Безопасность урсодезоксихолевой кислоты: доказательства или слухи о токсичности?

Яковенко Э.П., Вялов С.С. Безопасность урсодезоксихолевой кислоты: доказательства или слухи о токсичности? Consilium Medicum. 2017; 19 (8): 27–31. DOI: 10.26442/2075-1753_19.8.27-31

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Yakovenko E.P., Vialov S.S. Safety of ursodeoxycholic acid: evidence or rumors about toxicity? Consilium Medicum. 2017; 19 (8): 27–31. DOI: 10.26442/2075-1753_19.8.27-31

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Аннотация

В статье изучаются особенности применения урсодезоксихолевой кислоты (УДХК) в аспекте безопасности и рисков нежелательных реакций. Анализируются инструкции по медицинскому применению, результаты токсикологических исследований на животных, клинических исследований на пациентах с разной патологией, приводятся метаанализы результатов исследований. В статье приводятся актуальные данные об использовании УДХК при беременности и в детском возрасте. Учитывая особенности зарегистрированных в инструкции показаний в детском возрасте, обсуждается возможность использования УДХК в педиатрии. Инструкция по медицинскому применению является официальным документом, утвержденным Минздравом России, в основание ее положены данные исследований, что подтверждает безопасность применения в педиатрической практике. Изучаются терапевтические возможности УДХК, эффективность и безопасность. В результате анализа многочисленных исследований не обнаружено свидетельств токсичности или низкого профиля безопасности УДХК. Напротив, большое количество исследований посвящено категориям пациентов, являющихся эталоном безопасности, подтверждают отсутствие токсичности и высокую эффективность УДХК. Сообщения о токсичности УДХК следует считать некорректными и необоснованными.

Ключевые слова: урсодезоксихолевая кислота, безопасность, токсичность, побочные эффекты, нежелательные эффекты.

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The article studies the characteristics of ursodeoxycholic acid (UDCA) application in terms of safety and the risk of adverse effects. We have analyzed the instructions of medical application, the results of toxicological studies using animals, clinical trials of patients with different pathologies and meta-analysis of the results of the studies. This article deals with the actual results on the use of UDCA in pregnancy and childhood. We discuss the possibility of the usage the UDCA in pediatric patients, according to the characteristics of application of registered instruction in childhood. The instruction of medical application is an official document approved by the Ministry of Health, at the baseline of it are placed the results of the studies that confirm the safety of the usage of UDCA in pediatric practice. We have studied the therapeutic possibilities of UDCA usage and the safety and efficacy. As follows from the analysis of numerous studies we have found no evidence of toxicity or low-profile safety of the usage of UDCA. In contrast, the large number of studies are devoted to the categories of patients the so-called safety standard, confirm the absence of toxicity and high efficiency of UDCA. The reports of toxicity of UDCA should be considered incorrect and unfounded.

Key words: ursodeoxycholic acid, safety, toxicity, side effects, adverse effects.

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Список литературы

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7. Grymowicz M, Czajkowski K, Smolarczyk R. Pregnancy course in patients with intrahepatic cholestasis of pregnancy treated with very low doses of ursodeoxycholic acid. Scand J Gastroenterol 2015: 1–8. DOI: 10.3109/00365521.2015.1064990
8. Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and Safety of Ursodeoxycholic Acid Versus Cholestyramine in Intrahepatic Cholestasis of Pregnancy. Gastroenterology 2005; 129 (3): 894–901. DOI: 10.1053/j.gastro.2005.06.019
9. Liu Y, Qiao F, Liu H, Liu D. Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy. J Huajong Univ Sci Technolog Med Sci 2006; 26 (3): 350–2. DOI: 10.1007/bf02829573
10. Glantz A, Marschall HU, Lammert F, Mattsson LA. Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid. Hepatology 2005; 42: 1399–405. DOI: 10.1002/hep.20952
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14. Simić D, Milojević I, Bogićević D. Preventive effect of ursodeoxycholic acid on parenteral nutrition-associated liver disease in infants. Srp Arh Celok Lek 2014; 142 (3–4): 184–8. DOI: 10.2298/sarh1404184s
15. Thibault M, McMahon J, Faubert G. Parenteral nutrition-associated liver disease: a retrospective study of ursodeoxycholic Acid use in neonates. J Pediatr Pharmacol Ther 2014; 19 (1): 42–8. DOI: 10.5863/1551-6776-19.1.42
16. Peterson TC, Slysz G, Isbrucker R. The inhibitory effect of ursodeoxycholic acid and pentoxifylline on platelet derived growth factor-stimulated proliferation is distinct from an effect by cyclic AMP. Immunopharmacology 1998; 39 (3): 181–91. DOI: 10.1016/s0162-3109(98)00021-6
17. Bouscarel B, Gettys TW, Fromm H, Dubner H. Ursodeoxycholic acid inhibits glucagon-induced cAMP formation in hamster hepatocytes: a role for PKC. Am J Physiol 1995; 268 Helvetica Light(2; Pt 1): G300–10.
18. Corpechot C, Carrat F, Bahr A et al. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 2005; 128 (2): 297–303. DOI: 10.1053/j.gastro.2004.11.009
19. Poupon R. Treatment of primary biliary cirrhosis with ursodeoxycholic acid, budesonide and fibrates. Dig Dis 2011; 29 (1): 85–8. DOI: 10.1159/000324139
20. Pemberton PW, Aboutwerat A, Smith A, Warnes TW. Ursodeoxycholic acid in primary biliary cirrhosis improves glutathione status but fails to reduce lipid peroxidation. Redox Rep 2006; 11 (3): 117 23. DOI: 10.1179/135100006x116600
21. Joo SS, Kang HC, Won TJ, Lee DI. Ursodeoxycholic acid inhibits pro-inflammatory repertoires, IL-1 beta and nitric oxide in rat microglia. Arch Pharm Res 2003; 26 (12): 1067–73. DOI: 10.1007/bf02994760
22. Ramalho RM, Viana RJ, Low WC et al. Bile acids and apoptosis modulation: an emerging role in experimental Alzheimer's disease. Trends Mol Med 2008; 14 (2): 54–62. DOI: 10.1016/j.molmed.2007.12.001.
23. Fimognari C, Lenzi M, Cantelli-Forti G, Hrelia P. Apoptosis and modulation of cell cycle control by bile acids in human leukemia T cells. Ann NY Acad Sci 2009; 1171: 264–9. DOI: 10.1111/j.1749-6632.2009.04710.x.
24. Hiramatsu K, Matsumoto Y, Miyazaki M et al. Inhibition of hepatocytes growth factor production in human fibroblasts by ursodeoxycholic acid. Biol Pharm Bull 2005; 28 (4): 619–24. DOI: 10.1248/bpb.28.619
25. Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology 2006; 130 (3): 715–20. DOI: 10.1053/j.gastro.2005.12.029
26. Shi J, Li Z, Zeng X et al. Ursodeoxycholic acid in primary sclerosing cholangitis: meta-analysis of randomized controlled trials. Hepatol Res 2009; 39 (9): 865–73. DOI: 10.1111/j.1872-034x.2009.00527.x
27. ter Borg PC, Schalm SW, Hansen BE, van Buuren HR; Dutch PBC Study Group. Prognosis of ursodeoxycholic Acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients. Am J Gastroenterol 2006; 101 (9): 2044–50. DOI: 10.1111/j.1572-0241.2006.00699.x
28. Lee J, Belanger A, Doucette JT et al. Transplantation trends in primary biliary cirrhosis. Clin Gastroenterol Hepatol 2007; 5 (11): 1313–5. DOI: 10.1016/j.cgh.2007.07.015
29. Wertheim BC, Smith JW, Fang C et al. Risk modification of colorectal adenoma by CYP7A1 polymorphisms and the role of bile acid metabolism in carcinogenesis. Cancer Prev Res (Phila) 2012; 5 (2): 197–204. DOI: 10.1158/1940-6207.capr-11-0320
30. Rost D, Rudolph G, Kloeters-Plachky P, Stiehl A. Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis. Hepatology 2004; 40 (3): 693–8. DOI: 10.1002/hep.20370
31. Serfaty L, Bissonnette M, Poupon R. Ursodeoxycholic acid and chemoprevention of colorectal cancer. Gastroenterol Clin Biol 2010; 34 (10): 516–22. DOI: 10.1016/j.gcb.2010.05.005
32. Huang WK, Hsu HC, Liu JR et al. The Association of Ursodeoxycholic Acid Use With Colorectal Cancer Risk: A Nationwide Cohort Study. Medicine (Baltimore) 2016; 95 (11): e2980. DOI: 10.1097/md.0000000000002980
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34. Carotti S, Guarino MP, Cicala M et al. Effect of ursodeoxycholic acid on inflammatory infiltrate in gallbladder muscle of cholesterol gallstone patients. Neurogastroenterol Motil 2010; 22 (8): 866–73, e232. DOI: 10.1111/j.1365-2982.2010.01510.x
35. Sugerman HJ, Brewer WH, Shiffman ML et al. A multicenter, placebo-controlled, randomized, double-blind, prospective trial of prophylactic ursodiol for the prevention of gallstone formation following gastric-bypass-induced rapid weight loss. Am J Surg 1995; 169 (1): 91–6. DOI: 10.1016/s0002-9610(99)80115-9
36. Shiffman ML, Kaplan GD, Brinkman-Kaplan V, Vickers FF. Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet program. Ann Intern Med 1995; 122 (12): 899–905. DOI: 10.7326/0003-4819-122-12-199506150-00002
37. Colombo C. Liver disease in cystic fibrosis. Curr Opin Pulm Med 2007; 13 (6): 529–36. DOI: 10.1097/mcp.0b013e3282f10a16
38. Chen W, Liu J, Gluud C. Bile acids for viral hepatitis. Cochrane Database Syst Rev 2007; 4: CD003181. DOI: 10.1002/14651858.cd003181.pub2
39. Sato S, Miyake T, Tobita H et al. A dose-up of ursodeoxycholic acid decreases transaminases in hepatitis C patients. World J Gastroenterol 2009; 15 (22): 2782–6. DOI: 10.3748/wjg.15.2782
40. Tarao K, Fujiyama S, Ohkawa S et al. Ursodiol use is possibly associated with lower incidence of hepatocellular carcinoma in hepatitis C virus-associated liver cirrhosis. Cancer Epidemiol Biomarkers Prev 2005; 14 (1): 164–9.
41. Omata M, Yoshida H, Toyota J et al. A large-scale multicenter double-blind trial of ursodeoxycholic acid in patients with chronic hepatitis C. Gut 2007; 56 (12): 1747–53. DOI: 10.1136/gut.2007.120956
42. 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. DOI: 10.1186/1471-230x-13-140
43. Pietu F, Guillaud O, Walter T et al. Ursodeoxycholic acid with vitamin E in patients with nonalcoholic steatohepatitis: Long-term results. Clin Res Hepatol Gastroenterol 2012; 36: 146–55. DOI: 10.1016/j.clinre.2011.10.011

________________________________________________

1. Нageу LR, Сrombie DL, Еspinosa Е et al. Ursodeoхусholic aсid in the Ursidae: Biliary bile aсids of bears, pandas, and related carnivores. J Lipid Res 1993; 34: 1911–7.
2. Hofmann АF. Pharmaсologу of ursodeoхуcholiс acid, an entеrohepatic drug. Scand J Gastroenterol 1994; 204: l–15. DOI: 10.3109/00365529409103618
3. Angulo P. Use of ursodeoxycholic acid in patients with liver disease. Curr Gastroenterol Rep 2002; 4 (1): 37–44. DOI: 10.1007/s11894-002-0036-9
4. Lindor KD, Kowdley KV, Luketic VA et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009; 50 (3): 808–14. DOI: 10.1002/hep.23082
5. www.fda.gov
6. Joutsiniemi T, Timonen S, Linden M. Intrahepatic cholestasis of pregnancy: observational study of the treatment with low-dose ursodeoxycholic acid. BMC Gastroenterol 2015; 15 (1): 92. DOI: 10.1186/s12876-015-0324-0
7. Grymowicz M, Czajkowski K, Smolarczyk R. Pregnancy course in patients with intrahepatic cholestasis of pregnancy treated with very low doses of ursodeoxycholic acid. Scand J Gastroenterol 2015: 1–8. DOI: 10.3109/00365521.2015.1064990
8. Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and Safety of Ursodeoxycholic Acid Versus Cholestyramine in Intrahepatic Cholestasis of Pregnancy. Gastroenterology 2005; 129 (3): 894–901. DOI: 10.1053/j.gastro.2005.06.019
9. Liu Y, Qiao F, Liu H, Liu D. Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy. J Huajong Univ Sci Technolog Med Sci 2006; 26 (3): 350–2. DOI: 10.1007/bf02829573
10. Glantz A, Marschall HU, Lammert F, Mattsson LA. Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid. Hepatology 2005; 42: 1399–405. DOI: 10.1002/hep.20952
11. Geenes V, Lövgren-Sandblom A, Benthin L. The reversed feto-maternal bile acid gradient in intrahepatic cholestasis of pregnancy is corrected by ursodeoxycholic acid. PLoS One 2014; 9(1): e83828. DOI: 10.1371/journal.pone.0083828
12. Brites D. Intrahepatic cholestasis of pregnancy: changes in maternal-fetal bile acid balance and improvement by ursodeoxycholic acid. Ann Hepatol 2002; 1: 20–8. DOI: 10.1016/s0168-8278(98)80694-6
13. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology 2004; 40: 467–74. DOI: 10.1002/hep.20336
14. Simić D, Milojević I, Bogićević D. Preventive effect of ursodeoxycholic acid on parenteral nutrition-associated liver disease in infants. Srp Arh Celok Lek 2014; 142 (3–4): 184–8. DOI: 10.2298/sarh1404184s
15. Thibault M, McMahon J, Faubert G. Parenteral nutrition-associated liver disease: a retrospective study of ursodeoxycholic Acid use in neonates. J Pediatr Pharmacol Ther 2014; 19 (1): 42–8. DOI: 10.5863/1551-6776-19.1.42
16. Peterson TC, Slysz G, Isbrucker R. The inhibitory effect of ursodeoxycholic acid and pentoxifylline on platelet derived growth factor-stimulated proliferation is distinct from an effect by cyclic AMP. Immunopharmacology 1998; 39 (3): 181–91. DOI: 10.1016/s0162-3109(98)00021-6
17. Bouscarel B, Gettys TW, Fromm H, Dubner H. Ursodeoxycholic acid inhibits glucagon-induced cAMP formation in hamster hepatocytes: a role for PKC. Am J Physiol 1995; 268 Helvetica Light(2; Pt 1): G300–10.
18. Corpechot C, Carrat F, Bahr A et al. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 2005; 128 (2): 297–303. DOI: 10.1053/j.gastro.2004.11.009
19. Poupon R. Treatment of primary biliary cirrhosis with ursodeoxycholic acid, budesonide and fibrates. Dig Dis 2011; 29 (1): 85–8. DOI: 10.1159/000324139
20. Pemberton PW, Aboutwerat A, Smith A, Warnes TW. Ursodeoxycholic acid in primary biliary cirrhosis improves glutathione status but fails to reduce lipid peroxidation. Redox Rep 2006; 11 (3): 117 23. DOI: 10.1179/135100006x116600
21. Joo SS, Kang HC, Won TJ, Lee DI. Ursodeoxycholic acid inhibits pro-inflammatory repertoires, IL-1 beta and nitric oxide in rat microglia. Arch Pharm Res 2003; 26 (12): 1067–73. DOI: 10.1007/bf02994760
22. Ramalho RM, Viana RJ, Low WC et al. Bile acids and apoptosis modulation: an emerging role in experimental Alzheimer's disease. Trends Mol Med 2008; 14 (2): 54–62. DOI: 10.1016/j.molmed.2007.12.001.
23. Fimognari C, Lenzi M, Cantelli-Forti G, Hrelia P. Apoptosis and modulation of cell cycle control by bile acids in human leukemia T cells. Ann NY Acad Sci 2009; 1171: 264–9. DOI: 10.1111/j.1749-6632.2009.04710.x.
24. Hiramatsu K, Matsumoto Y, Miyazaki M et al. Inhibition of hepatocytes growth factor production in human fibroblasts by ursodeoxycholic acid. Biol Pharm Bull 2005; 28 (4): 619–24. DOI: 10.1248/bpb.28.619
25. Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology 2006; 130 (3): 715–20. DOI: 10.1053/j.gastro.2005.12.029
26. Shi J, Li Z, Zeng X et al. Ursodeoxycholic acid in primary sclerosing cholangitis: meta-analysis of randomized controlled trials. Hepatol Res 2009; 39 (9): 865–73. DOI: 10.1111/j.1872-034x.2009.00527.x
27. ter Borg PC, Schalm SW, Hansen BE, van Buuren HR; Dutch PBC Study Group. Prognosis of ursodeoxycholic Acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients. Am J Gastroenterol 2006; 101 (9): 2044–50. DOI: 10.1111/j.1572-0241.2006.00699.x
28. Lee J, Belanger A, Doucette JT et al. Transplantation trends in primary biliary cirrhosis. Clin Gastroenterol Hepatol 2007; 5 (11): 1313–5. DOI: 10.1016/j.cgh.2007.07.015
29. Wertheim BC, Smith JW, Fang C et al. Risk modification of colorectal adenoma by CYP7A1 polymorphisms and the role of bile acid metabolism in carcinogenesis. Cancer Prev Res (Phila) 2012; 5 (2): 197–204. DOI: 10.1158/1940-6207.capr-11-0320
30. Rost D, Rudolph G, Kloeters-Plachky P, Stiehl A. Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis. Hepatology 2004; 40 (3): 693–8. DOI: 10.1002/hep.20370
31. Serfaty L, Bissonnette M, Poupon R. Ursodeoxycholic acid and chemoprevention of colorectal cancer. Gastroenterol Clin Biol 2010; 34 (10): 516–22. DOI: 10.1016/j.gcb.2010.05.005
32. Huang WK, Hsu HC, Liu JR et al. The Association of Ursodeoxycholic Acid Use With Colorectal Cancer Risk: A Nationwide Cohort Study. Medicine (Baltimore) 2016; 95 (11): e2980. DOI: 10.1097/md.0000000000002980
33. Radchenko V.G., Safronenkova I.G., Sitkin S.I. i dr. Medikamentoznyi litoliz preparatom «Ursofal'k». Usovershenstvovannaia meditsinskaia tekhnologiia. SPb.: Komitet po zdravookhraneniiu Pravitel'stva Sankt-Peterburga, SPbGMA im. I.I.Mechnikova, 2010. [in Russian]
34. Carotti S, Guarino MP, Cicala M et al. Effect of ursodeoxycholic acid on inflammatory infiltrate in gallbladder muscle of cholesterol gallstone patients. Neurogastroenterol Motil 2010; 22 (8): 866–73, e232. DOI: 10.1111/j.1365-2982.2010.01510.x
35. Sugerman HJ, Brewer WH, Shiffman ML et al. A multicenter, placebo-controlled, randomized, double-blind, prospective trial of prophylactic ursodiol for the prevention of gallstone formation following gastric-bypass-induced rapid weight loss. Am J Surg 1995; 169 (1): 91–6. DOI: 10.1016/s0002-9610(99)80115-9
36. Shiffman ML, Kaplan GD, Brinkman-Kaplan V, Vickers FF. Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet program. Ann Intern Med 1995; 122 (12): 899–905. DOI: 10.7326/0003-4819-122-12-199506150-00002
37. Colombo C. Liver disease in cystic fibrosis. Curr Opin Pulm Med 2007; 13 (6): 529–36. DOI: 10.1097/mcp.0b013e3282f10a16
38. Chen W, Liu J, Gluud C. Bile acids for viral hepatitis. Cochrane Database Syst Rev 2007; 4: CD003181. DOI: 10.1002/14651858.cd003181.pub2
39. Sato S, Miyake T, Tobita H et al. A dose-up of ursodeoxycholic acid decreases transaminases in hepatitis C patients. World J Gastroenterol 2009; 15 (22): 2782–6. DOI: 10.3748/wjg.15.2782
40. Tarao K, Fujiyama S, Ohkawa S et al. Ursodiol use is possibly associated with lower incidence of hepatocellular carcinoma in hepatitis C virus-associated liver cirrhosis. Cancer Epidemiol Biomarkers Prev 2005; 14 (1): 164–9.
41. Omata M, Yoshida H, Toyota J et al. A large-scale multicenter double-blind trial of ursodeoxycholic acid in patients with chronic hepatitis C. Gut 2007; 56 (12): 1747–53. DOI: 10.1136/gut.2007.120956
42. 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. DOI: 10.1186/1471-230x-13-140
43. Pietu F, Guillaud O, Walter T et al. Ursodeoxycholic acid with vitamin E in patients with nonalcoholic steatohepatitis: Long-term results. Clin Res Hepatol Gastroenterol 2012; 36: 146–55. DOI: 10.1016/j.clinre.2011.10.011

Авторы

Э.П.Яковенко*1, С.С.Вялов2

1 ФГБОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И.Пирогова» Минздрава России. 117997, Россия, Москва, ул. Островитянова, д. 1;
2 ФГАОУ ВО «Российский университет дружбы народов». 117198, Россия, Москва, ул. Миклухо-Маклая, д. 6
*epia_1940@mail.ru

________________________________________________

E.P.Yakovenko*1, S.S.Vialov2

1 N.I.Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation. 117997, Russian Federation, Moscow, ul. Ostrovitianova, d. 1;
2 People’s Friendship University of Russia. 117198, Russian Federation, Moscow, ul. Miklukho-Maklaia, d. 6
*epia_1940@mail.ru

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