Клиническое значение инсулинорезистентности у недиабетических пациентов с ранними формами неалкогольной жировой болезни печени
Клиническое значение инсулинорезистентности у недиабетических пациентов с ранними формами неалкогольной жировой болезни печени
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Аннотация
Цель исследования – оценка наличия инсулинорезистентности (ИР) у недиабетических пациентов с ранними формами неалкогольной жировой болезни печени (НАЖБП), такими как стеатоз печени (СП) и стеатогепатит (СГ) слабой активности, и влияния ИР на клиническое течение данных заболеваний.
Материалы и методы. Обследовано 134 больных НАЖБП: 54 – со СП и 80 – со СГ. Контрольную группу составили 37 здоровых доноров. Оценивали антропометрические показатели [индекс массы тела (ИМТ), окружность талии (ОТ)], клинические, биохимические показатели крови, в том числе содержание в крови фрагментов цитокератина-18 (ФЦК-18), цитокинов фактора некроза опухоли-α (ФНО-α), интерлейкина-6 (ИЛ-6), инсулина. Рассчитывали HOMA-индекс и индекс фиброза (NAFLD FS). Больных СП и СГ разделили на группы: I – с отсутствием ИР (HOMA-индекс <2,7), II – c наличием ИР (HOMA-индекс >2,7).
Результаты и обсуждение. У больных СП II группы (с ИР) показатели печеночного повреждения, воспаления, холестаза, фиброза и атерогенной дислипидемии выше, чем у больных I группы (без ИР). У больных СГ II группы по сравнению с I группой достоверно выше ИМТ, ОТ, уровни гамма-глутамилтранспептидазы, ФЦК-18 и индекс фиброза, при этом нет значимой разницы в показателях цитолиза, воспаления и дислипидемии. Выявлены высокая частота встречаемости ИР у недиабетических пациентов с СП (37,0%) и СГ (55,0%) и выраженное влияние ИР на клиническое течение данных заболеваний.
Заключение. ИР у недиабетических пациентов c НАЖБП с чаще выявлялась при СГ (55,0%), чем при СП (37,0%). При СП ИР ассоциирована с ухудшением показателей печеночно-клеточного повреждения, внутрипеченочного холестаза, атерогенной дислипидемии и фиброза. При СГ ИР сочетается с достоверным ростом показателей апоптоза гепатоцитов, цитокинового провоспалительного статуса и фиброза. ИР определяет прогрессирующее течение НАЖБП, способствуя трансформации СП в СГ и СГ в фиброз и цирроз печени.
Ключевые слова: неалкогольная жировая болезнь печени, стеатоз, неалкогольный стеатогепатит, инсулинорезистентность, HOMA-индекс, индекс фиброза, фрагменты цитокератина-18, фактор некроза опухоли-α, интерлейкин-6.
Materials and methods. 134 patients with NAFLD were examined: 54 with LS and 80 with SH. The control group consisted of 37 healthy donors. Anthropometric parameters (body mass index (BMI), waist circumference (WC)), clinical and biochemical blood indices, including the blood level of cytokeratin-18 fragments (CK-18), TNF-α and IL-6 cytokines, insulin were evaluated. The HOMA index and the fibrosis index (NAFLD FS) were calculated. Patients were divided into groups: I – with the absence of IR (HOMA-index <2.7), II – with the presence of IR (HOMA-index> 2.7).
Results and discussion. Indicators of hepatic injury, inflammation, cholestasis, fibrosis and atherogenic dyslipidemia are higher in patients with LS of group II (with IR) than in group I patients (without IR). BMI, WC, γ-glutamil transpeptidase, CK-18 and fibrosis index are significantly higher in group II patients with SH compared with group I, there is no significant difference in the level of cytolysis, inflammation and dyslipidemia indices. A high incidence of IR in non-diabetic patients with LS (37.0%) and SH (55.0%) was found and the effect of IR on the clinical course of these diseases was revealed.
Conclusion. Insulin resistance in non-diabetic patients with NAFLD was detected in SH (55.0%) with higher frequency than in LS (37.0%). In LS, IR is associated with impaired hepatic cell damage, intrahepatic cholestasis, atherogenic dyslipidemia and fibrosis. In SH, IR is combined with reliable growth in indicators of hepatocyte apoptosis, cytokine proinflammatory status and fibrosis. IR determines the progressing course of NAFLD, promoting the transformation of steatosis into steatohepatitis and steatohepatitis into fibrosis and liver cirrhosis.
Key words: non-alcoholic fatty liver disease, steatosis, nonalcoholic steatohepatitis, insulin resistance, HOMA-index, fragments of cytokeratin-18, TNF-α, IL-6.
Материалы и методы. Обследовано 134 больных НАЖБП: 54 – со СП и 80 – со СГ. Контрольную группу составили 37 здоровых доноров. Оценивали антропометрические показатели [индекс массы тела (ИМТ), окружность талии (ОТ)], клинические, биохимические показатели крови, в том числе содержание в крови фрагментов цитокератина-18 (ФЦК-18), цитокинов фактора некроза опухоли-α (ФНО-α), интерлейкина-6 (ИЛ-6), инсулина. Рассчитывали HOMA-индекс и индекс фиброза (NAFLD FS). Больных СП и СГ разделили на группы: I – с отсутствием ИР (HOMA-индекс <2,7), II – c наличием ИР (HOMA-индекс >2,7).
Результаты и обсуждение. У больных СП II группы (с ИР) показатели печеночного повреждения, воспаления, холестаза, фиброза и атерогенной дислипидемии выше, чем у больных I группы (без ИР). У больных СГ II группы по сравнению с I группой достоверно выше ИМТ, ОТ, уровни гамма-глутамилтранспептидазы, ФЦК-18 и индекс фиброза, при этом нет значимой разницы в показателях цитолиза, воспаления и дислипидемии. Выявлены высокая частота встречаемости ИР у недиабетических пациентов с СП (37,0%) и СГ (55,0%) и выраженное влияние ИР на клиническое течение данных заболеваний.
Заключение. ИР у недиабетических пациентов c НАЖБП с чаще выявлялась при СГ (55,0%), чем при СП (37,0%). При СП ИР ассоциирована с ухудшением показателей печеночно-клеточного повреждения, внутрипеченочного холестаза, атерогенной дислипидемии и фиброза. При СГ ИР сочетается с достоверным ростом показателей апоптоза гепатоцитов, цитокинового провоспалительного статуса и фиброза. ИР определяет прогрессирующее течение НАЖБП, способствуя трансформации СП в СГ и СГ в фиброз и цирроз печени.
Ключевые слова: неалкогольная жировая болезнь печени, стеатоз, неалкогольный стеатогепатит, инсулинорезистентность, HOMA-индекс, индекс фиброза, фрагменты цитокератина-18, фактор некроза опухоли-α, интерлейкин-6.
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Materials and methods. 134 patients with NAFLD were examined: 54 with LS and 80 with SH. The control group consisted of 37 healthy donors. Anthropometric parameters (body mass index (BMI), waist circumference (WC)), clinical and biochemical blood indices, including the blood level of cytokeratin-18 fragments (CK-18), TNF-α and IL-6 cytokines, insulin were evaluated. The HOMA index and the fibrosis index (NAFLD FS) were calculated. Patients were divided into groups: I – with the absence of IR (HOMA-index <2.7), II – with the presence of IR (HOMA-index> 2.7).
Results and discussion. Indicators of hepatic injury, inflammation, cholestasis, fibrosis and atherogenic dyslipidemia are higher in patients with LS of group II (with IR) than in group I patients (without IR). BMI, WC, γ-glutamil transpeptidase, CK-18 and fibrosis index are significantly higher in group II patients with SH compared with group I, there is no significant difference in the level of cytolysis, inflammation and dyslipidemia indices. A high incidence of IR in non-diabetic patients with LS (37.0%) and SH (55.0%) was found and the effect of IR on the clinical course of these diseases was revealed.
Conclusion. Insulin resistance in non-diabetic patients with NAFLD was detected in SH (55.0%) with higher frequency than in LS (37.0%). In LS, IR is associated with impaired hepatic cell damage, intrahepatic cholestasis, atherogenic dyslipidemia and fibrosis. In SH, IR is combined with reliable growth in indicators of hepatocyte apoptosis, cytokine proinflammatory status and fibrosis. IR determines the progressing course of NAFLD, promoting the transformation of steatosis into steatohepatitis and steatohepatitis into fibrosis and liver cirrhosis.
Key words: non-alcoholic fatty liver disease, steatosis, nonalcoholic steatohepatitis, insulin resistance, HOMA-index, fragments of cytokeratin-18, TNF-α, IL-6.
Список литературы
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2. Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol. 2017;9(16):715-732. doi: 10.4254/wjh. v9.i16.715
3. Byrne CD, Targher G. Ectopic Fat, Insulin Resistance, and Nonalcoholic Fatty Liver Disease: Implications for Cardiovascular Disease. Arterioscler Thromb Vasc Biol. 2014;34(6):1155-1161. doi: 10.1161/atvbaha.114.303034
4. Boutens L, Stienstra R. Adipose tissue macrophages: going off track during obesity. Diabetologia. 2016;59:879-884. doi: 10.1007/s00125-016-3904-9
5. Lonardo A, Nascimbeni F, Maurantonio M, Marrazzo A, Rinaldi L, Adinolfi L. Nonalcoholic fatty liver disease: Evolving paradigms.
E World J Gastroenterol. 2017;23(36):6571-6592. doi: 10.3748/wjg. v23. i36.6571
6. Petta S, Gastaldelli A, Rebelos E, Bugianesi E, Messa P, Miele L, Svegliati-Baroni G, Valenti L, Bonino F. Pathophysiology of Non Alcoholic Fatty Liver Disease. Int J Mol Sci. 2016;17(12):pii: E2082.
7. Pasarín M, Abraldes JG, Liguori E, Kok B, La Mura V. Intrahepatic vascular changes in non-alcoholic fatty liver disease: potential role of insulin-resistance and endothelial dysfunction. World J Gastroenterol. 2017;23(37):6777-6787. doi: 10.3748/wjg.v23.i37.6777
8. [Roytberg GE, Sharkhun OO. Features of liver damage progression in insulin resistant patients. Meditsina. 2017;5:99-107 (In Russ.)].
9. Jung KY, Cho SY, Kim HJ, Kim SB, Song IH. Nonalcoholic steatohepatitis associated with metabolic syndrome: relationship to insulin resistance and liver histology. J Clin Gastroenterol. 2014;48(10):883-888. doi: 10.1097/mcg.0000000000000065
10. Ballestri S, Nascimbeni F, Romagnoli D, Lonardo A. The independent predictors of non-alcoholic steatohepatitis and its individual histological features: Insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment. Hepatol Res. 2016;46:1074-1087. doi: 10.1111/hepr.12656
11. Park BH, Yoon JM, Kim JH, Moon JH, Lee YH, Jang SM, Kim YJ. Pathologic Impact of Insulin Resistance and Sensitivity on the Severity of Liver Histopathology in Pediatric Non-Alcoholic Steatohepatitis. Yonsei Med J. 2017;58(4):756-762. doi: 10.3349/ymj.2017.58.4.756
12. Cruz MA, Cruz JF, Macena LB, de Santana DS, Oliveira CC, Lima SO, Franca AV. Association of the Nonalcoholic Hepatic Steatosis and Its Degrees With the Values of Liver Enzymes and Homeostasis Model Assessment-Insulin Resistance Index. Gastroenterol Res. 2015 Oct;8(5):260-264. doi: 10.14740/gr685w
13. Arata M, Nakajima J, Nishimata S, Nagata T, Kawashima H. Nonalcoholic steatohepatitis and insulin resistance in children. World J Diabetes. 2014;5(6):917-23. doi: 10.4239/wjd.v5.i6.917
14. Maximos M, Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Biernacki D, Suman A, Weber M, Cusi K. The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology. 2015;61(1):153-60.
doi: 10.1002/hep.27395
15. Kitade M, Yoshiji H, Noguchi R, Ikenaka Y, Kaji K, Shirai Y, Yamazaki M, Uemura M, Yamao J, Fujimoto M, Mitoro A, Toyohara M, Sawai M, Yoshida M, Morioka C, Tsujimoto T, Kawaratani H, Fukui H. Crosstalk between angiogenesis, cytokeratin-18, and insulin resistance in the progression of non-alcoholic steatohepatitis. World J Gastroenterol. 2009;15(41):5193-5199. doi: 10.3748/wjg.15.5193
16. Polyzos SA, Kountouras J, Papatheodorou A, Katsiki E, Patsiaoura K, Zafeiriadou E, Papadopoulou E, Zavos C, Terpos E. Adipocytokines and cytokeratin-18 in patients with nonalcoholic fatty liver disease: Introduction of CHA index. Ann Hepatol. 2013;12(5):749-757.
17. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, Enders F, Saksena S, Burt AD, Bida JP, Lindor K, Sanderson SO, Lenzi M, Adams LA, Kench J, Therneay TM, Day CP. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846-854. doi: 10.1002/ hep.21496
18. Wannamethee SG, Shaper AG, Lennon L, Whincup PH. Hepatic enzymes, the metabolic syndrome, and the risk of type 2 diabetes in older men. Diabetes Care. 2005 Dec;28(12):2913-2918. doi: 10.2337/diacare.28.12.2913
19. Sattar N, Scherbakova O, Ford I, O’Reilly DS, Stanley A, Forrest E, Macfarlane PW, Packard CJ, Cobbe SM, Shepherd J. The West of Scotland Coronary Prevention Study: Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the West of Scotland Coronary Prevention Study. Diabetes. 2004;53(11):2855-60. doi: 10.2337/diabetes.53.11.2855
20. Del Ben M, Polimeni L, Baratta F, Bartimoccia S, Carnevale R, Loffredo L, Pignatelli P, Violi F, Angelico F. Serum Cytokeratin-18 Is Associated with NOX2-Generated Oxidative Stress in Patients with Nonalcoholic Fatty Liver. Int J Hepatol. 2014;2014:784985. doi: 10.1155/ 2014/784985
21. Hossain IA, Rahman Shah MM, Rahman MK, Ali L. Gamma glutamyl transferase is an independent determinant for the association of insulin resistance with nonalcoholic fatty liver disease in Bangladeshi adults: Association of GGT and HOMA-IR with NAFLD. Diabetes Metab Syndr. 2016;10(1 Suppl 1):S25-S29. doi: 10.1016/j.dsx.2015.09.005
22. Mankowska-Cyl A, Krintus M, Rajewski P, Sypniewska G. Gamma-glutamyltransferase activity as a surrogate biomarker of metabolic health status in young nondiabetic obese women. Biomark Med. 2017;11(5):449-457. doi: 10.2217/bmm-2016-0332
23. Kunutsor SK, Apekey TA, Seddoh D. Gamma glutamyltransferase and metabolic syndrome risk: a systematic review and dose-response meta-analysis. Int J Clin Pract. 2015;69(1):136-344. doi: 10.1111/ ijcp.12507
24. Schreuder TC, Marsman HA, Lenicek M, van Werven JR, Nederveen AJ, Jansen PL, Schaap FG. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2010;298(3):G440-G445. doi: 10.1152/ajpgi.00322.2009
25. Chen Z, Yu R, Xiong Y, Du F, Zhu S. A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease. Lipids Health Dis. 2017;16(1):203. doi: 10.1186/s12944-017-0572-9
26. Bril F, Sninsky JJ, Baca AM, Superko HR, Portillo Sanchez P, Biernacki D, Maximos M, Lomonaco R, Orsak B, Suman A, Weber MH, McPhaul MJ, Cusi K. Hepatic Steatosis and Insulin Resistance, But Not Steatohepatitis, Promote Atherogenic Dyslipidemia in NAFLD.
J Clin Endocrinol Metab. 2016;101(2):644-52. doi: 10.1210/jc.2015-3111
27. Siddiqui MS, Fuchs M, Idowu MO, Luketic VA, Boyett S, Sargeant C, Stravitz RT, Puri P, Matherly S, Sterling RK, Contos M, Sanyal AJ. Severity of nonalcoholic fatty liver disease and progression to cirrhosis are associated with atherogenic lipoprotein profile. Clin Gastroenterol Hepatol. 2015;13(5):1000-1008.e3. doi: 10.1016/j.cgh.2014.10.008
28. Younossi ZM, Loomba R, Anstee QM, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, Serfaty L, Negro F, Caldwell SH, Ratziu V, Corey KE, Friedman SL, Abdelmalek MF, Harrison SA, Sanyal AJ, Lavine JE, Mathurin P, Charlton MR, Goodman ZD, Chalasani NP, Kowdley KV, George J, Lindor K. Diagnostic Modalities for Non-alcoholic Fatty Liver Disease (NAFLD), Non-alcoholic Steatohepatitis (NASH) and Associated Fibrosis. Hepatology. 2017 Dec 9 [Epub ahead of print].
29. Gentili A, Daviddi G, De Vuono S, Ricci MA, Di Filippo F, Alaeddin A, Mannarino MR, Boni M, Vaudo G, Lupattelli G. Non-alcoholic fatty liver disease fibrosis score and preclinical vascular damage in morbidly obese patients. Dig Liver Dis. 2016 Aug;48(8):904-908.
doi: 10.1016/j.dld.2016.04.004
2. Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol. 2017;9(16):715-732. doi: 10.4254/wjh. v9.i16.715
3. Byrne CD, Targher G. Ectopic Fat, Insulin Resistance, and Nonalcoholic Fatty Liver Disease: Implications for Cardiovascular Disease. Arterioscler Thromb Vasc Biol. 2014;34(6):1155-1161. doi: 10.1161/atvbaha.114.303034
4. Boutens L, Stienstra R. Adipose tissue macrophages: going off track during obesity. Diabetologia. 2016;59:879-884. doi: 10.1007/s00125-016-3904-9
5. Lonardo A, Nascimbeni F, Maurantonio M, Marrazzo A, Rinaldi L, Adinolfi L. Nonalcoholic fatty liver disease: Evolving paradigms.
E World J Gastroenterol. 2017;23(36):6571-6592. doi: 10.3748/wjg. v23. i36.6571
6. Petta S, Gastaldelli A, Rebelos E, Bugianesi E, Messa P, Miele L, Svegliati-Baroni G, Valenti L, Bonino F. Pathophysiology of Non Alcoholic Fatty Liver Disease. Int J Mol Sci. 2016;17(12):pii: E2082.
7. Pasarín M, Abraldes JG, Liguori E, Kok B, La Mura V. Intrahepatic vascular changes in non-alcoholic fatty liver disease: potential role of insulin-resistance and endothelial dysfunction. World J Gastroenterol. 2017;23(37):6777-6787. doi: 10.3748/wjg.v23.i37.6777
8. Ройтберг Г.Е., Шархун О.О. Особенности прогрессирования поражения печени при инсулинорезистентности. Медицина. 2017;5:99-107. [Roytberg GE, Sharkhun OO. Features of liver damage progression in insulin resistant patients. Meditsina. 2017;5:99-107 (In Russ.)].
9. Jung KY, Cho SY, Kim HJ, Kim SB, Song IH. Nonalcoholic steatohepatitis associated with metabolic syndrome: relationship to insulin resistance and liver histology. J Clin Gastroenterol. 2014;48(10):883-888. doi: 10.1097/mcg.0000000000000065
10. Ballestri S, Nascimbeni F, Romagnoli D, Lonardo A. The independent predictors of non-alcoholic steatohepatitis and its individual histological features: Insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment. Hepatol Res. 2016;46:1074-1087. doi: 10.1111/hepr.12656
11. Park BH, Yoon JM, Kim JH, Moon JH, Lee YH, Jang SM, Kim YJ. Pathologic Impact of Insulin Resistance and Sensitivity on the Severity of Liver Histopathology in Pediatric Non-Alcoholic Steatohepatitis. Yonsei Med J. 2017;58(4):756-762. doi: 10.3349/ymj.2017.58.4.756
12. Cruz MA, Cruz JF, Macena LB, de Santana DS, Oliveira CC, Lima SO, Franca AV. Association of the Nonalcoholic Hepatic Steatosis and Its Degrees With the Values of Liver Enzymes and Homeostasis Model Assessment-Insulin Resistance Index. Gastroenterol Res. 2015 Oct;8(5):260-264. doi: 10.14740/gr685w
13. Arata M, Nakajima J, Nishimata S, Nagata T, Kawashima H. Nonalcoholic steatohepatitis and insulin resistance in children. World J Diabetes. 2014;5(6):917-23. doi: 10.4239/wjd.v5.i6.917
14. Maximos M, Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Biernacki D, Suman A, Weber M, Cusi K. The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology. 2015;61(1):153-60.
doi: 10.1002/hep.27395
15. Kitade M, Yoshiji H, Noguchi R, Ikenaka Y, Kaji K, Shirai Y, Yamazaki M, Uemura M, Yamao J, Fujimoto M, Mitoro A, Toyohara M, Sawai M, Yoshida M, Morioka C, Tsujimoto T, Kawaratani H, Fukui H. Crosstalk between angiogenesis, cytokeratin-18, and insulin resistance in the progression of non-alcoholic steatohepatitis. World J Gastroenterol. 2009;15(41):5193-5199. doi: 10.3748/wjg.15.5193
16. Polyzos SA, Kountouras J, Papatheodorou A, Katsiki E, Patsiaoura K, Zafeiriadou E, Papadopoulou E, Zavos C, Terpos E. Adipocytokines and cytokeratin-18 in patients with nonalcoholic fatty liver disease: Introduction of CHA index. Ann Hepatol. 2013;12(5):749-757.
17. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, Enders F, Saksena S, Burt AD, Bida JP, Lindor K, Sanderson SO, Lenzi M, Adams LA, Kench J, Therneay TM, Day CP. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846-854. doi: 10.1002/ hep.21496
18. Wannamethee SG, Shaper AG, Lennon L, Whincup PH. Hepatic enzymes, the metabolic syndrome, and the risk of type 2 diabetes in older men. Diabetes Care. 2005 Dec;28(12):2913-2918. doi: 10.2337/diacare.28.12.2913
19. Sattar N, Scherbakova O, Ford I, O’Reilly DS, Stanley A, Forrest E, Macfarlane PW, Packard CJ, Cobbe SM, Shepherd J. The West of Scotland Coronary Prevention Study: Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the West of Scotland Coronary Prevention Study. Diabetes. 2004;53(11):2855-60. doi: 10.2337/diabetes.53.11.2855
20. Del Ben M, Polimeni L, Baratta F, Bartimoccia S, Carnevale R, Loffredo L, Pignatelli P, Violi F, Angelico F. Serum Cytokeratin-18 Is Associated with NOX2-Generated Oxidative Stress in Patients with Nonalcoholic Fatty Liver. Int J Hepatol. 2014;2014:784985. doi: 10.1155/ 2014/784985
21. Hossain IA, Rahman Shah MM, Rahman MK, Ali L. Gamma glutamyl transferase is an independent determinant for the association of insulin resistance with nonalcoholic fatty liver disease in Bangladeshi adults: Association of GGT and HOMA-IR with NAFLD. Diabetes Metab Syndr. 2016;10(1 Suppl 1):S25-S29. doi: 10.1016/j.dsx.2015.09.005
22. Mankowska-Cyl A, Krintus M, Rajewski P, Sypniewska G. Gamma-glutamyltransferase activity as a surrogate biomarker of metabolic health status in young nondiabetic obese women. Biomark Med. 2017;11(5):449-457. doi: 10.2217/bmm-2016-0332
23. Kunutsor SK, Apekey TA, Seddoh D. Gamma glutamyltransferase and metabolic syndrome risk: a systematic review and dose-response meta-analysis. Int J Clin Pract. 2015;69(1):136-344. doi: 10.1111/ ijcp.12507
24. Schreuder TC, Marsman HA, Lenicek M, van Werven JR, Nederveen AJ, Jansen PL, Schaap FG. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2010;298(3):G440-G445. doi: 10.1152/ajpgi.00322.2009
25. Chen Z, Yu R, Xiong Y, Du F, Zhu S. A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease. Lipids Health Dis. 2017;16(1):203. doi: 10.1186/s12944-017-0572-9
26. Bril F, Sninsky JJ, Baca AM, Superko HR, Portillo Sanchez P, Biernacki D, Maximos M, Lomonaco R, Orsak B, Suman A, Weber MH, McPhaul MJ, Cusi K. Hepatic Steatosis and Insulin Resistance, But Not Steatohepatitis, Promote Atherogenic Dyslipidemia in NAFLD.
J Clin Endocrinol Metab. 2016;101(2):644-52. doi: 10.1210/jc.2015-3111
27. Siddiqui MS, Fuchs M, Idowu MO, Luketic VA, Boyett S, Sargeant C, Stravitz RT, Puri P, Matherly S, Sterling RK, Contos M, Sanyal AJ. Severity of nonalcoholic fatty liver disease and progression to cirrhosis are associated with atherogenic lipoprotein profile. Clin Gastroenterol Hepatol. 2015;13(5):1000-1008.e3. doi: 10.1016/j.cgh.2014.10.008
28. Younossi ZM, Loomba R, Anstee QM, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, Serfaty L, Negro F, Caldwell SH, Ratziu V, Corey KE, Friedman SL, Abdelmalek MF, Harrison SA, Sanyal AJ, Lavine JE, Mathurin P, Charlton MR, Goodman ZD, Chalasani NP, Kowdley KV, George J, Lindor K. Diagnostic Modalities for Non-alcoholic Fatty Liver Disease (NAFLD), Non-alcoholic Steatohepatitis (NASH) and Associated Fibrosis. Hepatology. 2017 Dec 9 [Epub ahead of print].
29. Gentili A, Daviddi G, De Vuono S, Ricci MA, Di Filippo F, Alaeddin A, Mannarino MR, Boni M, Vaudo G, Lupattelli G. Non-alcoholic fatty liver disease fibrosis score and preclinical vascular damage in morbidly obese patients. Dig Liver Dis. 2016 Aug;48(8):904-908.
doi: 10.1016/j.dld.2016.04.004
________________________________________________
2. Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol. 2017;9(16):715-732. doi: 10.4254/wjh. v9.i16.715
3. Byrne CD, Targher G. Ectopic Fat, Insulin Resistance, and Nonalcoholic Fatty Liver Disease: Implications for Cardiovascular Disease. Arterioscler Thromb Vasc Biol. 2014;34(6):1155-1161. doi: 10.1161/atvbaha.114.303034
4. Boutens L, Stienstra R. Adipose tissue macrophages: going off track during obesity. Diabetologia. 2016;59:879-884. doi: 10.1007/s00125-016-3904-9
5. Lonardo A, Nascimbeni F, Maurantonio M, Marrazzo A, Rinaldi L, Adinolfi L. Nonalcoholic fatty liver disease: Evolving paradigms.
E World J Gastroenterol. 2017;23(36):6571-6592. doi: 10.3748/wjg. v23. i36.6571
6. Petta S, Gastaldelli A, Rebelos E, Bugianesi E, Messa P, Miele L, Svegliati-Baroni G, Valenti L, Bonino F. Pathophysiology of Non Alcoholic Fatty Liver Disease. Int J Mol Sci. 2016;17(12):pii: E2082.
7. Pasarín M, Abraldes JG, Liguori E, Kok B, La Mura V. Intrahepatic vascular changes in non-alcoholic fatty liver disease: potential role of insulin-resistance and endothelial dysfunction. World J Gastroenterol. 2017;23(37):6777-6787. doi: 10.3748/wjg.v23.i37.6777
8. [Roytberg GE, Sharkhun OO. Features of liver damage progression in insulin resistant patients. Meditsina. 2017;5:99-107 (In Russ.)].
9. Jung KY, Cho SY, Kim HJ, Kim SB, Song IH. Nonalcoholic steatohepatitis associated with metabolic syndrome: relationship to insulin resistance and liver histology. J Clin Gastroenterol. 2014;48(10):883-888. doi: 10.1097/mcg.0000000000000065
10. Ballestri S, Nascimbeni F, Romagnoli D, Lonardo A. The independent predictors of non-alcoholic steatohepatitis and its individual histological features: Insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment. Hepatol Res. 2016;46:1074-1087. doi: 10.1111/hepr.12656
11. Park BH, Yoon JM, Kim JH, Moon JH, Lee YH, Jang SM, Kim YJ. Pathologic Impact of Insulin Resistance and Sensitivity on the Severity of Liver Histopathology in Pediatric Non-Alcoholic Steatohepatitis. Yonsei Med J. 2017;58(4):756-762. doi: 10.3349/ymj.2017.58.4.756
12. Cruz MA, Cruz JF, Macena LB, de Santana DS, Oliveira CC, Lima SO, Franca AV. Association of the Nonalcoholic Hepatic Steatosis and Its Degrees With the Values of Liver Enzymes and Homeostasis Model Assessment-Insulin Resistance Index. Gastroenterol Res. 2015 Oct;8(5):260-264. doi: 10.14740/gr685w
13. Arata M, Nakajima J, Nishimata S, Nagata T, Kawashima H. Nonalcoholic steatohepatitis and insulin resistance in children. World J Diabetes. 2014;5(6):917-23. doi: 10.4239/wjd.v5.i6.917
14. Maximos M, Bril F, Portillo Sanchez P, Lomonaco R, Orsak B, Biernacki D, Suman A, Weber M, Cusi K. The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology. 2015;61(1):153-60.
doi: 10.1002/hep.27395
15. Kitade M, Yoshiji H, Noguchi R, Ikenaka Y, Kaji K, Shirai Y, Yamazaki M, Uemura M, Yamao J, Fujimoto M, Mitoro A, Toyohara M, Sawai M, Yoshida M, Morioka C, Tsujimoto T, Kawaratani H, Fukui H. Crosstalk between angiogenesis, cytokeratin-18, and insulin resistance in the progression of non-alcoholic steatohepatitis. World J Gastroenterol. 2009;15(41):5193-5199. doi: 10.3748/wjg.15.5193
16. Polyzos SA, Kountouras J, Papatheodorou A, Katsiki E, Patsiaoura K, Zafeiriadou E, Papadopoulou E, Zavos C, Terpos E. Adipocytokines and cytokeratin-18 in patients with nonalcoholic fatty liver disease: Introduction of CHA index. Ann Hepatol. 2013;12(5):749-757.
17. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, Enders F, Saksena S, Burt AD, Bida JP, Lindor K, Sanderson SO, Lenzi M, Adams LA, Kench J, Therneay TM, Day CP. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846-854. doi: 10.1002/ hep.21496
18. Wannamethee SG, Shaper AG, Lennon L, Whincup PH. Hepatic enzymes, the metabolic syndrome, and the risk of type 2 diabetes in older men. Diabetes Care. 2005 Dec;28(12):2913-2918. doi: 10.2337/diacare.28.12.2913
19. Sattar N, Scherbakova O, Ford I, O’Reilly DS, Stanley A, Forrest E, Macfarlane PW, Packard CJ, Cobbe SM, Shepherd J. The West of Scotland Coronary Prevention Study: Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the West of Scotland Coronary Prevention Study. Diabetes. 2004;53(11):2855-60. doi: 10.2337/diabetes.53.11.2855
20. Del Ben M, Polimeni L, Baratta F, Bartimoccia S, Carnevale R, Loffredo L, Pignatelli P, Violi F, Angelico F. Serum Cytokeratin-18 Is Associated with NOX2-Generated Oxidative Stress in Patients with Nonalcoholic Fatty Liver. Int J Hepatol. 2014;2014:784985. doi: 10.1155/ 2014/784985
21. Hossain IA, Rahman Shah MM, Rahman MK, Ali L. Gamma glutamyl transferase is an independent determinant for the association of insulin resistance with nonalcoholic fatty liver disease in Bangladeshi adults: Association of GGT and HOMA-IR with NAFLD. Diabetes Metab Syndr. 2016;10(1 Suppl 1):S25-S29. doi: 10.1016/j.dsx.2015.09.005
22. Mankowska-Cyl A, Krintus M, Rajewski P, Sypniewska G. Gamma-glutamyltransferase activity as a surrogate biomarker of metabolic health status in young nondiabetic obese women. Biomark Med. 2017;11(5):449-457. doi: 10.2217/bmm-2016-0332
23. Kunutsor SK, Apekey TA, Seddoh D. Gamma glutamyltransferase and metabolic syndrome risk: a systematic review and dose-response meta-analysis. Int J Clin Pract. 2015;69(1):136-344. doi: 10.1111/ ijcp.12507
24. Schreuder TC, Marsman HA, Lenicek M, van Werven JR, Nederveen AJ, Jansen PL, Schaap FG. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2010;298(3):G440-G445. doi: 10.1152/ajpgi.00322.2009
25. Chen Z, Yu R, Xiong Y, Du F, Zhu S. A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease. Lipids Health Dis. 2017;16(1):203. doi: 10.1186/s12944-017-0572-9
26. Bril F, Sninsky JJ, Baca AM, Superko HR, Portillo Sanchez P, Biernacki D, Maximos M, Lomonaco R, Orsak B, Suman A, Weber MH, McPhaul MJ, Cusi K. Hepatic Steatosis and Insulin Resistance, But Not Steatohepatitis, Promote Atherogenic Dyslipidemia in NAFLD.
J Clin Endocrinol Metab. 2016;101(2):644-52. doi: 10.1210/jc.2015-3111
27. Siddiqui MS, Fuchs M, Idowu MO, Luketic VA, Boyett S, Sargeant C, Stravitz RT, Puri P, Matherly S, Sterling RK, Contos M, Sanyal AJ. Severity of nonalcoholic fatty liver disease and progression to cirrhosis are associated with atherogenic lipoprotein profile. Clin Gastroenterol Hepatol. 2015;13(5):1000-1008.e3. doi: 10.1016/j.cgh.2014.10.008
28. Younossi ZM, Loomba R, Anstee QM, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, Serfaty L, Negro F, Caldwell SH, Ratziu V, Corey KE, Friedman SL, Abdelmalek MF, Harrison SA, Sanyal AJ, Lavine JE, Mathurin P, Charlton MR, Goodman ZD, Chalasani NP, Kowdley KV, George J, Lindor K. Diagnostic Modalities for Non-alcoholic Fatty Liver Disease (NAFLD), Non-alcoholic Steatohepatitis (NASH) and Associated Fibrosis. Hepatology. 2017 Dec 9 [Epub ahead of print].
29. Gentili A, Daviddi G, De Vuono S, Ricci MA, Di Filippo F, Alaeddin A, Mannarino MR, Boni M, Vaudo G, Lupattelli G. Non-alcoholic fatty liver disease fibrosis score and preclinical vascular damage in morbidly obese patients. Dig Liver Dis. 2016 Aug;48(8):904-908.
doi: 10.1016/j.dld.2016.04.004
Авторы
А.А. Шиповская 1, О.П. Дуданова 1, И.В. Курбатова 2
1 ФГБОУ ВО «Петрозаводский государственный университет» Медицинский институт, кафедра пропедевтики внутренних болезней
и гигиены, Петрозаводск, Россия;
2 Институт биологии – обособленное подразделение ФГБУН Федерального исследовательского центра «Карельский научный центр Российской академии наук», Петрозаводск, Россия
1 Petrozavodsk State University, Institute of Medicine, Department of Propaedeutics of Internal Diseases and Hygiene, Petrozavodsk, Russia;
2 The Institute of Biology – a separate subdivision of Karelian Research Centre of Russian Academy of Sciences, Petrozavodsk, Russia
1 ФГБОУ ВО «Петрозаводский государственный университет» Медицинский институт, кафедра пропедевтики внутренних болезней
и гигиены, Петрозаводск, Россия;
2 Институт биологии – обособленное подразделение ФГБУН Федерального исследовательского центра «Карельский научный центр Российской академии наук», Петрозаводск, Россия
________________________________________________
1 Petrozavodsk State University, Institute of Medicine, Department of Propaedeutics of Internal Diseases and Hygiene, Petrozavodsk, Russia;
2 The Institute of Biology – a separate subdivision of Karelian Research Centre of Russian Academy of Sciences, Petrozavodsk, Russia
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