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Кардиометаболические и генетические факторы прогрессирования метаболически ассоциированной жировой болезни печени
© ООО «КОНСИЛИУМ МЕДИКУМ», 2025 г.
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Gomonova VP, Raikhelson KL. Cardiometabolic and genetic factors in the progression of metabolic dysfunction-associated steatotic liver disease. Terapevticheskii Arkhiv (Ter. Arkh.). 2025;97(2):149–156. DOI: 10.26442/00403660.2025.02.203203
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Материалы и методы. Включены 108 пациентов с МАЖБП – они составили группу внутренней валидации. Для внешней валидации отобраны 30 пациентов с МАЖБП. Оценивались анамнестические, антропометрические и лабораторные данные, наличие полиморфизма гена PNPLA3 I148M (rs738409 C>G). Стеатоз выявлялся путем оценки контролируемого параметра затухания ультразвука (КПЗУ). Жесткость печени оценивалась методом транзиентной эластографии. КПХЗП устанавливалось при значении жесткости печени ≥8 кПа.
Результаты. В группе внутренней валидации получены статистически значимые различия при сравнении частоты КПХЗП в зависимости от наличия артериальной гипертензии (отношение шансов – ОШ 5,58; 95% доверительный интервал – ДИ 1,21–25,71), сахарного диабета 2-го типа – СД 2 (ОШ 4,58; 95% ДИ 1,59–13,21), ожирения (ОШ 3,13; 95% ДИ 1,1–8,9), дислипидемии (ОШ 6,12; 95% ДИ 1,33–28,19) и мутантного G-аллеля гена PNPLA3 (ОШ 3,9; 95% ДИ 1,28–11,88). У пациентов с КПХЗП выявлены достоверно более высокие средние значения окружности талии (ОТ), аланинаминотрансферазы, аспартатаминотрансферазы, γ-глутамилтрансферазы и триглицеридов, неинвазивных показателей стеатоза. Составленная прогностическая модель продемонстрировала прямую связь вероятности возникновения КПХЗП с наличием СД 2 (ОШ 3,28; 95% ДИ 0,62–17,33), дислипидемией (ОШ 5,89; 95% ДИ 1,21–28,67) и значением ОТ (ОШ 1,05; 95% ДИ 1,01–1,11). Полиморфизм гена PNPLA3 I148M не оказал значимого влияния на формирование поздних стадий заболевания. Внешняя валидация модели показала ее умеренную диагностическую способность.
Заключение. СД 2, дислипидемия и значения ОТ являются определяющими факторами в развитии КПХЗП у пациентов с МАЖБП. Полиморфизм гена PNPLA3 I148M не имеет ведущего значения в развитии прогрессирующего течения МАЖБП в исследуемой когорте.
Ключевые слова: метаболически ассоциированная жировая болезнь печени, компенсированное продвинутое хроническое заболевание печени, кардиометаболические факторы риска, PNPLA3, транзиентная эластография
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Aim. To evaluate the contribution of cardiometabolicfactors and PNPLA3 I148M (rs738409 C>G) gene polymorphism to the development of compensated advanced chronic liver disease (cACLD) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).
Materials and methods. 108 patients with MASLD were enrolled and formed the internal validation group; 30 patients with MASLD were selected for external validation. Anamnestic data, anthropometric and laboratory parameters and the presence of PNPLA3 gene polymorphism I148M (rs738409 C>G) were assessed. Steatosis was detected by assessing the controlled attenuation parameter. Liver elasticity was assessed by transient elastography. cACLD was detected when the liver stiffness was ≥8 kPa.
Results. Statistically significant difference was observed in the internal validation group during comparison of the incidence of cACLD depending on the presence of arterial hypertension (odds ratio – OR 5.58; 95% confidence interval – CI 1.21–25.71), type 2 diabetes mellitus – T2DM (OR 4.58; 95% CI 1.59–13.21), obesity (OR 3.13; 95% CI 1.1–8.9), dyslipidemia (OR 6.12; 95% CI 1.33–28.19) and the mutant G allele of the PNPLA3 gene (OR 3.9; 95% CI 1.28–11.88). Patients with cACLD had significantly higher mean values of waist circumference (WC), alanine aminotransaminase, aspartate aminotransaminase, gamma-glutamyl transferase and triglycerides, non-invasive markers of steatosis and fibrosis. The compiled prognostic model demonstrated a direct relationship between the likelihood of developing cACLD and the presence of T2DM (adjusted odds ratio – AOR 3.28; 95% CI 0.62–17.33), dyslipidemia (AOR 5.89; 95% CI 1.21–28.67) and WC value (AOR 1.05; 95% CI 1.01–1.11). PNPLA3 I148M gene polymorphism did not significantly affect the development of late stages of the disease. External validation of the model showed its moderate diagnostic ability.
Conclusion. T2DM, dyslipidemia and WC values are the determining factors in the development of cACLD in patients with MASLD. The PNPLA3 I148M gene polymorphism has no leading importance for the development of the progressive course of MASLD in the studied cohort.
Keywords: metabolic dysfunction-associated steatotic liver disease, compensated advanced chronic liver disease, cardiometabolic risk factors, PNPLA3, transient elastography
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3. Younossi ZM, Golabi P, Paik JM, et al. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023;77(4):1335-47. DOI:10.1097/HEP.0000000000000004
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7. Mundi MS, Velapati S, Patel J, et al. Evolution of NAFLD and Its Management. Nutr Clin Pract. 2020;35(1):72-84. DOI:10.1002/ncp.10449
8. Sanyal AJ, Castera L, Wong VW. Noninvasive Assessment of Liver Fibrosis in NAFLD. Clin Gastroenterol Hepatol. 2023;21(8):2026-39. DOI:10.1016/j.cgh.2023.03.042
9. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update. J Hepatol. 2021;75(3):659-89. DOI:10.1016/j.jhep.2021.05.025
10. Shiha G, Ibrahim A, Helmy A, et al. Asian-Pacific Association for the Study of the Liver (APASL) consensus guidelines on invasive and non-invasive assessment of hepatic fibrosis: a 2016 update. Hepatol Int. 2017;11(1):1-30. DOI:10.1007/s12072-016-9760-3
11. Sterling RK, Duarte-Rojo A, Patel K, et al. AASLD Practice Guideline on imaging-based noninvasive liver disease assessment of hepatic fibrosis and steatosis. Hepatology. 2025;81(2):672-724. DOI:10.1097/HEP.0000000000000843
12. de Franchis R; Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63(3):743-52. DOI:10.1016/j.jhep.2015.05.022
13. de Franchis R, Bosch J, Garcia-Tsao G, et al. Baveno VII – Renewing consensus in portal hypertension. J Hepatol. 2022;76(4):959-74. DOI:10.1016/j.jhep.2021.12.022
14. Papatheodoridi M, Hiriart JB, Lupsor-Platon M, et al. Refining the Baveno VI elastography criteria for the definition of compensated advanced chronic liver disease. J Hepatol. 2021;74(5):1109-16. DOI:10.1016/j.jhep.2020.11.050
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16. Calzadilla Bertot L, Adams LA. The Natural Course of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci. 2016;17(5):774. DOI:10.3390/ijms17050774
17. Carlsson B, Lindén D, Brolén G, et al. Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2020;51(12):1305-20. DOI:10.1111/apt.15738
18. Куртанов Х.А., Сыдыкова Л.А., Павлова Н.И., и др. Полиморфизм гена адипонутрина (PNPLAЗ) у коренных жителей Республики Саха (Якутия), страдающих сахарным диабетом 2-го типа. Альманах клинической медицины. 2018;46(3):258-63 [Kurtanov KhA, Sydykova LA, Pavlova NI, 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):258-63 (in Russian)]. DOI:10.18786/2072-0505-2018-46-3-258-263
19. Кролевец Т.С., Ливзан М.А., Ахмедов В.А., Новиков Д.Г. Исследование полиморфизма гена PNPLA3 у пациентов с неалкогольной жировой болезнью печени и различной стадией фиброза. Экспериментальная и клиническая гастроэнтерология. 2018;159(11):24-32 [Krolevets TS, Livzan MA, Akhmedov VA, Novikov DG. Study of PNPLA3 gene polymorphism in patients with non-alcoholic fatty liver disease and various stages of fibrosis. Experimental and Clinical Gastroenterology. 2018;159(11):24-32 (in Russian)]. DOI:10.31146/1682-8658-ecg-159-11-24-32
20. Райхельсон К.Л., Ковязина В.П., Сидоренко Д.В., и др. Влияние полиморфизма гена PNPLA3 на течение неалкогольной жировой болезни печени. РМЖ. 2019;12:85-8 [Raikhelson KL, Kovyazina VP, Sidorenko DV, et al. PNPLA gene polymorphism impact on the nonalcoholic fatty liver disease course. RMJ. 2019;12:85-8 (in Russian)].
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22. Peck-Radosavljevic M. Thrombocytopenia in chronic liver disease. Liver Int. 2017;37(6):778-93. DOI:10.1111/liv.13317
23. Kanwal F, Kramer JR, Li L, et al. Effect of Metabolic Traits on the Risk of Cirrhosis and Hepatocellular Cancer in Nonalcoholic Fatty Liver Disease. Hepatology. 2020;71(3):808-19. DOI:10.1002/hep.31014
24. Méndez-Sánchez N, Cerda-Reyes E, Higuera-de-la-Tijera F. Dyslipidemia as a risk factor for liver fibrosis progression in a multicentric population with non-alcoholic steatohepatitis. F1000Res. 2020;9:56. DOI:10.12688/f1000research.21918.1
25. Nderitu P, Bosco C, Garmo H, et al. The association between individual metabolic syndrome components, primary liver cancer and cirrhosis: A study in the Swedish AMORIS cohort. Int J Cancer. 2017;141(6):1148-60. DOI:10.1002/ijc.30818
26. Alexander M, Loomis AK, van der Lei, J, et al. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC Med. 2019;17(1):95. DOI:10.1186/s12916-019-1321-x
27. Unalp-Arida A, Ruhl CE. Patatin-Like Phospholipase Domain-Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population. Hepatology. 2020;71(3):820-34. DOI:10.1002/hep.31032
28. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis patients with HIV/HCV co-infection. Hepatology. 2006;43:1317-25. DOI:10.1002/hep.21178
29. Dai G, Liu P, Li X, et al. Association between PNPLA3 rs738409 polymorphism and nonalcoholic fatty liver disease (NAFLD) susceptibility and severity: A meta-analysis. Medicine (Baltimore). 2019;98(7):e14324. DOI:10.1097/MD.0000000000014324
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1. Nassir F. NAFLD: Mechanisms, Treatments, and Biomarkers. Biomolecules. 2022;12(6):824. DOI:10.3390/biom12060824
2. Riazi K, Azhari H, Charette JH, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7(9):851-61. DOI:10.1016/S2468-1253(22)00165-0
3. Younossi ZM, Golabi P, Paik JM, et al. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023;77(4):1335-47. DOI:10.1097/HEP.0000000000000004
4. Maev IV, Andreev DN. Kucheryavyy YuA. Prevalence of non-alcoholic fat disease liver in Russian Federation: meta-analysis. Consilium Medicum. 2023;25(5):313-9 (in Russian). DOI:10.26442/20751753.2023.5.202155
5. Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966-86. DOI:10.1097/HEP.0000000000000520
6. Raikhelson KL, Maevskaya MV, Zharkova MS, et al. Steatotic Liver Disease: New Nomenclature and Its Localization in the Russian Federation. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2024;34(2):35-44 (in Russian). DOI:10.22416/1382-4376-2024-961
7. Mundi MS, Velapati S, Patel J, et al. Evolution of NAFLD and Its Management. Nutr Clin Pract. 2020;35(1):72-84. DOI:10.1002/ncp.10449
8. Sanyal AJ, Castera L, Wong VW. Noninvasive Assessment of Liver Fibrosis in NAFLD. Clin Gastroenterol Hepatol. 2023;21(8):2026-39. DOI:10.1016/j.cgh.2023.03.042
9. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update. J Hepatol. 2021;75(3):659-89. DOI:10.1016/j.jhep.2021.05.025
10. Shiha G, Ibrahim A, Helmy A, et al. Asian-Pacific Association for the Study of the Liver (APASL) consensus guidelines on invasive and non-invasive assessment of hepatic fibrosis: a 2016 update. Hepatol Int. 2017;11(1):1-30. DOI:10.1007/s12072-016-9760-3
11. Sterling RK, Duarte-Rojo A, Patel K, et al. AASLD Practice Guideline on imaging-based noninvasive liver disease assessment of hepatic fibrosis and steatosis. Hepatology. 2025;81(2):672-724. DOI:10.1097/HEP.0000000000000843
12. de Franchis R; Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63(3):743-52. DOI:10.1016/j.jhep.2015.05.022
13. de Franchis R, Bosch J, Garcia-Tsao G, et al. Baveno VII – Renewing consensus in portal hypertension. J Hepatol. 2022;76(4):959-74. DOI:10.1016/j.jhep.2021.12.022
14. Papatheodoridi M, Hiriart JB, Lupsor-Platon M, et al. Refining the Baveno VI elastography criteria for the definition of compensated advanced chronic liver disease. J Hepatol. 2021;74(5):1109-16. DOI:10.1016/j.jhep.2020.11.050
15. Ivashkin VT, Maevskaya MV, Zharkova MS, 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. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2022;32(4):104-40 (in Russian). DOI:10.22416/1382-4376-2022-32-4-104-140
16. Calzadilla Bertot L, Adams LA. The Natural Course of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci. 2016;17(5):774. DOI:10.3390/ijms17050774
17. Carlsson B, Lindén D, Brolén G, et al. Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2020;51(12):1305-20. DOI:10.1111/apt.15738
18. Kurtanov KhA, Sydykova LA, Pavlova NI, 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):258-63 (in Russian). DOI:10.18786/2072-0505-2018-46-3-258-263
19. Krolevets TS, Livzan MA, Akhmedov VA, Novikov DG. Study of PNPLA3 gene polymorphism in patients with non-alcoholic fatty liver disease and various stages of fibrosis. Experimental and Clinical Gastroenterology. 2018;159(11):24-32 (in Russian). DOI:10.31146/1682-8658-ecg-159-11-24-32
20. Raikhelson KL, Kovyazina VP, Sidorenko DV, et al. PNPLA gene polymorphism impact on the nonalcoholic fatty liver disease course. RMJ. 2019;12:85-8 (in Russian).
21. Gomonova VP, Raikhelson KL, Pazenko EV, et al. Compensated advanced chronic liver disease in patients with metabolic dysfunction-associated steatotic liver disease: association with cardiometabolic factors. Sechenov Medicine Journal. 2024;15(3):15-25 (in Russian). DOI:10.47093/2218-7332.2024.1075.16
22. Peck-Radosavljevic M. Thrombocytopenia in chronic liver disease. Liver Int. 2017;37(6):778-93. DOI:10.1111/liv.13317
23. Kanwal F, Kramer JR, Li L, et al. Effect of Metabolic Traits on the Risk of Cirrhosis and Hepatocellular Cancer in Nonalcoholic Fatty Liver Disease. Hepatology. 2020;71(3):808-19. DOI:10.1002/hep.31014
24. Méndez-Sánchez N, Cerda-Reyes E, Higuera-de-la-Tijera F. Dyslipidemia as a risk factor for liver fibrosis progression in a multicentric population with non-alcoholic steatohepatitis. F1000Res. 2020;9:56. DOI:10.12688/f1000research.21918.1
25. Nderitu P, Bosco C, Garmo H, et al. The association between individual metabolic syndrome components, primary liver cancer and cirrhosis: A study in the Swedish AMORIS cohort. Int J Cancer. 2017;141(6):1148-60. DOI:10.1002/ijc.30818
26. Alexander M, Loomis AK, van der Lei, J, et al. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC Med. 2019;17(1):95. DOI:10.1186/s12916-019-1321-x
27. Unalp-Arida A, Ruhl CE. Patatin-Like Phospholipase Domain-Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population. Hepatology. 2020;71(3):820-34. DOI:10.1002/hep.31032
28. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis patients with HIV/HCV co-infection. Hepatology. 2006;43:1317-25. DOI:10.1002/hep.21178
29. Dai G, Liu P, Li X, et al. Association between PNPLA3 rs738409 polymorphism and nonalcoholic fatty liver disease (NAFLD) susceptibility and severity: A meta-analysis. Medicine (Baltimore). 2019;98(7):e14324. DOI:10.1097/MD.0000000000014324
30. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846-54. DOI:10.1002/hep.21496
ФГБОУ ВО «Санкт-Петербургский государственный университет», Санкт-Петербург, Россия
*veronikakovyazina@yandex.ru
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Veronika P. Gomonova*, Karina L. Raikhelson
Saint Petersburg State University, Saint Petersburg, Russia
*veronikakovyazina@yandex.ru