turati F. Galeone C. Rota M., et al. Alcohol and liver cancer: a systematic review and meta-analysis of prospective studies. Ann Oncol. 2014; 25: 1526–1535.

81. Kolly P., Knopfl i M., Dufour J. F. Eff ect of smoking on survival of patients with hepatocellular carcinoma. Liver Int. 2017; 37: 1682–1687.

82. Petrick J. L. Campbell P. T. Koshiol J.et al. Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: Th e Liver Cancer Pooling Project. Br J Cancer. 2018; 118: 1005–1012.

83. Sanyal A.J., Chalasani N., Kowdley K. V., McCullough A., Diehl A. M., Bass N. M., et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steato- hepatitis. N Engl J Med. 2010;362:1675–1685.

84. Lavine E., Schwimmer J. B., VanNatta M.L., Molleston J. P., Murray K. F., Rosenthal P. et al. Eff ect of Vitamin e or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents the tonic randomized controlled trial. Journal of the American Medical Association. 305 (2011), pp. 1659–1668.

85. Vilar Gomez E., Vuppalanchi R., Gawrieh S., Ghabril M., Saxena R., Cummings O. W., Chalasani N. Vitamin E Improves Transplant Free Survival and Hepatic Decompensation Among Patients With Nonalcoholic Steatohepatitis and Advanced Fibrosis. Hepatology. 2020 Feb;71(2):495–509. doi: 10.1002/hep.30368. Epub 2019 Mar 6. PMID: 30506586.

86. Mayevskaya M. V., Nadinskaia M. Yu., Lunkov V. D., et al. An Eff ect of Ursodeoxycholic Acid on Infl ammation, Steatosis and Liver Fibrosis and Atherogenesis Factors in Patients with Non Alcoholic Fatty Liver Disease: Results of the USPEH Study. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2019;29(6):22–29. (In Russ.) doi:10.22416/1382–4376–2019–29–6–22–29

87. Martsevich S. Yu., Kutishenko N. P., Drozdova L. Yu., et al. Study of ursodeoxycholic acid infl uence on efficacy and safety of statin therapy in patients with diseases of the liver, gall bladder and/or biliary tract (the RAKURS study). Rational Pharmacotherapy in Cardiology. 2014;10(2):147–152. (In Russ.) doi: 10.20996/1819–6446–2014–10–2–147–152

88. Higinio Mappala et al. The efficacy of ursodeoxycholic acid in the treatment of non-alcoholic steatohepatitis: A 15-year systematic review. Gut. 2019;68 (Suppl 1): A1–A166

89. Simental- Mendía Luis E. Eff ect of ursodeoxycholic acid on liver markers: A systematic review and meta-analysis of randomized placebo- controlled. Br J Clin Pharmacol. 2020 Apr 14. doi: 10.1111/bcp.14311. [Epub ahead of print] clinical trials

90. Zhang Y., Jiang R., Zheng X., Lei S., Huang F., Xie G., Kwee S., Yu H., Farrar C., Sun B., Zhao A., Jia W. Ursodeoxycholic acid accelerates bile acid enterohepatic circulation. Br J Pharmacol. 2019 Aug;176(16):2848–2863. doi: 10.1111/bph.14705. Epub 2019 Jul 6. PMID: 31077342; PMCID: PMC6637225.

91. Pirogova I. Yu., Yakovleva S. V., Neujmina T. V., Sinitsyn S. P., Chulkov V. S. Pleiotropic eff ects of ursosan in non-alcoholic fatty liver disease and metabolic syndrome. Consilium medicum. 2018, no.1, pp.7–14. (in Russ)

92. Pirogova I. Yu., Yakovleva S. V., Neuimina T. V. et al. Pleiotropic effects of ursodeoxycholic acid in non-alcoholic fatty liver disease and metabolic syndrome. Consilium Medicum. 2019; 21 (8): 65–70. (in Russ) DOI: 10.26442/20751753.2019.8.190365

93. Kozlova I. V. et al., Optimization of therapy for hepatobiliary disorders in psoriatic patients. Ter Arkh. 2017, vol.89, no. 12(2), pp. 204–210. (in Russ)

94. Leuschner U., Lindenthal B., Herrmann, G. Arnold J. C., Rössle M., Cordes H. J. et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double blind, randomized, placebo controlled trial. Hepatology. 2010, no.52, pp.472–479.

95. Sauter G.H., Th iessen K., Parhofer K. G., Jüngst C., Fischer S. Jüngst. D: Effects of Ursodeoxycholic Acid on Synthesis of Cholesterol and Bile Acids in Healthy Subjects. Digestion. 2004;70:79–83. doi: 10.1159/000080925

96. Guarino M. P., Cocca S., Altomare A., Emerenziani S., Cicala M. Ursodeoxycholic acid therapy in gallbladder disease, a story not yet completed. World J Gastroenterol. 2013 Aug 21;19(31):5029–34. doi: 10.3748/wjg.v19.i31.5029. PMID: 23964136; PMCID: PMC3746374.

97. Trauner M., Claudel T., Fickert P., Moustafa T., Wagner M. Bile acids as regulators of hepatic lipid and glucose metabolism. Dig Dis. 2010;28(1):220–4. doi: 10.1159/000282091. Epub 2010 May 7. PMID: 20460915.

98. Simental Mendía L. E., Simental Mendía M., Sánchez García A., et al. Impact of ursodeoxycholic acid on circulating lipid concentrations: a systematic review and metaanalysis of randomized placebo controlled trials. Lipids Health Dis. 2019;18(1):88. Published 2019 Apr 6. doi:10.1186/s12944–019–1041–4

99. Gundermann K.J., Gundermann S., Drozdzik M., Mohan Prasad V. G. Essential phospholipids in fatty liver: a scientifi c update. Clin Exp Gastroenterol. 2016 May 5;9:105–17. doi: 10.2147/CEG.S96362. PMID: 27217791; PMCID: PMC4861608

100. Gonciarz Z, Besser P, Lelek E, Gundermann KJ, Johannes KJ. Randomised placebo controlled double blind trial on “essential” phospholipids in the treatment of fatty liver associated with diabetes. Méd Chir Dig. 1988;17(1):61–65.

101. Li JH, Chen XY, Zhong CF, Min J. A randomized controlled study of essential phospholipids (Essentiale capsules) in the treatment of fatty liver. Infect Dis Info. 2000;13(4):180–181.

102. Yin D, Kong L. Observation for curative effect of Essentiale in treatment of fatty liver caused by diabetes mellitus. Med J Q Ilu. 2000;15:277–278.

103. Sun C, Zheng X, Tan Z, Cui F, Zhang R, Zhang H. Clinical observation on polyene phosphatidyl choline and metformin in the treatment of type 2 diabetes and non-alcoholic fatty liver disease. Clin Focus. 2008;23(17):1272–1273.

104. Wu Yan, Efficacy analysis of polyene phosphatidylcholine for type 2 diabetes complicated with fatty liver. Journal of TCM University of Hunan. 2009, 29(12): 41–42.

105. Sas E., Grinevich V., Efimov O., Shcherbina N.. Beneficial influence of polyunsaturated phosphatidylcholine enhances functional liver condition and liver structure in patients with nonalcoholic steatohepatitis accompanied by diabetes type 2. Results of prolonged randomized blinded prospective clinical study [abstract]. J Hepatol. 2013;58: S549.

106. Li Zhiguo, et al, Efficacy of polyene phosphatidylcholine in combination with metformin for diabetes complicated with non-alcoholic fatty liver disease. Inner Mongol Journal of Traditional Chinese Medicine. 2013 No. 31, 10–11.

107. Dajani, et al, Essential phospholipids for nonalcoholic fatty liver disease associated with metabolic syndrome: A systematic review and network meta-analysis. World J Clin Cases. 2020 November 6; 8(21): 5070–5495

108. Maev I.V., Samsonov A. A., Palgova L. K., et al. Effectiveness of phosphatidylcholine in alleviating steatosis in patients with non-alcoholic fatty liver disease and cardiometabolic comorbidities (MANPOWER study). BMJ Open Gastroenterology. 2020;7: e000341.

109. Lieber C.S., Packer L. S-adenosylmethionine: molecular, biological, and clinical aspects – an introduction. Am J Clin Nutr. 2002;76 (5):1148S-1150S.

110. Ou X, Yang H, Ramani K, Ara AI, Chen H, Mato JM, et al. Inhibition of human betaine homocysteine methyltransferase expression by S-adenosylmethionine and methylthioadenosine. Biochem J. 2007;401 (1):87–96.

111. Gil B, Casado M., Pajares M. A., Bosca L., Mato J. M., Martin Sanz P., et al. Differential expression pattern of S-adenosylmethionine synthetase soenzymes during rat liver development. Hepatology. 1996;24 (4):876–881.

112. Mato J.M., Corrales F. J., Lu S. C., Avila M. A. S-adenosylmethionine: a control switch that regulates liver function. FASEB J. 2002;16 (1):15–26.

113. Vendemiale G, Altomare E, Trizio T, Le Grazie C, Di Padova C, Salerno MT, et al. Eff ects of oral S-adenosyl L-methionine on hepatic glutathione in patients with liver disease. Scand J Gastroenterol. 1989;24 (4):407–415.

114. Virukalpattigopalratnam M.P., Singh T., Ravi shan kar A. C. Heptral (ademetionine) in patients with intrahepatic cholestasis in chronic liver disease due to non-alcoholic liver disease: results of a multicentre observational study in India. J Indian Med Assoc. 2013 Dec;111(12):856–9. PMID: 25154164.

115. Raikhelson K. L., Kondrashina E. A. Àdåmethionine in the treatment of fatigue in liver diseases: a systematic review. Therapeutic Archive. 2019; 91 (2): 134–142. (in Russ) DOI: 10.26442/00403660.2019.02.000130

116. Frezza M., Surrenti C., Manzillo G., Fiaccadori F., Bortolini M., Di Padova C. Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis. Gastroenterology. 1990;99(1):211–5. doi: 10.1016/0016–5085(90)91250-a

117. Fiorelli G. S-Adenosylmethionine in the treatment of intrahepatic cholestasis of chronic liver disease: A fi eld trial. Curr Th er Res. 1999;60(6):335–48. doi: 10.1016/s0011–393x(99)80010–1

118. Di Perri T., Sacco T., Festi D. Th e SMACK Investigator Group. Ademetionine in the treatment of chronic hepatic disease. Gastroenterol Int. 1999;12(2):62–8.

119. Podymova S. D., Nadinskaya M. Yu. Evaluation of the effectiveness of the drug Heptral in patients with chronic diff use liver diseases with intrahepatic cholestasis syndrome. Clinical medicine. 1998; 76 (10): 45–48. (in Russ)

120. Baranovsky A. Yu., Raykhelson K. L., Marchenko N. V. Application of s-adenosylmethionine (Heptral®) in treatment of patients with non-alcoholic steatohepatitis. Clinical prospects of gastroenterology, hepatology. 2010;9(1):3–10. (in Russ).

121. Bressa G.M. S-Adenosyl L-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand. 1994;154: 7–14.

122. Butterworth R.F., Kircheis G., Hilger N., McPhail M. J. W. Effect of L-ornithine L-aspartate for the treatment of hepatic encephalopathy and hyperammonemia in cirrhosis: systematic review and meta-analysis of ran- domized controlled trials. J Clin Exp Hepatol. 2018. DOI: 10.1016/j.jceh.2018.05.004

123. Grungreiff K., Lambert Baumann J. Efficacy of L-ornithine L-aspartate granules in chronic liver diseases. Med Welt. 2001;52:219–226.

124. Tian L.Y., Lu L. G., Tang C. W., Xie Y., Luo H. S., Tan S. Y. et al. Aspartate ornithine granules in the treatment of non-alcoholic steatohepatitis: a multiple-dose parallel controlled clinical trial. Zhonghua Gan Zang Bing Za Zhi. 2013;21:528–32.

125. Ermolova T., Ermolov S. Correction of intrahepatic microcirculation disorders by L-ornithine L-aspartate in chronic liver disease patients. J Hepatol. 2018;68(Sup-pl 1): S585–6.].

126. Butterworth R. F., Canbay A. Hepatoprotection by L-Ornithine L-Aspartate in Non Alcoholic Fatty Liver Disease. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2019;29(1):24–30. (In Russ.) doi: 10.22416/1382–4376–2019–29–1–24–30

127. Lazebnik L. B., Golovanova E. V., Alekseenko S. A., et al. Russian Consensus “Hyperammonemia in Adults”. Experimental and Clinical Gastroenterology. 2019;(12):4–23. (In Russ.) doi:10.31146/1682–8658-ecg-172–12–4–23

128. Federico A, Dallio M, Loguercio C. Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years. Molecules. 2017; 22: [PMID: 28125040 DOI: 10.3390/molecules22020191]

129. Abenavoli L., Greco M., Nazionale I., Peta V., et al. Effects of Mediterranean diet supplemented with silybin vitamin E-phospholipid complex in overweight patients with non-alcoholic fatty liver disease. Expert Rev. Gastroenterol Hepatol. 2015; 9: 519–527 [PMID: 25617046 DOI: 10.1586/17474124.2015.1004312]

130. C. Wah Kheong, N. R. Nik Mustapha, S. Mahadeva. A randomized trial of silymarin for the treatment of nonalcoholic steatohepatitis. Clinical Gastroenterology and Hepatology. 15 (2017), pp. 1940–1949, e1948

131. Navarro V.J., Belle S. H., D’Amato M., Adfh al N., Brunt E. M., Fried M. W., et al. Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: a randomized, double blind, placebo controlled trial. PloS One. 14 (2019), Article e0221683.

132. Santini D. et al. S-adenosylmethionine (AdoMet) supplementation for treatment of chemotherapy induced liver injury. Anticancer Res. 2003, Vol. 23, no. 6D, pp. 5173–5179.

133. Bjornsson ES. Epidemiology and risk factors for idiosyncratic drug-induced liver injury. Semin Liver Dis. 2014, 34(2): 115–122

134. Larionova V. B., Gromova E. G., Snegovoy A. V. Clinical guidelines for the correction of hepatotoxicity induced by antitumor chemotherapy. Moscow, 2014. (in Russ)

135. Murakami S, Kondo Y, Nagate T. Effects of long-term treatment with taurine in mice fed a high-fat diet: improvement of cholesterol metabolism and vascular lipid accumulation by taurine. Adv Exp Med Biol. 2000; 483: 177–86.

136. De la Puerta C, Arrieta FJ, Balsa JA et al. Taurine and glucose metabolism: a review. Nutr Hosp. 2010; 25: 910–919.

137. Rodella P, Takase L, dos Santos L et al. Th e Eff ect of Taurine on Hepatic Disorders [Version 2]. Curr Updates. Hepatol Gastroenterol. 2017; 1: 1.2.

138. Murakami S, Ono A, Kawasaki A, Takenaga T, Ito T. Taurine attenuates the development of hepatic steatosis through the inhibition of oxidative stress in a model of nonalcoholic fatty liver disease in vivo and in vitro. Amino Acids. 2018;50(9):1279–1288. doi:10.1007/s00726–018–2605–8

139. Obinata K, Maruyama T, Hayashi M, Watanabe T, Nittono H. Eff ect of taurine on the fatty liver of children with simple obesity. Adv Exp Med Biol. 1996;403:607–613. Doi:10.1016/j.jcjd.2020.05.004

140. Statsenko M. E., Turkina S. V., Shilina N. N. et al. Nonalcoholic fatty liver disease pharmacotherapy: accent on fi brosis. Consilium Medicum. 2018; 20 (8): 37–41. (in Russ) DOI: 10.26442/2075–1753_2018.8.37–41

141. Statsenko M. E., Turkina S. V., Gorbacheva E. E. et al. Infl uence of taurin at the degree of internal obesity and severity of visceral fat dysfunction in patients with non-alcoholic fatty liver disease. Consilium Medicum. 2019; 21 (12): 128–133. (in Russ) DOI: 10.26442/20751753.2019.12.190666

142. Sun Q., Wang, B., Li Y., et al. Taurine supplementation lowers blood pressure and improves vascular function in prehypertension: randomized, double blind, placebo controlled study. Hypertension. 2016. V. 67. P. 541–549.

143. Statsenkо M. E., Turkina S. V., Shilina N. N. Liver damage in patients with ischemic chronic heartand type 2 diabetes – a treacherous tandem: possible additional organoprotective therapy. Consilium Medicum. 2016; 18 (5): 103–9. (in Russ.)

144. Ito T., Schaff er S. W., Azuma J. Th e potential usefulness of taurine on diabetes mellitus and its complications. Amino Acids. 2012 May;42(5):1529–39. doi: 10.1007/s00726–011–0883–5. Epub 2011 Mar 25. PMID: 21437784; PMCID: PMC3325402.

145. Guan L, Miao P. The effects of taurine supplementation on obesity, blood pressure and lipid profile: A meta-analysis of randomized controlled trials. Eur J Pharmacol. 2020 Oct 15;885:173533. doi: 10.1016/j.ejphar.2020.173533. Epub 2020 Aug 29. PMID: 32871172.

146. Сhen W., Guo J., Zhang Y. Z., Zhang J. Th e beneficial effects of taurine in preventing metabolic syndrome. Food Funct. 2016. 33 р. doi: 10.1039/C5FO01295C.

147. Lazebnik L. B., Radchenko V. G., Dzhadhav S. N., Sitkin S. I., Seliverstov P. V. Systemic inflammation and non-alcoholic fatty liver disease. Experimental and Clinical Gastroenterology. 2019;(5):29–41. (In Russ.) doi:10.31146/1682–8658-ecg-165–5–29–41

148. Polukhina A. V., Vinnitskaya Ye.V., Bordin D. S., Sandler Yu. G. Non- Alcoholic Fatty Liver Disease in Patients with Comorbidities: the Experience of Th erapy with the Use of Th iotriazolin. Effective pharmacotherapy. 2018, No. 3. (in Russ).

149. Sandler Yu.G., Matveeva Yu.A., Vinnitskaya E. V. et al. Antihypoxants and antioxidants for non-alcoholic liver disease. RMJ. 2016, no. 26, pp. 1815–1818. (in Russ)

150. Kinoshenko E. I., Nikonov V. V., Bila I. Ye., Kolomyiets V. I. Complex approach to treatment of myocardial infarction combined with non-alcoholic fatty liver disease. Emergency medicine. 2017, Vol: 0, Issue: 1.80, pp. 47–60. (in Russ) DOI: 10.22141/2224–0586.1.80.2017.94451

151. Savchenko S. A., Filippov A. E. Materials of the symposium “Th iotriazoline: cardioprotection from the standpoint of evidence based medicine” in the framework of the Russian National Congress of Cardiology. Russian Medical Journal. 2017, no. 27, pp. 1638–1643. (in Russ)

152. Kadin D. V., Chumak B. A., Filippov A. E., Shustov S. B. Th iotriazoline in the treatment of stable angina II–III functional class. Kardiologiia. 2015, no. 8, pp. 72–81. (In Russ.)

153. Lazebnik L. B., Golovanova E. V., Simanenkov V. I., et al. Possibilities of polytropic therapy with thiotriazoline in patients with non-alcoholic steatohepatosis and cardiovascular risk factors. Th e results of the TRIGON-1 observation program. Experimental and Clinical Gastroenterology. 2020;(8):10–18. (In Russ.) DOI: 10.31146/1682–8658-ecg-180–8–10–18

154. Pirogova I. Yu., Sinitsyn S. P., Chulkov V. S. Clinical effi cacy of Heptrong in patients with non-alcoholic liver disease in real clinical practice (pilot study). Experimental and Clinical Gastroenterology. 2020;(12):109–118. (In Russ.) https://doi.org/10.31146/1682–8658-ecg-184–12–109–118.

155. Caroline Stokes, et al. Ursodeoxycholic Acid and Diets Higher in Fat Prevent Gallbladder Stones During Weight Loss: A Meta-analysis of Randomized Controlled Trials. Clinical Gastroenterology and Hepatology. 2014;12:1090–1100.

156. Tamer M. Nabil, et al. Effect of Oral Ursodeoxycholic Acid on Cholelithiasis Following Laparoscopic Sleeve Gastrectomy for Morbid Obesity. Surg Obes Relat Dis. 2019 Jun;15(6):827–831. doi: 10.1016/j.soard.2019.03.028

157. Virstyuk N. G., Senyutovich N. R. Th e role of growth factors in pathogenesis of hepatic lesions in patients with metabolic syndrome and chronic non-calculous cholecystitis. Klinicheskaya Meditsina. 2013, no.9, pp. 22–25. (in Russ)

158. Efremova L. I., Pecherskikh M. V., Kazakova I. A., Shaverskaya E. S. Dysfunctions of liver in patients with chronic acalculous cholecystitis and their correction. Medical alphabet. 2018;1(7):38–41. (In Russ.)

159. Kashaeva M. D., Proshina L. G., Artiushin B. S., Shvetsov D. A. Morphofunctional changes of the liver in cholelithic illness and their treatment. Vestnik NovSU. 2015, no.2(85), pp. 141–146. (in Russ)

160. Filippova A. Yu. Diagnostics of progression of liver fi brosis in patients with non-alcoholic steatohepatitis combined with obesity and chronic calculous cholecystitis. Medicni perspektivi. 2020;25(1):65–73. (in Russ) DOI: 10.26641/2307–0404.2020.1.200403

161. EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones. Journal of Hepatology. 2016, Vol. 65, Iss. 1, pp. 146–181.

162. Ivashkin V. T., Mayev I. V., Baranskaya Ye.K., et al. Gallstone disease diagnosis and treatment: guidelines of the Russian gastroenterological association. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2016, no.3, pp. 64–80. (in Russ)

163. Ivashkin V. T., Mayev I. V., Shulpekova Yu.O., et al. Diagnostics and treatment of biliary dyskinesia: clinical guidelines of the Russian gastroenterological Association. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2018;28(3):63–80. (In Russ.) doi:10.22416/1382–4376–2018–28–3–63–80

164. Khokhlachyova N. А., Glazyrina N. N. Cholelithiasis: chances to avoid cholecystectomy. Medical alphabet. 2019;3(20):5–10. (In Russ.) doi:10.33667/2078–5631–2019–3–20(395)-5–10.

165. Maev I. V., Dicheva D. T., Buragina T. A. Diagnostics and treatment of biliary sludge in patients with gastric ulcer disease. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2007, no. 4, pp. 55–58. (in Russ)

166. Mekhtiev S. N., Mekhtieva О. А. Functional disorders of the gallЫadder in the practice of the therapist. Consilium Medicum. 2017; 19 (8.1. Gastroenterology):35–41. (in Russ)

167. Pittler M. H., Thompson C. J., and Ernst E. Artichoke leaf extract for treating hypercholesterolaemia. Th e Cochrane Database of Systematic Reviews. 2009. no. 4, Article ID CD003335.

168. Shima K.R., Ota T., Kato K., et al. Ursodeoxycholic acid potentiates dipeptidyl peptidase-4 inhibitor sitagliptin by enhancing glucagon-like peptide-1 secretion in patients with type 2 diabetes and chronic liver disease: a pilot randomized controlled and add-on study BMJ Open Diabetes Research and Care. 2018;6: e000469. doi: 10.1136/bmjdrc-2017–000469

169. Nowrouzi-Sohrabi P., Rezaei S, Jalali M., et al. The effects of glucagon-like peptide-1 receptor agonists on glycemic control and anthropometric profi les among diabetic patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials. Eur J Pharmacol. 2021;893:173823. doi: 10.1016/j.ejphar.2020.173823Nowrouzi- Sohrabi

170. Fan S., Shi X., Yao J., et al. Th e effi cacy of glucagon-like peptide 1 receptor agonists in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials. Rev Esp Enferm Dig. 2020;112(8):627–635. doi: 10.17235/reed.2020.6392/2019

171. Dugherty J.A., Guirguis E., Thornby K. A. A systematic review of newer antidiabetic agents in the treatment of nonalcoholic fatty liver disease. Ann Pharmacother. 2021;55(1):65–79. doi: 10.1177/1060028020935105

172. Shahid I., et al. Antidiabetic drugs and non-alcoholic fatty liver disease: a systematic review, meta-analysis and evidence map. Dig Liver Dis. 2021;53(1):44–51. doi: 10.1016/j.dld.2020.08.021

173. Lv X., Dong Y., Hu L., et al. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the management of nonalcoholic fatty liver disease (NAFLD): a systematic review. Endocrinol Diabetes Metab. 2020;3(3): e00163. doi: 10.1002/edm2.163

174. Targher G. Non-alcogolic fatty liver disease and cardiovascular disease risk. Curr. Cardio Risk. Rep. 2010; 4: 32–9.

175. Golofeevsky V. Yu. Th e most important problems of the pathomorphogenesis and treatment of nonalcoholic fatty liver disease in patients with diabetes mellitus. Doctor. 2012.7, 8–10. (in Russ)

176. Standards for specialized medical care for diabetic polyneuropathy: order of the Ministry of Health of the Russian Federation of 12.24.2012 No. 1544-n and order of the Ministry of Health of the Russian Federation of 28.12.2012 No. 1577-n 2. (in Russ)

177. Ipatova O. M. Phosphogliv: mechanism of action and clinical use. Moscow. GU Research Institute of Biomedical Chemistry, Russian Academy of Medical Sciences Publ., 2005. 318 p.

178. Okovity S. V., Raikhelson K. L., Volnukhin A. V., Kudlai D. A. Hepatoprotective properties of glycyrrhizic acid. Experimental and Clinical Gastroenterology. 2020;(12):96–108. (In Russ.) doi: 10.31146/1682–8658-ecg-184–12–96–108

179. Vyuchnova E. S., Maev I. V., Babina S. M. Efficiency of essential phospholipids in the treatment of patients with non-alcoholic steatohepatitis. Clinical perspectives of gastroenterology, hepatology. 2010; 3: 3–11. (in Russ)

180. Ivashkin V. T., Bakulin I. G., Bogomolov P. O., et al. Efficacy and safety of glycyrrhizic acid combined to essential phospholipids (Phosphogliv) at non-alcoholic fatty liver disease: results of multicenter double blind randomized placebo controlled post-registration clinical study (IV phase) “Gepard” (PHG-M2/P02–12). Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2017;27(2):34–43. (In Russ.) doi: 10.22416/1382–4376–2017–27–2–34–43

181. Nikitin I. G., Volnukhin A. V. Cholelithiasis: epidemiological data, key aspects of the pathogenesis and comorbidity, relevant therapeutic targets. Russian Medical Inquiry. 2020;4(5):290–296. DOI: 10.32364/2587–6821–2020–4–5–290–296

182. Mekhtiev S. N., Mekhtieva O. A., Ibragimova Z. M. Functional gall-bladder disorders and non-alcoholic fatty liver disease: clinical features and new approaches to therapy. Meditsinskiy sovet = Medical Council. 2020;(15):54–64. (In Russ.) DOI: 10.21518/2079–701X-2020–15–54–64

183. Semiserin V. A., Karakozov A. G., Malkuta M. A., et al. Evaluation of the efficiency of hepatoprotective monotherapy using succinic acid and methionine for nonalcoholic fatty liver disease at the stage of steatohepatitis. Th erapeutic archive. 2016;88(2):58–63. (in Russ) doi: 10.17116/terarkh201688258–63

184. Okovity S. V. Combined use of hepatoprotectors. Attending physician. 2020, August, No. 8, pp. 38–42. (in Russ) DOI: 10.26295/OS.2020.65.19.005

185. Riordan S.M., Williams R. Treatment of hepatic encephalopathy. N Engl J Med. 1997, no. 337, pp.473–9.

186. Baja jJ.S., Riggio O. Drugtherapy: rifaximin. Hepatology. 2010;52:1484–1488.

187. Kimer N., Krag A., Gluud L. L. Safety, effi cacy, and patient acceptability of rifaximin for hepatic encephalopathy. Patient Prefer. Adherence. 2014;8:331–338.

188. Sharma B.C., Sharma P., Lunia M. K., Srivastava S., Goyal R., Sarin S. K. A randomized, double blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am. J. Gastroenterol. 2013;108:1458–1463.

189. Kimer N., Krag A., Møller S., Bendtsen F., Gluud L. L. Systematic review with meta-analysis: the eff ects of rifaximin in hepatic encephalopathy. Aliment Pharmacol Th er. 2014 Jul;40(2):123–32. doi: 10.1111/apt.12803. Epub 2014 May 21. PMID: 24849268.

190. World Gastroenterology Organisation Global Guidelines ‘Probiotics and Prebiotics’. 2017 Feb. Available at: http://www.worldgastroenterology.org/guidelines/global guidelines/probiotics-and-prebiotics/probiotics-and-prebiotics english [Accessed 21 August 2020]

191. Grabherr F., Grander C., Eff enberger M., Adolph T. E., Tilg H. Gut Dysfunction and Non-alcoholic Fatty Liver Disease. Frontiers in Endocrinology. 2019;10:611. DOI: 10.3389/

192. fendo.2019.00611

193. Domenica Maria Di Palo, et al. Increased Colonic Permeability and Lifestyles as Contributing Factors to Obesity and Liver Steatosis. Nutrients. 2020, 12 (2), 564; https://doi.org/10.3390/nu12020564

194. Pang, J., Xu W., Zhang X., et al. Signifi cant positive association of endotoxemia with histological severity in 237 patients with non‐alcoholic fatty liver disease. Aliment Pharmacol Th er. 2017; 46: 175–182. https://doi.org/10.1111/apt.14119

195. Harte A.L., da Silva N. F., Creely S. J. et al. Elevated endotoxin alcoholic in non alhogolic fatty liver disease. J Infl amm. 7, 15 (2010). Doi:10.1186/1476–9255–7–15

196. Hong K.W., Kim K. E., Rhim B. Y., Lee W. S., Kim C. D. Eff ect of rebamipide on liver damage and increased tumor necrosis factor in a rat model of endotoxin shock. Digestive Diseases and Sciences. 1998 Sep;43(9 Suppl):154S-159S.

197. Sherin Zakaria & Alaa El Sisi Rebamipide retards CCl4-induced hepatic fi brosis in rats: possible role for PGE2. Journal of Immunotoxicology. 2016. 13:4, 453–462, DOI: 10.3109/1547691X.2015.1128022