Metabolically associated fatty liver disease. What is the danger of a "safe" disease? Pathogenesis of cardiovascular complications

Background. Nonalcoholic fatty liver disease is most often a latent disease with absent or mild clinical manifestations. It is usually detected as an incidental finding when transaminase levels are elevated or imaging signs of fatty liver degeneration are detected. The definition of non-alcoholic fatty liver disease is based on two main principles – morphological picture of biopsy microscopy, which fully corresponds to the changes of alcoholic hepatosis and the absence of the main etiologic factor – alcohol intake in hepatotoxic doses. The epidemiological burden of hepatic steatosis associated with metabolic dysfunction is constantly increasing worldwide and in all age groups. Non-alcoholic fatty liver disease is not a single disease but a spectrum of conditions that range from mild steatosis to non-alcoholic fatty liver disease with associated fibrosis and possible cirrhosis. High index of suspicion is required in patients with components of metabolic syndrome including diabetes, obesity, dyslipidemia and/or hypertension, since the progression of non-alcoholic fatty liver disease from simple steatosis to cirrhosis and hepatocellular carcinoma increases exponentially in these patients. There is a strong association between non-alcoholic fatty liver disease and cardiovascular diseases, such as hypertension, atherosclerosis, coronary artery disease (CAD) and congestive heart failure. Cardiovascular diseases are the leading cause of death in patients with non-alcoholic fatty liver disease.

Results. The article discusses pathogenesis. Understanding the progression of the disease and the specific hepatic and extrahepatic diseases associated with each stage is critical for optimal patient management. Methods for correcting disorders are discussed. One of the most studied drugs in recent decades has been ursodeoxycholic acid, which is of great interest in the treatment of non-alcoholic fatty liver disease in combination with cardiovascular diseases due to its pleiotropic effects.

1. Ludwig J., Viggiano T. R., McGill D. B., Oh B. J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin. Proc. 1980; 55: 434-438.

2. Murag S, Ahmed A, Kim D. Recent epidemiology of nonalcoholic fatty liver disease. Gut Liver. 2021; 15: 206-16. DOI: 10.5009/gnl20127.

3. Evstifeeva S. E., Shalnova S. A., Kutsenko V. A., Yarovaya E. V., Balanova Yu. A., Imaeva A. E., Kapustina A. V., Muromtseva G. A., Maksimov S. A., Karamnova N. S., Soplenkova A. G., Filichkina E. M., Viktorova I. A., Prischepa N. N., Redko A. N., Yakushin S. S., Drapkina O. M. Prevalence of non-alcoholic fatty liver disease among the working-age population: associations with socio-demographic indicators and behavioral risk factors (ESSE RF-2 data). Kardiovaskulyarnaya terapiya i profilaktika. 2022; 21 (9): 3356. https://doi.org/10.15829/1728-8800-2022-3356. (In Russ.)

4. Ivashkin V. T., Drapkina O. M., Maev I. V., et al. Prevalence of nonalcoholic fatty liver disease in patients of outpatient and polyclinic practice in the Russian Federation: results of the DIREG 2 study. Rossiyskiy zhurnal gastrojenterologii, gepatologii, koloproktologii. 2015; 25 (6): 31-34. (In Russ.)

5. Neuschwander-Tetri B. A., Caldwell S. H. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003; 37: 1202-1219.

6. Byrne C. D., Targher G. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease: Is universal screening appropriate? Diabetologia. 2016; 59: 1141-1144.

7. Estes C., Razavi H., Loomba R., et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018; 67: 123-133.

8. Stahl E. P., Dhindsa D. S., Lee S. K., Sandesara P. B., Chalasani N. P., Sperling L. S. Nonalcoholic Fatty Liver Disease and the Heart: JACC Stateof-the-Art Review. J Am Coll Cardiol. 2019; 73 (8): 948-963. DOI: 10.1016/j.jacc.2018.11.050.

9. Younossi Z. M., Stepanova M., Ong J., Trimble G., AlQahtani S., Younossi I., Ahmed A., Racila A., Henry L. Nonalcoholic Steatohepatitis Is the Most Rapidly Increasing Indication for Liver Transplantation in the United States. Clin Gastroenterol Hepatol. 2021; 19 (3): 580-589. DOI: 10.1016/j.cgh.2020.05.064.

10. Buzzetti E., Pinzani M., Tsochatzis E. A. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD) Metabolism. 2016; 65: 1038-1048. DOI: 10.1016/j.metabol.2015.12.012.

11. Pafili K., Roden M. Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans. Mol Metab. 2021; 50: 101122. DOI: 10.1016/j.molmet.2020.101122.

12. Chalasani N., Younossi Z., Lavine J. E., et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67: 328-357. DOI: 10.1002/hep.29367.

13. Powell E. E., Wong V. W., Rinella M. Non-alcoholic fatty liver disease. Lancet. 2021; 397: 2212-2224. DOI: 10.1016/S0140-6736 (20)32511-3.

14. Sanyal A. J., Harrison S. A., Ratziu V., Abdelmalek M. F., Diehl A. M., Caldwell S., Shiffman M. L., Aguilar Schall R., Jia C., McColgan B., et al. The Natural History of Advanced Fibrosis due to Nonalcoholic Steatohepatitis: Data from the Simtuzumab Trials. Hepatology. 2019; 70: 1913-1927. DOI: 10.1002/hep.30664.

15. Lee C. M., Yoon E. L., Kim M., Kang B. K., Cho S., Nah E. H., Jun D. W. Prevalence, distribution, and hepatic fibrosis burden of the different subtypes of steatotic liver disease in primary care settings. Hepatology. 2023; 79: 1393-1400. DOI: 10.1097/HEP.0000000000000664.

16. Saiman Y., Duarte-Rojo A., Rinella M. E. Fatty Liver Disease: Diagnosis and Stratification. Annu Rev Med. 2022; 73: 529-544. DOI: 10.1146/annurevmed-042220-020407.

17. Hassen G., Singh A., Belete G., Jain N., de la Hoz I., Camacho-Leon G. P., et al. Nonalcoholic fatty liver disease: an emerging modern-day risk factor for cardiovascular disease. Cureus. 2022; 14: e25495. DOI: 10.7759/cureus.25495.

18. Ekstedt M., Hagström H., Nasr P., et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015; 61: 1547-1554.

19. Hagström H., Nasr P., Ekstedt M., et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J. Hepatol. 2017; 67: 1265-1273.

20. Allen A. M., Hicks S. B., Mara K. C., et al. The risk of incident extrahepatic cancers is higher in nonalcoholic fatty liver disease than obesity – a longitudinal cohort study. J. Hepatol. 2019; 71: 1229-1236.

21. Shea S., Lionis C., Atkinson L., Kite C., Lagojda L., Chaggar S. S., et al. Support needs and coping strategies in non-alcoholic fatty liver disease (NAFLD): A multidisciplinary approach to potential unmet challenges beyond pharmacological treatment. Livers. 2023. DOI: 10.3390/livers3010001.

22. Kim D., Choi S. Y., Park E. H., et al. Nonalcoholic fatty liver disease is associated with coronary artery calcification. Hepatology. 2012; 56: 605-613.

23. Noureddin M., Jones C., Alkhouri N., Gomez E. V., Dieterich D. T., Rinella M. E.; NASHNET. Screening for Nonalcoholic Fatty Liver Disease in Persons with Type 2 Diabetes in the United States Is Cost-effective: A Comprehensive Cost-Utility Analysis. Gastroenterology. 2020; 159 (5): 1985-1987. DOI: 10.1053/j.gastro.2020.07.050.

24. Davyduke T., Tandon P., Al-Karaghouli M., et al. Impact of implementing a "FIB-4 first" strategy on a pathway for patients with NAFLD referred from primary care. Hepatol. Commun. 2019;. 3: 1322-1333.

25. Srivastava A., Gailer R., Tanwar S., et al. Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease. J. Hepatol. 2019; 71: 371-378.

26. Papatheodoridi M., Hiriart J. B., Lupsor-Platon M., Bronte F., Boursier J., Elshaarawy O., Marra F., Thiele M., Markakis G., Payance A., Brodkin E., Castera L., Papatheodoridis G., Krag A., Arena U., Mueller S., Cales P., Calvaruso V., de Ledinghen V., Pinzani M., Tsochatzis E. A. Refining the Baveno VI elastography criteria for the definition of compensated advanced chronic liver disease. J Hepatol. 2021; 74 (5): 1109-1116. DOI: 10.1016/j.jhep.

27. Kudaravalli P., John S. Nonalcoholic Fatty Liver. 2023 Apr 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan. PMID: 31082077.

28. Unalp-Arida A., Ruhl C. E. Liver fat scores predict liver disease mortality in the United States population. Aliment Pharmacol Ther. 2018; 48: 1003-1016. DOI: 10.1111/apt.14967.

29. Takahashi Y., Fukusato T. Histopathology of nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis. World J Gastroenterol. 2014; 20: 15539-15548. DOI: 10.3748/wjg.v20.i42.15539.

30. Chiriac S., Stanciu C., Girleanu I., Cojocariu C., Sfarti C., Singeap A. M., Cuciureanu T., Huiban L., Muzica C. M., Zenovia S., Nastasa R., Trifan A. Nonalcoholic Fatty Liver Disease and Cardiovascular Diseases: The Heart of the Matter. Can J Gastroenterol Hepatol. 2021; 2021: 6696857. DOI: 10.1155/2021/6696857.

31. Cai J., Zhang X. J., Ji Y. X., Zhang P., She Z. G., Li H. Circ Res Nonalcoholic fatty liver disease pandemic fuels the upsurge in cardiovascular diseases. 2020; 126: 679-704. DOI: 10.1161/CIRCRESAHA.119.316337.

32. Targher G., Byrne C. D., Tilg H. NAFLD and increased risk of cardiovascular disease: clinical associations., pathophysiological mechanisms and pharmacological implications. Gut. 2020; 69 (9): 1691-1705. DOI: 10.1136/gutjnl-2020-320622.

33. Younossi Z. M., Koenig A. B., Abdelatif D., Fazel Y., Henry L., Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016; 64 (1): 73-84. DOI: 10.1002/hep.28431. Epub 2016 Feb 22. PMID: 26707365.

34. Targher G., Byrne C. D., Lonardo A., Zoppini G., Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J Hepatol. 2016; 65 (3): 589-600. DOI: 10.1016/j.jhep.2016.05.013.

35. Bonnet F., Gastaldelli A., Pihan-Le Bars F., et al. Gamma-glutamyltransferase, fatty liver index and hepatic insulin resistance are associated with incident hypertension in two longitudinal studiesJ Hypertens. 2017; 35: 493-500. DOI: 10.1097/HJH.0000000000001204.

36. Dongiovanni P., Paolini E., Corsini A., Sirtori C. R., Ruscica M. Nonalcoholic fatty liver disease or metabolic dysfunction-associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches. Eur J Clin Invest. 2021; 51 (7): e13519. DOI: 10.1111/eci.13519.

37. Byrne CD., Targher G. Non-alcoholic fatty liver disease-related risk of cardiovascular disease and other cardiac complications. Diabetes Obes Metab. 2022 Feb;24 Suppl 2: 28-43. doi: 10.1111/dom.14484.

38. Stols-Goncalves D., Hovingh G. K., Nieuwdorp M., Holleboom A. G. NAFLD and atherosclerosis: two sides of the same dysmetabolic coin? Trends Endocrinol Metab. 2019; 30 (12): 891-902.

39. Salah H. M., Pandey A., Soloveva A., Abdelmalek M. F., Diehl A. M., Moylan C. A., et al. Relationship of nonalcoholic fatty liver disease and heart failure with preserved ejection fraction. JACC Basic Transl Sci. 2021; 6 (11): 918-932.

40. Fudim M., Zhong L., Patel K. V., Khera R., Abdelmalek M. F., Diehl A. M., et al. Nonalcoholic fatty liver disease and risk of heart failure among Medicare beneficiaries. J Am Heart Assoc. 2021; 10 (22): e021654.

41. Lee J. I., Kim M. C., Moon B. S., Song Y. S., Han E. N., Lee H. S., Son Y., Kim J., Han E. J., Park H. J., Park S. E., Park C. Y., Lee W. Y., Oh K. W. Park S. W., Rhee E. J. The Relationship between 10-Year Cardiovascular Risk Calculated Using the Pooled Cohort Equation and the Severity of Non-Alcoholic Fatty Liver Disease. Endocrinol Metab (Seoul). 2016 ; 31 (1): 86-92. DOI: 10.3803/EnM.2016.31.1.86.

42. Janičko M., Veselíny E., Leško D., Jarčuška P. Serum cholesterol is a significant and independent mortality predictor in liver cirrhosis patients. Ann Hepatol. 2013; 12 (4): 581-587.

43. Lee S., Kim K. W., Lee J., Park T., Khang S., Jeong H., et al. Visceral adiposity as a risk factor for lean non-alcoholic fatty liver disease in potential living liver donors. J Gastroenterol Hepatol. 2021; 36 (11): 3212-3218.

44. Samala N., Desai A., Vilar-Gomez E., Smith E. R., Gawrieh S., Kettler C. D., Pike F., Chalasani N. Decreased Quality of Life Is Significantly Associated With Body Composition in Patients With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol. 2020; 18 (13): 2980-2988. DOI: 10.1016/j.cgh.2020.04.046.

45. Bhanji R. A., Narayanan P., Moynagh M. R., Takahashi N., Angirekula M., Kennedy C. C., Mara K. C., Dierkhising R. A., Watt K. D. Differing Impact of Sarcopenia and Frailty in Nonalcoholic Steatohepatitis and Alcoholic Liver Disease. Liver Transpl. 2019; 25 (1): 14-24. DOI: 10.1002/lt.25346.

46. Cai C., Song X., Chen Y., Chen X., Yu C. Relationship between relative skeletal muscle mass and nonalcoholic fatty liver disease: a systematic review and meta-analysis. Hepatol Int. 2020; 14 (1): 115-126. DOI: 10.1007/s12072-019-09964-1.

47. Finer N. Weight loss interventions and nonalcoholic fatty liver disease: optimizing liver outcomes. Diabetes Obes Metab. 2022; 24: 44-54. DOI: 10.1111/dom.14569.

48. Duell P. B., Welty F. K., Miller M., Chait A., Hammond G., Ahmad Z., et al. Nonalcoholic fatty liver disease and cardiovascular risk: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2022; 42 (6): e168-185.

49. Pérez Fernández T., López Serrano P., Tomás E., Gutiérrez M. L., Lledó J. L., Cacho G., et al. Diagnostic and therapeutic approach to cholestatic liver disease. Rev Esp Enferm Dig. 2004; 96: 60-73. DOI: 10.4321/s1130-01082004000100008.

50. Perugorria M. J., Labiano I., Esparza-Baquer A., Marzioni M., Marin J. J., Bujanda L., et al. Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression Potential Solution for Treatment. Dig Dis. 2017; 35: 275-281. DOI: 10.1159/000450989.

51. Feldstein A. E., Canbay A., Angulo P., Taniai M., Burgart L. J., Lindor K. D., et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology. 2003; 125: 437-443. DOI: 10.1016/s0016-5085 (03)00907-7.

52. Amaral J. D., Viana R. J., Ramalho R. M., Steer C. J., Rodrigues C. M. Bile acids: regulation of apoptosis by ursodeoxycholic acid. J Lipid Res. 2009; 50: 1721-1734. DOI: 10.1194/jlr.R900011-JLR200.

53. Ivashkin V. T., Maevskaya M. V., Zharkova M. S., Kotovskaya Yu. V., Tkacheva O. N., Troshina E. A., et al. Clinical Practice Guidelines of the Russian Scientific Liver Society, Russian Gastroenterological Association, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians and National Society for Preventive Cardiology on Diagnosis and Treatment of Non-Alcoholic Liver Disease. Rossiyskiy zhurnal gastrojenterologii, gepatologii, koloproktologii. 2022; 32 (4): 104-140. https://doi.org/10.22416/1382-4376-2022-32-4-104-140 (In Russ.)

54. Zhang W., Tang Y., Huang J., Hu H. Efficacy of ursodeoxycholic acid in nonalcoholic fatty liver disease: An updated meta-analysis of randomized controlled trials. Asia Pac J Clin Nutr. 2020; 29: 696-705. DOI: 10.6133/apjcn.202012_29(4).0004.

55. Lin X., Mai M., He T., Huang H., Zhang P., Xia E., et al. Efficiency of ursodeoxycholic acid for the treatment of nonalcoholic steatohepatitis: A systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol. 2022; 16: 537-545. DOI: 10.1080/17474124.2022.2083605.

56. Maev I. V., Kucheryavy Yu. A., Andreev D. N. Liver and biliary tract in metabolic syndrome: a manual for doctors. М., 2020. (In Russ.)

57. Martsevich S. Yu, Kutishenko N. P., Drozdova L. Yu, Lerman O. V., Nevzorova V. A., Reznik I. I., et al. The RACURS study: improving the efficacy and safety of statin therapy in patients with liver, gallbladder and/or biliary tract diseases using ursodeoxycholic acid. Terapevticheskiy arhiv. 2014; 86 (12): 48-52. https://doi.org/10.17116/terarkh2014861248-52. (In Russ.)

58. Sánchez-García A., Sahebkar A., Simental-Mendía M., Simental-Mendía L. E. Effect of ursodeoxycholic acid on glycemic markers: A systematic review and meta-analysis of clinical trials. Pharmacol Res. 2018; 135: 144-149. DOI: 10.1016/j.phrs.2018.08.008.

59. Akhmedov V. A. Metabolic effects of ursodeoxycholic acid in patients with nonalcoholic fatty liver disease. Lechaschi Vrach. 2024; 4 (27): 71-76. (In Russ.)

60. Kucheryavy Yu. A., Cheryomushkin S. V. Evaluation of therapeutic efficacy of the reference drug ursodeoxycholic acid and its analogs in the dissolution of biliary sludge: a metaanalysis. Consilium Medicum. 2022; 24 (5). DOI: 10.26442/20751753.2022.12.201429. (In Russ.)

61. Clinical recommendations "Algorithms of specialized medical care for patients with diabetes mellitus". Edited by I. I. Dedov. I. Dedov, M. V. Shestakova, Yu Mayorov. 9th ed. (supplemented). M., 2019. (In Russ.)