Хронические заболевания печени как причина развития саркопении

Печень является крупным органом, масса которого превышает 1% массы тела человека. Печень участвует в обмене белков, жиров и углеводов, выполняет функции депо гликогена. Саркопения является известным осложнением хронического заболевания печени, и почти всегда наблюдается у пациентов с циррозом, особенно, у пациентов с декомпенсированным заболеванием. Представляет интерес исследование механизмов патогенеза печеночной патологии как причины развития саркопении. Нарушенный синтез белка скелетных мышц и повышенный протеолиз посредством аутофагии способствуют саркопении. Гипераммониемия является наиболее изученным медиатором оси печень-мышцы. На фоне гипераммониемии отмечается повышенная экспрессия миостатина, нарушение митохондриальной функции и промежуточных продуктов цикла трикарбоновых кислот. Нарушение гормонального равновесия организма, мальнутриция, недостаточность витаминов, хроническое воспаление, гиперметаболизм и инсулинорезистентность являются важными звеньями патогенеза хронических заболеваний печени. Саркопения встречается у большинства пациентов с заболеваниями печени. Эффективных методов профилактики или устранения саркопении при заболеваниях печени не существует. В этом обзоре обсуждаются основные механизмы патогенеза саркопении при хронических заболеваниях печени.

цирроз печени, саркопения, белково-энергетическая недостаточность, депо гликогена, мальнутриция, хроническое воспаление, ожирение, иммуносупрессия

1. Bulgakova S.V., Dolgikh Y.A., Sharonova L.A. et al. Modern aspects of therapy of metabolic associated liver disease in patients with type 2 diabetes mellitus. Meditsinskiy sovet = Medical Council. 2024;(16):184-192. (In Russ.) doi: 10.21518/ms2024-414.@@ Булгакова С.В., Долгих Ю.А., Шаронова Л.А. и др. Современные аспекты терапии метаболически ассоциированной жировой болезни печени у пациентов с сахарным диабетом 2-го типа. Медицинский Совет. 2024;(16):184-192. doi: 10.21518/ms2024-414.

2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on nutrition in chronic liver disease. J Hepatol. 2019;70(1):172-193. doi: 10.1016/j.jhep.2018.06.024.

3. Gallo P., Flagiello V., Falcomatà A. et al. Approaching the Sarcopenic Patient with Nonalcoholic Steatohepatitis-related Cirrhosis. J Clin Transl Hepatol. 2024;12(3):278-286. doi: 10.14218/JCTH.2023.00207.

4. Cruz-Jentoft A.J., Bahat G., Bauer J. et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48(1):16-31. doi: 10.1093/ageing/afy169.

5. Kurmaev D.P., Bulgakova S.V., Treneva E.V. et al. Malnutrition, dysfunction of the gastrointestinal tract and sarcopenia - features of combined pathology. Experimental and Clinical Gastroenterology. 2024;(2):111-119. (In Russ.) doi: 10.31146/1682-8658-ecg-222-2-111-119.@@ Курмаев Д.П., Булгакова С.В., Тренева Е.В. и др. Мальнутриция, нарушение функции желудочно-кишечного тракта и саркопения - особенности сочетанной патологии. Экспериментальная и клиническая гастроэнтерология. 2024;(2):111-119. doi: 10.31146/1682-8658-ecg-222-2-111-119.

6. Kurmaev D.P., Bulgakova S.V., Treneva E.V. et al. Nutritional support in a comprehensive program of prevention and treatment of sarcopenia.Russian Journal of Geriatric Medicine. 2023;(1):29-38. (In Russ.) doi: 10.37586/2686-8636-1-2023-29-38,@@ Курмаев Д.П., Булгакова С.В., Тренева Е.В. и др. Нутритивная поддержка в комплексной программе профилактики и лечения саркопении. Российский журнал гериатрической медицины. 2023;(1):29-38. doi: 10.37586/2686-8636-1-2023-29-38.

7. Berns S.A., Sheptulina A.F., Mamutova E.M. et al. Sarcopenic obesity: epidemiology, pathogenesis and diagnostic criteria. Cardiovascular Therapy and Prevention. 2023;22(6):3576. (In Russ.) doi: 10.15829/1728-8800-2023-3576.@@ Бернс С.А., Шептулина А.Ф., Мамутова Э.М. и др. Саркопеническое ожирение: эпидемиология, патогенез и особенности диагностики. Кардиоваскулярная терапия и профилактика. 2023;22(6):3576. doi: 10.15829/1728-8800-2023-3576.

8. Samoilova Yu.G., Matveeva M.V., Khoroshunova E.A. et al. Cardiometabolic risk factors in patients with type 2 diabetes and sarcopenia. Cardiovascular Therapy and Prevention. 2024;23(1):3655. (In Russ.) doi: 10.15829/1728-8800-2024-3655.@@ Самойлова Ю.Г., Матвеева М.В., Хорошунова Е.А. и др. Кардиометаболические факторы риска у пациентов с сахарным диабетом 2 типа и саркопенией. Кардиоваскулярная терапия и профилактика. 2024;23(1):3655. doi: 10.15829/1728-8800-2024-3655.

9. Tkacheva O.N., Kotovskaya Yu.V., Runikhina N.K. et al. Clinical guidelines on frailty.Russian Journal of Geriatric Medicine. 2020;(1):11-46. (In Russ.) doi: 10.37586/2686-8636-1-2020-11-46.@@ Ткачева О.Н., Котовская Ю.В., Рунихина Н.К. и др. Клинические рекомендации «Старческая астения». Российский журнал гериатрической медицины. 2020;(1):11-46. doi: 10.37586/2686-8636-1-2020-11-46.

10. Kurmaev DP, Bulgakova SV, Treneva EV. et al. The Triple Burden of Osteoporosis, Sarcopenia, and Aging in Geriatrics (review).Russian Journal of Geriatric Medicine. 2024;(3):225-239. (In Russ.) doi: 10.37586/2686-8636-3-2024-225-239.@@ Курмаев Д.П., Булгакова С.В., Тренева Е.В. и др. Остеопороз, саркопения и старение - тройная сочетанная патология в гериатрии (обзор литературы). Российский журнал гериатрической медицины. 2024;(3):225-239. doi: 10.37586/2686-8636-3-2024-225-239.

11. Welch N., Dasarathy J., Runkana A. et al. Continued muscle loss increases mortality in cirrhosis: Impact of aetiology of liver disease. Liver Int. 2020;40(5):1178-1188. doi: 10.1111/liv.14358.

12. Dasarathy S. Cause and management of muscle wasting in chronic liver disease. Curr Opin Gastroenterol. 2016;32(3):159-165. doi: 10.1097/MOG.0000000000000261.

13. Sergeeva V.A., Runikhina N.K., Shulpina N.Yu. Exploring the Clinical and Pathophysiological Links between Sarcopenia and Liver Pathology.Russian Journal of Geriatric Medicine. 2024;(3):216-224. (In Russ.) doi: 10.37586/2686-8636-3-2024-216-224.@@ Сергеева В.А., Рунихина Н.К., Шульпина Н.Ю. Клинико-патофизиологические взаимосвязи саркопении и патологии печени. Российский журнал гериатрической медицины. 2024;(3):216-224. doi: 10.37586/2686-8636-3-2024-216-224.

14. Kusnik A., Penmetsa A., Chaudhary F. et al. Clinical Overview of Sarcopenia, Frailty, and Malnutrition in Patients With Liver Cirrhosis. Gastroenterology Res. 2024;17(2):53-63. doi: 10.14740/gr1707.

15. Kim H.Y., Jang J.W. Sarcopenia in the prognosis of cirrhosis: Going beyond the MELD score. World J Gastroenterol. 2015;21(25):7637-7647. doi: 10.3748/wjg.v21.i25.7637.

16. Montano-Loza A.J., Meza-Junco J., Prado C.M. et al. Muscle wasting is associated with mortality in patients with cirrhosis. Clin Gastroenterol Hepatol. 2012;10(2):166-173.e1. doi: 10.1016/j.cgh.2011.08.028.

17. Habig G., Smaltz C., Blumhof B., Guglielmo F.F., Halegoua-DeMarzio D. The Role of Cirrhosis Etiology on the Prevalence of Sarcopenia. Am J Gastroenterol. 2021;116(1): S567-S567. doi: 10.14309/01.ajg.0000778448.14173.7f.

18. Hong H.C., Hwang S.Y., Choi H.Y. et al. Relationship between sarcopenia and nonalcoholic fatty liver disease: the Korean Sarcopenic Obesity Study. Hepatology. 2014;59(5):1772-1778. doi: 10.1002/hep.26716.

19. Koo B.K., Kim D., Joo S.K. et al. Sarcopenia is an independent risk factor for non-alcoholic steatohepatitis and significant fibrosis. J Hepatol. 2017.;66(1):123-131. doi: 10.1016/j.jhep.2016.08.019.

20. Lee Y.H., Kim S.U., Song K. et al. Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: Nationwide surveys (KNHANES 2008-2011). Hepatology. 2016;63(3):776-786. doi: 10.1002/hep.28376.

21. Montano-Loza A.J., Angulo P., Meza-Junco J. et al. Sarcopenic obesity and myosteatosis are associated with higher mortality in patients with cirrhosis. J Cachexia Sarcopenia Muscle. 2016;7(2):126-135. doi: 10.1002/jcsm.12039.

22. Li A.A., Kim D., Ahmed A. Association of Sarcopenia and NAFLD: An Overview. Clin Liver Dis (Hoboken). 2020;16(2):73-76. Published 2020 Sep 4. doi: 10.1002/cld.900.

23. Allen S.L., Quinlan J.I., Dhaliwal A. et al. Sarcopenia in chronic liver disease: mechanisms and countermeasures. Am J Physiol Gastrointest Liver Physiol. 2021;320(3): G241-G257. doi: 10.1152/ajpgi.00373.2020.

24. Chen H.W., Dunn M.A. Arresting frailty and sarcopenia in cirrhosis: Future prospects. Clin Liver Dis (Hoboken). 2018;11(2):52-57. Published 2018 Feb 28. doi: 10.1002/cld.691.

25. Holeček M. Muscle Amino Acid and Adenine Nucleotide Metabolism during Exercise and in Liver Cirrhosis: Speculations on How to Reduce the Harmful Effects of Ammonia. Metabolites. 2022 Oct 13;12(10):971. doi: 10.3390/metabo12100971.

26. Lowenstein J.M. Ammonia production in muscle and other tissues: The purine nucleotide cycle. Physiol. Rev. 1972;52:382-414. doi: 10.1152/physrev.1972.52.2.382.

27. Warner Ii E.R., Satapathy S.K. Sarcopenia in the Cirrhotic Patient: Current Knowledge and Future Directions. J Clin Exp Hepatol. 2023;13(1):162-177. doi: 10.1016/j.jceh.2022.06.005.

28. Jacobsen E.B., Hamberg O., Quistorff B., Ott P. Reduced mitochondrial adenosine triphosphate synthesis in skeletal muscle in patients with Child-Pugh class B and C cirrhosis. Hepatology. 2001;34:7-12. doi: 10.1053/jhep.2001.25451.

29. Möller P., Bergström J., Fürst P., Hellström K. Muscle biopsy studies in patients with moderate liver cirrhosis with special reference to energy-rich phosphagens and electrolytes. Scand. J. Gastroenterol. 1984;19:267-272. doi: 10.1080/00365521.1984.12005719.

30. Davuluri G., Allawy A., Thapaliya S. et al. Hyperammonaemia-induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress. J. Physiol. 2016;594:7341-7360. doi: 10.1113/JP272796.

31. Holeček M. Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy-therapeutic perspectives. Metab. Brain Dis. 2014;29:9-17. doi: 10.1007/s11011-013-9428-9.

32. Olde Damink S.W., Jalan R., Dejong C.H.Interorgan ammonia trafficking in liver disease. Metab Brain Dis. 2009;24(1):169-181. doi: 10.1007/s11011-008-9122-5.

33. Takeda K., Takemasa T. Expression of ammonia transporters Rhbg and Rhcg in mouse skeletal muscle and the effect of 6-week training on these proteins. Physiol Rep. 2015;3(10): e12596. doi: 10.14814/phy2.12596.

34. Qiu J., Tsien C., Thapalaya S. et al. Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis. Am J Physiol Endocrinol Metab. 2012;303(8): E983-E993. doi: 10.1152/ajpendo.00183.2012.

35. Jindal A., Jagdish R.K. Sarcopenia: Ammonia metabolism and hepatic encephalopathy. Clin Mol Hepatol. 2019;25(3):270-279. doi: 10.3350/cmh.2019.0015.

36. Santangeli E., Abbati C., Chen R. et al. Pathophysiological-Based Nutritional Interventions in Cirrhotic Patients with Sarcopenic Obesity: A State-of-the-Art Narrative Review. Nutrients. 2024;16(3):427. Published 2024 Jan 31. doi: 10.3390/nu16030427.

37. Schiavo L., Busetto L., Cesaretti M., Zelber-Sagi S., Deutsch L., Iannelli A. Nutritional issues in patients with obesity and cirrhosis. World J Gastroenterol. 2018;24(30):3330-3346. doi: 10.3748/wjg.v24.i30.3330.

38. Kubesch A., Quenstedt L., Saleh M. et al. Vitamin D deficiency is associated with hepatic decompensation and inflammation in patients with liver cirrhosis: A prospective cohort study. PLoS One. 2018;13(11): e0207162. Published 2018 Nov 8. doi: 10.1371/journal.pone.0207162.

39. Remelli F., Vitali A., Zurlo A., Volpato S. Vitamin D Deficiency and Sarcopenia in Older Persons. Nutrients. 2019;11(12):2861. Published 2019 Nov 21. doi: 10.3390/nu11122861.

40. Machekhina L.V., Balashova A.V., Tkacheva O.N. et al. Vitamin D and Geriatric Assessment: A Cross-Sectional Study on the Cohort of Centenarians in the Central Region of Russian Federation.Russian Journal of Geriatric Medicine. 2024;(1):21-29. (In Russ.) doi: 10.37586/2686-8636-1-2024-21-29.@@ Мачехина Л.В., Балашова А.В., Ткачева О.Н. и др. Витамин D и гериатрический статус: когортное исследование долгожителей центрального региона Российской Федерации. Российский журнал гериатрической медицины. 2024;(1):21-29. doi: 10.37586/2686-8636-1-2024-21-29.

41. Zhang F., Li W. Vitamin D and Sarcopenia in the Senior People: A Review of Mechanisms and Comprehensive Prevention and Treatment Strategies. Ther Clin Risk Manag. 2024;20:577-595. Published 2024 Sep 5. doi: 10.2147/TCRM.S471191.

42. Montenegro K.R., Cruzat V., Carlessi R., Newsholme P. Mechanisms of vitamin D action in skeletal muscle. Nutr Res Rev. 2019;32(2):192-204. doi: 10.1017/S0954422419000064.

43. Bo Y., Liu C., Ji Z. et al. A high whey protein, vitamin D and E supplement preserves muscle mass, strength, and quality of life in sarcopenic older adults: A double-blind randomized controlled trial. Clin Nutr. 2019;38(1):159-164. doi: 10.1016/j.clnu.2017.12.020.

44. Barchetta I., Cimini F.A., Cavallo M.G. Vitamin D and Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD): An Update. Nutrients. 2020;12(11):3302. Published 2020 Oct 28. doi: 10.3390/nu12113302.

45. Widajanti N., Hadi U., Soelistijo S.A., Syakdiyah N.H., Rosaudyn R., Putra H.B.P. The Effect of Vitamin D Supplementation to Parameter of Sarcopenia in Elderly People: a Systematic Review and Meta-Analysis. Can Geriatr J. 2024;27(1):63-75. Published 2024 Mar 1. doi: 10.5770/cgj.27.694.

46. Hosoyama T., Kawai-Takaishi M., Iida H. et al. Lack of vitamin D signalling in mesenchymal progenitors causes fatty infiltration in muscle. J Cachexia Sarcopenia Muscle. 2024;15(3):907-918. doi: 10.1002/jcsm.13448.

47. Safonova Yu.A. Efficacy of Native Vitamin D3 Therapy in Older Patients with Sarcopenia.Russian Journal of Geriatric Medicine. 2024;(3):193-201. (In Russ.) doi: 10.37586/2686-8636-3-2024-193-201.@@ Сафонова Ю.А. Эффективность нативных форм витамина D3 в лечении саркопении у людей пожилого и старческого возраста. Российский журнал гериатрической медицины. 2024;(3):193-201. doi: 10.37586/2686-8636-3-2024-193-201.

48. McCann J.C., Ames B.N. Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging?. Am J Clin Nutr. 2009;90(4):889-907. doi: 10.3945/ajcn.2009.27930.

49. Teriaky A., Mosli M., Chandok N., Al-Judaibi B., Marotta P., Qumosani K. Prevalence of fat-soluble vitamin (A, D, and E) and zinc deficiency in patients with cirrhosis being assessed for liver transplantation. Acta Gastroenterol Belg. 2017;80(2):237-241.

50. Aytekin N., Mileva K.N., Cunliffe A.D. Selected B vitamins and their possible link to the aetiology of age-related sarcopenia: relevance of UK dietary recommendations. Nutr Res Rev. 2018;31(2):204-224. doi: 10.1017/S0954422418000045.

51. Robinson S., Granic A., Sayer A.A. Micronutrients and sarcopenia: current perspectives. Proc Nutr Soc. 2021;80(3):311-318. doi: 10.1017/S0029665121001956.

52. Vidoni M.L., Pettee Gabriel K., Luo S.T., Simonsick E.M., Day R.S. Relationship between Homocysteine and Muscle Strength Decline: The Baltimore Longitudinal Study of Aging. J Gerontol A Biol Sci Med Sci. 2018;73(4):546-551. doi: 10.1093/gerona/glx161.

53. Ates Bulut E., Soysal P., Aydin A.E., Dokuzlar O., Kocyigit S.E., Isik A.T. Vitamin B12 deficiency might be related to sarcopenia in older adults. Exp Gerontol. 2017;95:136-140. doi: 10.1016/j.exger.2017.05.017.

54. Hanai T., Shiraki M., Imai K., Suetugu A., Takai K., Shimizu M. Usefulness of Carnitine Supplementation for the Complications of Liver Cirrhosis. Nutrients. 2020;12(7):1915. Published 2020 Jun 29. doi: 10.3390/nu12071915.

55. Rudman D., Sewell C.W., Ansley J.D. Deficiency of carnitine in cachectic cirrhotic patients. J Clin Invest. 1977;60(3):716-723. doi: 10.1172/JCI108824.

56. Seo J.H., Koh J.M., Cho H.J. et al. Carnitine Metabolite as a Potential Circulating Biomarker for Sarcopenia in Men. Endocrinol Metab (Seoul). Published online November 28, 2024. doi: 10.3803/EnM.2024.2117.

57. Rodriguez J., Vernus B., Chelh I. et al. Myostatin and the skeletal muscle atrophy and hypertrophy signaling pathways. Cell Mol Life Sci. 2014;71(22):4361-4371. doi: 10.1007/s00018-014-1689-x.

58. Ruiz-Margáin A., Pohlmann A., Lanzerath S. et al. Myostatin is associated with the presence and development of acute-on-chronic liver failure. JHEP Rep. 2023;5(8):100761. Published 2023 Apr 14. doi: 10.1016/j.jhepr.2023.100761.

59. McCroskery S., Thomas M., Maxwell L., Sharma M., Kambadur R. Myostatin negatively regulates satellite cell activation and self-renewal. J Cell Biol. 2003;162(6):1135-1147. doi: 10.1083/jcb.200207056.

60. Nishikawa H., Enomoto H., Ishii A. et al. Elevated serum myostatin level is associated with worse survival in patients with liver cirrhosis. J Cachexia Sarcopenia Muscle. 2017;8(6):915-925. doi: 10.1002/jcsm.12212.

61. Dasarathy S. Myostatin and beyond in cirrhosis: all roads lead to sarcopenia. J Cachexia Sarcopenia Muscle. 2017;8(6):864-869. doi: 10.1002/jcsm.12262.

62. Shen S., Liao Q., Chen X., Peng C., Lin L. The role of irisin in metabolic flexibility: Beyond adipose tissue browning. Drug Discov Today. 2022;27(8):2261-2267. doi: 10.1016/j.drudis.2022.03.019.

63. Zhao M., Zhou X., Yuan C., Li R., Ma Y., Tang X. Association between serum irisin concentrations and sarcopenia in patients with liver cirrhosis: a cross-sectional study. Sci Rep. 2020;10(1):16093. Published 2020 Sep 30. doi: 10.1038/s41598-020-73176-z.

64. Gao F., Zheng K.I., Zhu P.W. et al. FNDC5 polymorphism influences the association between sarcopenia and liver fibrosis in adults with biopsy-proven non-alcoholic fatty liver disease. Br J Nutr. 2021;126(6):813-824. doi: 10.1017/S0007114520004559.

65. Rashid F.A., Abbas H.J., Naser N.A., Addai Ali H. Effect of Long-Term Moderate Physical Exercise on Irisin between Normal Weight and Obese Men. ScientificWorldJournal. 2020;2020:1897027. Published 2020 Sep 1. doi: 10.1155/2020/1897027.

66. Kukla M., Skladany L., Menżyk T. et al. Irisin in Liver Cirrhosis. J Clin Med. 2020;9(10):3158. Published 2020 Sep 29. doi: 10.3390/jcm9103158.

67. Rachakonda V., Borhani A.A., Dunn M.A., Andrzejewski M., Martin K., Behari J. Serum Leptin Is a Biomarker of Malnutrition in Decompensated Cirrhosis. PLoS One. 2016;11(9): e0159142. Published 2016 Sep 1. doi: 10.1371/journal.pone.0159142.

68. Elaghori A., Salem P.E.S., Azzam E., Abu Elfotoh N. Ghrelin level in patients with liver cirrhosis. Acta Endocrinol (Buchar). 2019;-5(1):62-68. doi: 10.4183/aeb.2019.62.

69. Robinson M.M., Soop M., Sohn T.S. et al. High insulin combined with essential amino acids stimulates skeletal muscle mitochondrial protein synthesis while decreasing insulin sensitivity in healthy humans. J Clin Endocrinol Metab. 2014;99(12): E2574-E2583. doi: 10.1210/jc.2014-2736.

70. Najjar S.M., Perdomo G. Hepatic Insulin Clearance: Mechanism and Physiology. Physiology (Bethesda). 2019;34(3):198-215. doi: 10.1152/physiol.00048.2018.

71. Thiessen S.E., Derde S., Derese I. et al. Role of Glucagon in Catabolism and Muscle Wasting of Critical Illness and Modulation by Nutrition. Am J Respir Crit Care Med. 2017;196(9):1131-1143. doi: 10.1164/rccm.201702-0354OC.

72. Suppli M.P., Bagger J.I., Lund A. et al. Glucagon Resistance at the Level of Amino Acid Turnover in Obese Subjects With Hepatic Steatosis. Diabetes. 2020;69(6):1090-1099. doi: 10.2337/db19-0715.

73. Adeva-Andany M.M., Funcasta-Calderón R., Fernández-Fernández C., Castro-Quintela E., Carneiro-Freire N. Metabolic effects of glucagon in humans. J Clin Transl Endocrinol. 2018;15:45-53. Published 2018 Dec 20. doi: 10.1016/j.jcte.2018.12.005.

74. Sinclair M., Grossmann M., Gow P.J., Angus P.W. Testosterone in men with advanced liver disease: abnormalities and implications. J Gastroenterol Hepatol. 2015;30(2):244-251. doi: 10.1111/jgh.12695.

75. White J.P., Gao S., Puppa M.J., Sato S., Welle S.L., Carson J.A. Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle. Mol Cell Endocrinol. 2013;365(2):174-186. doi: 10.1016/j.mce.2012.10.019.

76. Irvine K.M., Ratnasekera I., Powell E.E., Hume D.A. Causes and Consequences of Innate Immune Dysfunction in Cirrhosis. Front Immunol. 2019 Feb 25;10:293. doi: 10.3389/fimmu.2019.00293.

77. Dirchwolf M., Ruf A.E. Role of systemic inflammation in cirrhosis: From pathogenesis to prognosis. World J Hepatol. 2015;7(16):1974-1981. doi: 10.4254/wjh.v7.i16.1974.

78. Kronsten V.T., Shawcross D.L. Clinical Implications of Inflammation in Patients With Cirrhosis. Am J Gastroenterol. 2025;120(1):65-74. doi: 10.14309/ajg.0000000000003056.

79. Bojko M. Causes of Sarcopenia in Liver Cirrhosis. Clin Liver Dis (Hoboken). 2019;14(5):167-170. Published 2019 Dec 20. doi: 10.1002/cld.851.

80. Aller de la Fuente R. Nutrition and Chronic Liver Disease. Clin Drug Investig. 2022;42(Suppl 1):55-61. doi: 10.1007/s40261-022-01141-x.

81. Elsabaawy M. Liver at crossroads: unraveling the links between obesity, chronic liver diseases, and the mysterious obesity paradox. Clin Exp Med. 2024;24(1):240. Published 2024 Oct 14. doi: 10.1007/s10238-024-01493-y.

82. Fujii H., Kawada N., Japan Study Group Of Nafld Jsg-Nafld. The Role of Insulin Resistance and Diabetes in Nonalcoholic Fatty Liver Disease.Int J Mol Sci. 2020;21(11):3863. Published 2020 May 29. doi: 10.3390/ijms21113863.

83. Abdul-Ghani M.A., DeFronzo R.A. Pathogenesis of insulin resistance in skeletal muscle. J Biomed Biotechnol. 2010;2010:476279. doi: 10.1155/2010/476279.

84. Bhanji R.A., Narayanan P., Allen A.M., Malhi H., Watt K.D. Sarcopenia in hiding: The risk and consequence of underestimating muscle dysfunction in nonalcoholic steatohepatitis. Hepatology. 2017;66(6):2055-2065. doi: 10.1002/hep.29420.

85. Bali T., Chrysavgis L., Cholongitas E. Metabolic-Associated Fatty Liver Disease and Sarcopenia. Endocrinol Metab Clin North Am. 2023;52(3):497-508. doi: 10.1016/j.ecl.2023.02.004.

86. Tuttle C.S.L., Thang L.A.N., Maier A.B. Markers of inflammation and their association with muscle strength and mass: A systematic review and meta-analysis. Ageing Res Rev. 2020;64:101185. doi: 10.1016/j.arr.2020.101185.

87. Fernández-Mincone T., Contreras-Briceño F., Espinosa-Ramírez M. et al. Nonalcoholic fatty liver disease and sarcopenia: pathophysiological connections and therapeutic implications. Expert Rev Gastroenterol Hepatol. 2020;14(12):1141-1157. doi: 10.1080/17474124.2020.1810563.

88. Amir M., Yu M., He P, Srinivasan S. Hepatic Autonomic Nervous System and Neurotrophic Factors Regulate the Pathogenesis and Progression of Non-alcoholic Fatty Liver Disease. Front Med (Lausanne). 2020;7:62. Published 2020 Feb 27. doi: 10.3389/fmed.2020.00062.

89. Streba L.A., Vere C.C., Ionescu A.G., Streba C.T., Rogoveanu I. Role of intrahepatic innervation in regulating the activity of liver cells. World J Hepatol. 2014;6(3):137-143. doi: 10.4254/wjh.v6.i3.137.

90. Mizuno K., Ueno Y. Autonomic Nervous System and the Liver. Hepatol Res. 2017;47(2):160-165. doi: 10.1111/hepr.12760.

91. McCullough A.J., Mullen K.D., Kalhan S.C. Body cell mass and leucine metabolism in cirrhosis. Pt 1 Gastroenterology. 1992;102:1325-1333. doi: 10.1016/0016-5085(92)90772-Q.