Неалкогольная жировая болезнь печени и сахарный диабет: мишени метаболического тандема

Звенигородская Л.А., Шинкин М.В. Неалкогольная жировая болезнь печени и сахарный диабет: мишени метаболического тандема. Consilium Medicum. 2017; 19 (4): 50–57.

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Zvenigorodskaya L.A., Shinkin M.V. Non-alcoholic fatty liver disease and diabetes mellitus: targets of metabolic tandem. Consilium Medicum. 2017; 19 (4): 50–57.

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Аннотация

Неалкогольная жировая болезнь печени (НАЖБП) согласно прогнозам Всемирной организации здравоохранения к 2020 г. будет занимать 1-е место в структуре заболеваний печени. Трансплантация печени у пациентов с циррозом в исходе НАЖБП в настоящее время занимает 2-е место после циррозов печени вирусной этиологии. У больных НАЖБП смертность в 1-й месяц после операции значительно превышает данный показатель при циррозах печени другой этиологии, а также отмечается повышенный риск других осложнений трансплантации печени, таких как сепсис, отторжение трансплантата и развитие патологии со стороны сердечно-сосудистой системы. Согласно современным взглядам НАЖБП представляет собой поражение печени, включающее жировую дистрофию, жировую дистрофию с воспалением и повреждением гепатоцитов (неалкогольный/метаболический стеатогепатит) и фиброзом (с возможностью исхода в цирроз). Причинно-следственная связь НАЖБП и сахарного диабета является предметом многочисленных дискуссий. Связующим патогенетическим звеном одного и другого заболевания является инсулинорезистентность. Реализация инсулинорезистентности осуществляется прежде всего на уровне гепатоцита. Специфических диагностических критериев НАЖБП практически не существует, скорее всего диагноз НАЖБП – «диагноз исключения». До настоящего времени не существует стандартной терапии НАЖБП. Ни один из применяемых препаратов в лечении НАЖБП не имеет высокой доказательной базы. Коррекция массы тела, изменение пищевой аддикции, физическая активность – наиболее эффективные меры, предупреждающие развитие НАЖБП и сахарного диабета.

Ключевые слова: неалкогольная жировая болезнь печени, сахарный диабет, патогенез, метаболизм, ожирение, орлистат, коррекция, рецепторы.

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The prognosis of the World Health Organization indicates that by 2020 non-alcoholic fatty liver disease (NAFLD) will occupy the first position within liver diseases. Liver transplantation in NAFLD patients with cirrhosis occupies second position after viral cirrhosis, nowadays. Mortality in NAFLD patients 1 month after surgery is significantly higher than mortality rate in patients with cirrhosis of different etiology. We also indicate the increased risk of other complications of liver transplantation, such as sepsis, transplant rejection and the development of cardiovascular pathology. According to modern point of view NAFLD is a liver damage, including fatty degeneration, fatty degeneration and inflammatory cell infiltration and injury of hepatocytes (non-alcoholic steatohepatitis/metabolic liver disease) and fibrosis (results in cirrhosis). Cause-effect relation of NAFLD and diabetes mellitus (DM) is the subject of numerous discussions. The connecting pathogenetic link between NAFLD and DM is insulin resistance. The realization of insulin resistance is primarily carried out in hepatocytes. Specific diagnostic criteria for NAFLD practically do not exist; the most likely NAFLD diagnosis is an "exclusion diagnosis". There is no standard therapy for patients with NAFLD, nowadays. None of the drugs used in the treatment of NAFLD has high evidential base. Correction of body-mass index, food addiction and physical activity is the most effective actions to prevent the development of NAFLD and diabetes mellitus.

Key words: non-alcoholic fatty liver disease, diabetes mellitus, pathogenesis, metabolism, obesity, orlistat, correction, receptors.

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Список литературы

1. Буеверов А.О., Богомолов П.О., Маевская М.В. Патогенетическое лечение неалкогольного стеатогепатита: обоснование, эффективность, безопасность. Терапевт. арх. 2007; 79 (8): 1–4. / Bueverov A.O., Bogomolov P.O., Maevskaia M.V. Patogeneticheskoe lechenie nealkogol'nogo steatogepatita: obosnovanie, effektivnost', bezopasnost'. Terapevt. arkh. 2007; 79 (8): 1–4. [in Russian]
2. Драпкина О.М., Гацолаева Д.С., Ивашкин В.Т. Неалкогольная жировая болезнь печени как компонент метаболического синдрома. Рос. мед. вести. 2010; 2: 72–8. / Drapkina O.M., Gatsolaeva D.S., Ivashkin V.T. Nealkogol'naia zhirovaia bolezn' pecheni kak komponent metabolicheskogo sindroma. Ros. med. vesti. 2010; 2: 72–8. [in Russian]
3. Звенигородская Л.А Органы пищеварения и атеросклероз. М.: Медпрактика-М, 2011; с. 149–76. / Zvenigorodskaia L.A Organy pishchevareniia i ateroskleroz. M.: Medpraktika-M, 2011; s. 149–76. [in Russian]
4. Ивашкин В.Т. Ядерные рецепторы в патологии печени. Роc. журн. гастроэнтерологии, гепатологии, колопроктологии. 2010; 4: 7–15. / Ivashkin V.T. Iadernye retseptory v patologii pecheni. Roc. zhurn. gastroenterologii, gepatologii, koloproktologii. 2010; 4: 7–15. [in Russian]
5. Ивашкин В.Т., Драпкина О.М., Маев И.В. и др. Распространенность неалкогольной жировой болезни печени у пациентов амбулаторно-поликлинической практики в РФ: результаты исследования DIREG 2. Роc. журн. гастроэнтерологии, гепатологии, колопроктологии. 2015; 6: 31–41. / Ivashkin V.T., Drapkina O.M., Maev I.V. i dr. Rasprostranennost' nealkogol'noi zhirovoi bolezni pecheni u patsientov ambulatorno-poliklinicheskoi praktiki v RF: rezul'taty issledovaniia DIREG 2. Roc. zhurn. gastroenterologii, gepatologii, koloproktologii. 2015; 6: 31–41. [in Russian]
6. European Association for the Study of the Liver (EASL). European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64 (6): 1388–402.
7. Dajani A, Abu Hammour A. Treatment of nonalcoholic fatty liver disease: Where do we stand? an overview. Saudi J Gastroenterol 2016; 22 (2): 91–105.
8. Neuschwander-Tetri BA, Loomba R, Sanyal AJ et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385 (9972): 956–65.
9. Fang S, Suh JM, Reilly SM et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015; 21 (2): 159–65.
10. Staels B, Rubenstrunk A, Noel B et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 2013; 58 (6): 1941–52.
11. Athyros VG et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010; 376 (9756): 1916–22.
12. Nozaki Y, Fujita K, Yoneda M et al. Long-term combination therapy of ezetimibe and acarbose for nonalcoholic fatty liver disease. J Hepatol 2009; 51: 548–56.
13. Park H, Shima T, Yamaguchi K et al. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol 2011; 46: 101–7.
14. Loomba R, Sirlin CB, Ang B et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 2015; 61 (4): 1239–50.
15. Charlton MR, Burns JM, Pederson RA et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011; 141: 1249–53.
16. Yalamanchili K, Saadeh S, Klintman GB et al. Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease. Liver Transplant 2010; 16: 431–9.
17. Haukeland JW, Konopski Z, Eggesbo HB et al. Metformin in patients with nonalcoholic fatty liver disease: A randomized, controlled trial. Scand J Gastroenterol 2009; 44: 853–60.
18. Zhang ZJ, Zheng ZJ, Shi R et al. Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2012; 97 (7): 2347–53.
19. Hussein O et al. Orlistat reverse fatty infiltration and improves hepatic fibrosis in obese patients with nonalcoholic steatohepatitis (NASH). Digestive diseases and sciences 2007; 20. 10: 2512–9.
20. Sanyal AJ et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2004; 2 (12): 1107–15.
21. Younossi ZM, Koenig AB, Abdelatif D et al. Global epidemiology of nonalcoholic fatty liver disease – Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64 (1): 73–84.
22. Solga SF, Diehl A. Non-alcoholic fatty liver disease: lumen-liver interactions and possible role for probiotics. J Hepatol 2003; 38: 681–7.
23. Parnell JA, Raman M, Rioux KP, Reimer RA. The potential role of prebiotic fibre for treatment and management of non-alcoholic fatty liver disease and associated obesity and insulin resistance. Liver Int 2012; 32: 701–11.
24. Xiang Z, Chen YP, Ma KF et al. The role of ursodeoxycholic acid in non-alcoholic steatohepatitis: a systematic review. BMC Gastroenterol 2013; 13: 140.
25. Ratziu V, de Ledinghen V, Oberti F et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 2011; 54 (5): 1011–19.
26. Houghton D, Thoma C, Hallsworth K et al. Exercise Reduces Liver Lipids and Visceral Adiposity in Patients With Nonalcoholic Steatohepatitis in a Randomized Controlled Trial. Clin Gastroenterol Hepatol 2016; Aug 10 [Epub ahead of print].
27. Hallsworth K, Fattakova G, Hollingsworth KG et al. Resistance exercise reduces liver fat and its mediators in nonalcoholic fatty liver disease independent of weight loss. Gut 2011; 60: 1278–83.
28. Fang S, Suh JM, Reilly SM et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015; 21 (2): 159–65.
29. Brunzell JD, Ayyobi AF. Dyslipidemia in the metabolic syndrome and type 2 diabetes mellitus. Am J Med 2003; 115 (Suppl. 8A): 24S–28S.
30. Burt AD, Mutton A, Day CP. Diagnosis and interpretation of steatosis and steatohepatitis. Semin Diagh Pathol 1998; 4: 246–58.
31. Lewis GF, Carpentier A, Adeli K et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002; 23 (2): 201–29.
32. Azzout-Marniche D, Becard D, Guichard C et al. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. Biochem J 2000; 350: 389–93.
33. Namikawa C, Shu-Ping Z, Vyselaar JR et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese su-peroxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol 2004; 40: 781–6.
34. Loomba R, Lutchman G, Kleiner DE et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic. steatohepatitis. Aliment Pharmacol Ther 2009; 29 (2): 172–82.
35. Haukeland JW, Konopski Z, Eggesbo HB et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009; 44 (7): 853–60.
36. Nar A, Gedik O. The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Acta Diabetol 2009; 46 (2): 113–8.
37. Lavine JE, Schwimmer JB, Molleston JP et al. Treatment of nonalcoholic fatty liver disease in children: TONIC trial design. Contemp Clin Trials 2010; 31 (1): 62–70.
38. Babu A. Canagliflozin for the treatment of type 2 diabetes. Drugs Today (Barc) 2013; 49 (6): 363–76.
39. Nisly SA, Kolanczyk DM, Walton AM. Canagliflozin, a new sodium-glucose cotransporter 2 inhibitor, in the treatment of diabetes. Am J Health Syst Pharm 2013; 70 (4): 311–19.
40. INVOKANATM [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; March 2013.

41. James Toouli, Michael Fried et al. Obesity. World Gastroenterology Organisation Global Guideline. 2009. http://www.worldgastroenterology.org/UserFiles/file/guidelines/obesity-russian-2009.pdf

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1. Bueverov A.O., Bogomolov P.O., Maevskaia M.V. Patogeneticheskoe lechenie nealkogol'nogo steatogepatita: obosnovanie, effektivnost', bezopasnost'. Terapevt. arkh. 2007; 79 (8): 1–4. [in Russian]
2. Drapkina O.M., Gatsolaeva D.S., Ivashkin V.T. Nealkogol'naia zhirovaia bolezn' pecheni kak komponent metabolicheskogo sindroma. Ros. med. vesti. 2010; 2: 72–8. [in Russian]
3. Zvenigorodskaia L.A Organy pishchevareniia i ateroskleroz. M.: Medpraktika-M, 2011; s. 149–76. [in Russian]
4. Ivashkin V.T. Iadernye retseptory v patologii pecheni. Roc. zhurn. gastroenterologii, gepatologii, koloproktologii. 2010; 4: 7–15. [in Russian]
5. Ivashkin V.T., Drapkina O.M., Maev I.V. i dr. Rasprostranennost' nealkogol'noi zhirovoi bolezni pecheni u patsientov ambulatorno-poliklinicheskoi praktiki v RF: rezul'taty issledovaniia DIREG 2. Roc. zhurn. gastroenterologii, gepatologii, koloproktologii. 2015; 6: 31–41. [in Russian]
6. European Association for the Study of the Liver (EASL). European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64 (6): 1388–402.
7. Dajani A, Abu Hammour A. Treatment of nonalcoholic fatty liver disease: Where do we stand? an overview. Saudi J Gastroenterol 2016; 22 (2): 91–105.
8. Neuschwander-Tetri BA, Loomba R, Sanyal AJ et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385 (9972): 956–65.
9. Fang S, Suh JM, Reilly SM et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015; 21 (2): 159–65.
10. Staels B, Rubenstrunk A, Noel B et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 2013; 58 (6): 1941–52.
11. Athyros VG et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010; 376 (9756): 1916–22.
12. Nozaki Y, Fujita K, Yoneda M et al. Long-term combination therapy of ezetimibe and acarbose for nonalcoholic fatty liver disease. J Hepatol 2009; 51: 548–56.
13. Park H, Shima T, Yamaguchi K et al. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol 2011; 46: 101–7.
14. Loomba R, Sirlin CB, Ang B et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 2015; 61 (4): 1239–50.
15. Charlton MR, Burns JM, Pederson RA et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011; 141: 1249–53.
16. Yalamanchili K, Saadeh S, Klintman GB et al. Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease. Liver Transplant 2010; 16: 431–9.
17. Haukeland JW, Konopski Z, Eggesbo HB et al. Metformin in patients with nonalcoholic fatty liver disease: A randomized, controlled trial. Scand J Gastroenterol 2009; 44: 853–60.
18. Zhang ZJ, Zheng ZJ, Shi R et al. Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 2012; 97 (7): 2347–53.
19. Hussein O et al. Orlistat reverse fatty infiltration and improves hepatic fibrosis in obese patients with nonalcoholic steatohepatitis (NASH). Digestive diseases and sciences 2007; 20. 10: 2512–9.
20. Sanyal AJ et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2004; 2 (12): 1107–15.
21. Younossi ZM, Koenig AB, Abdelatif D et al. Global epidemiology of nonalcoholic fatty liver disease – Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64 (1): 73–84.
22. Solga SF, Diehl A. Non-alcoholic fatty liver disease: lumen-liver interactions and possible role for probiotics. J Hepatol 2003; 38: 681–7.
23. Parnell JA, Raman M, Rioux KP, Reimer RA. The potential role of prebiotic fibre for treatment and management of non-alcoholic fatty liver disease and associated obesity and insulin resistance. Liver Int 2012; 32: 701–11.
24. Xiang Z, Chen YP, Ma KF et al. The role of ursodeoxycholic acid in non-alcoholic steatohepatitis: a systematic review. BMC Gastroenterol 2013; 13: 140.
25. Ratziu V, de Ledinghen V, Oberti F et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 2011; 54 (5): 1011–19.
26. Houghton D, Thoma C, Hallsworth K et al. Exercise Reduces Liver Lipids and Visceral Adiposity in Patients With Nonalcoholic Steatohepatitis in a Randomized Controlled Trial. Clin Gastroenterol Hepatol 2016; Aug 10 [Epub ahead of print].
27. Hallsworth K, Fattakova G, Hollingsworth KG et al. Resistance exercise reduces liver fat and its mediators in nonalcoholic fatty liver disease independent of weight loss. Gut 2011; 60: 1278–83.
28. Fang S, Suh JM, Reilly SM et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015; 21 (2): 159–65.
29. Brunzell JD, Ayyobi AF. Dyslipidemia in the metabolic syndrome and type 2 diabetes mellitus. Am J Med 2003; 115 (Suppl. 8A): 24S–28S.
30. Burt AD, Mutton A, Day CP. Diagnosis and interpretation of steatosis and steatohepatitis. Semin Diagh Pathol 1998; 4: 246–58.
31. Lewis GF, Carpentier A, Adeli K et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002; 23 (2): 201–29.
32. Azzout-Marniche D, Becard D, Guichard C et al. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. Biochem J 2000; 350: 389–93.
33. Namikawa C, Shu-Ping Z, Vyselaar JR et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese su-peroxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol 2004; 40: 781–6.
34. Loomba R, Lutchman G, Kleiner DE et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic. steatohepatitis. Aliment Pharmacol Ther 2009; 29 (2): 172–82.
35. Haukeland JW, Konopski Z, Eggesbo HB et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009; 44 (7): 853–60.
36. Nar A, Gedik O. The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Acta Diabetol 2009; 46 (2): 113–8.
37. Lavine JE, Schwimmer JB, Molleston JP et al. Treatment of nonalcoholic fatty liver disease in children: TONIC trial design. Contemp Clin Trials 2010; 31 (1): 62–70.
38. Babu A. Canagliflozin for the treatment of type 2 diabetes. Drugs Today (Barc) 2013; 49 (6): 363–76.
39. Nisly SA, Kolanczyk DM, Walton AM. Canagliflozin, a new sodium-glucose cotransporter 2 inhibitor, in the treatment of diabetes. Am J Health Syst Pharm 2013; 70 (4): 311–19.
40. INVOKANATM [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; March 2013.
41. James Toouli, Michael Fried et al. Obesity. World Gastroenterology Organisation Global Guideline. 2009. http://www.worldgastroenterology.org/UserFiles/file/guidelines/obesity-russian-2009.pdf

Авторы

Л.А.Звенигородская*, М.В.Шинкин

ГБУЗ «Московский клинический научно-практический центр» Департамента здравоохранения г. Москвы. 111123, Россия, Москва, ш. Энтузиастов, д. 86
*msll@rambler.ru

________________________________________________

L.A.Zvenigorodskaya*, M.V.Shinkin

Moscow Clinical Science-Research Center of the Department of Health of Moscow. 111123, Russian Federation, Moscow, sh. Entuziastov, d. 86
*msll@rambler.ru

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