Внутрипеченочный холестаз при неалкогольной жировой болезни печени
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Материалы и методы. Обследовано 163 пациента с НАЖБП: 92 (56,4%) – со стеатозом печени (СП), 56 (34,4%) – со стеатогепатитом (СГ) и 15 (9,2%) – с циррозом печени (ЦП). Диагноз устанавливался на основании клинико-лабораторных, ультразвуковых и гистологических данных. Методом иммуноферментного анализа определялись: инсулин, фактор некроза опухоли α (ФНО-α), фрагменты цитокератина-18 (ФЦК-18). Рассчитывали индекс инсулинорезистентности (НОМА-IR), индекс фиброза NAFLD Fibrosis Score (NAFLD-FS) с учетом возраста пациента, индекса массы тела, наличия или отсутствия нарушений углеводного обмена, уровней аспартатаминотрансферазы, аланинаминотрансферазы, тромбоцитов и альбумина крови.
Результаты. Синдром ВПХ выявлялся у 49 (30,1%) пациентов с НАЖБП: у 23 (25%) – со СП, у 19 (33,9%) – со СГ и у 7 (46,7%) – с ЦП. У больных СП, СГ и ЦП с признаками холестаза, по сравнению с пациентами с СП, СГ и ЦП без холестаза, отмечались достоверно более высокие уровни таких показателей, как аминотрансферазы, триглицериды, HOMA-IR, ФНО-α, ФЦК-18, NAFLD-FS; число же тромбоцитов снижалось, косвенно подтверждая более быстрое развитие фиброза при холестазе. Данные факты согласовывались с данными литературы о нарушении при холестазе регулирующей функции желчных кислот, которые являются лиганадами многих ядерных рецепторов гепатоцитов, ответственных за нормальный гомеостаз.
Заключение. При всех формах НАЖБП у больных с холестазом выявлялись более выраженное печеночно-клеточное воспаление, некроз и апоптоз гепатоцитов, фиброз, нарушения углеводного и липидного обмена, что способствовало прогрессирующему течению НАЖБП и подтверждало необходимость медикаментозной коррекции холестаза, начиная с самой ранней формы НАЖБП – стеатоза печени.
Ключевые слова: неалкогольная жировая болезнь печени, холестаз, фиброз, фактор некроза опухоли α, фрагменты цитокератина-18, апоптоз, инсулин.
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Aim. to determine the frequency of intrahepatic cholestasis and its impact on the clinical features of the different forms of non-alcoholic fatty liver disease (NAFLD).
Materials and methods. The study involved 163 patients with NAFLD: 92 (56.4%) with hepatic steatosis (HS), 56 (34.4%) with steatohepatitis (SH) and 15 (9.2%) with liver cirrhosis (LC). Diagnosis is based on clinical, laboratory, ultrasound and histological data. Insulin, tumor necrosis factor α (TNF-α), fragments of cytokeratin-18 (FCK-18) were determined by ELISA. The index of insulin resistance (HOMA-IR) was calculated. NAFLD fibrosis score (NAFLD-FS) was determined, taking into account the patient's age, body mass index, presence or absence of carbohydrate metabolism disturbances, levels of ASAT, ALAT, albumin and blood platelets.
Results. Cholestatic syndrome was detected in 49 (30.1%) NAFLD patients: in 23 (25%) with HS, in 19 (33.9%) with SH and in 7 (46.7%) with LC. Patients with HS, SH and LC with signs of cholestasis as compared to patients with the same forms of NAFLD without cholestasis had significantly higher levels of the following indicators: aminotransferases, triglycerides, HOMA-IR, TNF-α, FCK-18, NAFLD-FS, – the number of platelets is reduced, indirectly confirming the more rapid development of fibrosis in cholestasis. These findings were consistent with published data on the violation in cholestasis regulatory functions of bile acids, which are ligands of hepatocyte nuclear receptor, responsible for normal homeostasis.
Сonclusion. In all forms of NAFLD with cholestasis were detected more pronounced liver cell inflammation, hepatocyte necrosis and apoptosis, fibrosis, disturbance of carbohydrate and lipid metabolism, which contributed to a progressive course of NAFLD and confirmed the need for medical correction of cholestasis, starting with the earliest form of NAFLD – hepatosteatosis.
Keywords: non-alcoholic fatty liver disease, cholestasis, fibrosis, tumor necrosis factor-α, fragments of cytokeratin-18, apoptosis, insulin.
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doi: 10.3892/br.2016.681
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1. Ivashkin VT, Drapkina OM, Maev IV, Trukhmanov AS, Blinov DV, Pal'gova LK, Tsukanov VV, Ushakova TI. Prevalence of non-alcoholic fatty liver disease in out-patients of the Russian Federation: DIREG 2 study results. Rossiiskii Zhurnal Gastroenterologii, Gepatologii, Koloproktologii = Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2015;(6):31-41 (In Russ.)
2. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of non‐alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005-23. doi: 10.1038/ajg.2012.128
3. Sheptulina AF, Shirokova EN, Ivashkin VT. Nuclear receptors in regulation of bile acids transport and metabolism. Klinicheskie Perspektivy Gastroenterologii i Gepatologii. 2013;(6):14-26 (In Russ.)
4. Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy. Pharmacological Reviews. 2014;66(4):948-83. doi: 10.1124/pr. 113.008201
5. Fiorucci S, Distrutti E. Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders. Trends Mol Med. 2015;21(11):702-14. doi: 10.1016/j.molmed.2015.09.001
6. Halilbasic E, Claudel T, Trauner M. Bile acid transporters and regulatory nuclear receptors in the liver and beyond. J Hepatol. 2013;58(1):155-68. doi: 10.1016/j.jhep.2012.08.002
7. Stel'makh VV, Kozlov VK, Radchenko VG, Nekrasova AS. Pathogenetic therapy of metabolic syndrome at the stage of visceral lesions. Klinicheskaya Meditsina. 2012;(6):61-5 (In Russ.)
8. Сao X, Gao Y, Zhang W, Xu P, Fu Q, Chen C, Li C, Yang C, Ma G, Qu Y, Xu M, Lu L. Cholestasis morbidity rate in first-hospitalized patients with chronic liver disease in Shanghai. Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chin J Hepatol. 2015;23(8):569-73. doi: 10.3760/cma.j.issn.1007-3418.2015.08.003
9. Kalhan SC, Guo L, Edmison J, Dasarathy S, McCullough AJ, Hanson RW, Milburn M. Plasma metabolomic profile in nonalcoholic fatty liver disease. Metabolism. 2011;60(3):404-13. doi: 10.1016/j.metabol.2010.03. 006
10. Zagorova M, Prasnicka A, Kadova Z, Dolezelova E, Kazdova L, Cermanova J, Rozkydalova L, Hroch M, Mokry J, Micuda S. Boldine attenuates cholestasis associated with nonalcoholic fatty liver disease in hereditary hypertriglyceridemic rats fed by high-sucrose diet. Physiol Res. 2015;64:S467.
11. Jungst C, Berg T, Cheng J, Green RM, Jia J, Mason AL, Lammert F. Intrahepatic cholestasis in common chronic liver diseases. Eur J Clin Investigat. 2013;43(10):1069-83. doi: 10.1111/eci.12128
12. 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, Therneau TM, Day CP. 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
13. Brunt EM, Tiniakos DG. Histopathology of nonalcoholic fatty liver disease. World J Gastroenterol. 2010;16(42):5286-96.
14. Gujral JS, Farhood A, Bajt ML, Jaeschke H. Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct-ligated mice. Hepatology. 2003;38(2):355-63. doi: 10.1053/jhep.2003. 50341
15. Kim DH, Xiao Z, Kwon S, Sun X, Ryerson D, Tkac D, Ma P, Wu SY, Chiang CM, Zhou E, Xu HE, Palvimo JJ, Chen LF, Kemper B, Kemper JK. A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity. EMBO J. 2015;34(2):184-99. doi: 10.15252/ embj.201489527
16. Tang N, Zhang Y, Liu Z, Fu T, Liang Q, Ai X. Correlation analysis between four serum biomarkers of liver fibrosis and liver function in infants with cholestasis. Biomed Reports. 2016;5(1):107-12.
doi: 10.3892/br.2016.681
17. Xing Y, Zhao T, Gao X, Wu Y. Liver X receptor α is essential for the capillarization of liver sinusoidal endothelial cells in liver injury. Scient Reports. 2016;18(6):21309. doi: 10.1038/srep21309
18. Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, Macchiarulo A, Yamamoto H, Mataki C, Pruzanski M, Pellicciari R, Auwerx J, Schoonjans K. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metabolism. 2009;10(3):167-77. doi: 10.1016/ j.cmet.2009.08.001
19. Schulz S, Schmitt S, Wimmer R, Aichler M, Eisenhofer S, Lichtmannegger J, Eberhagen C, Artmann R, Tookos F, Walch A, Krappmann D, Brenner C, Rust C, Zischka H. Progressive stages of mitochondrial destruction caused by cell toxic bile salts. Biochim Biophys Acta (BBA) – Biomembranes. 2013;1828(9):2121-33. doi: 10.1016/j.bbamem. 2013.05.007
20. Faubion WA, Guicciardi ME, Miyoshi H, Bronk SF, Roberts PJ, Svingen PA, Kaufmann SH, Gores GJ. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J Clin Investigat. 1999;103(1):137-45. doi: 10.1172/JCI4765
ФГБОУ ВО «Петрозаводский государственный университет», Минобрнауки России, медицинский институт, кафедра пропедевтики внутренних болезней и гигиены, Петрозаводск, Россия
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A.A. Shipovskaya, O.P. Dudanova
Petrozavodsk State University, Medical Institute, Propaedeutics of Internal Diseases and Hygiene Department, Petrozavodsk, Russia