nogrЭкспериментальная и клиническая гастроэнтерологияExperimental and Clinical Gastroenterology1682-8658«Global Media Technologies»nogr-388Research ArticleОБЗОРREVIEWНЕАЛКОГОЛЬНАЯ ЖИРОВАЯ БОЛЕЗНЬ ПЕЧЕНИ: ПЕРСПЕКТИВЫ ЛЕЧЕНИЯNONALCOHOLIC FATTY LIVER DISEASE: PROSPECTS FOR TREATMENTРайхельсонК. Л.RaikhelsonK. L.kraikhelson@mail.ruПрашноваМ. К.PrashnovaM. K.noemail@neicon.ruНаучно-клинический и образовательный центр гастроэнтерологии и гепатологии Санкт-Петербургского государственного университетаРоссияScientific and Educational Center of Gastroenterology and Hepatology of Saint-Petersburg UniversityRussian Federation2017200220170297102Copyright © Райхельсон К.Л., Прашнова М.К., 20172017Райхельсон К.Л., Прашнова М.К.Raikhelson K.L., Prashnova M.K.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.nogr.org/jour/article/view/388

Целью работы являлось изучение существующих и перспективных направлений в терапии неалкогольной жировой болезни печени. Проведен обзор рекомендаций ведущих гепатологических ассоциаций по лечению неалкогольной жировой болезни печени (НАБЖ). Рассмотрены результаты исследований, направленных на разработку новых направлений в терапии данного заболевания, оценены наиболее перспективные препараты для ее терапии. Выводы. В настоящее время активно изучаются лекарственные средства, перспективные для терапии неалкогольной жировой болезни печени, но необходимы дальнейшие исследования по оценке их долгосрочной эффективности и безопасности. Одним из наиболее патогенетически обоснованных препаратов для лечения НАЖБП является адеметионин.

The aim of our research was to study the current and future trends in the treatment of nonalcoholic fatty liver disease. This review presents recommendations of leading hepatology Associations in the treatment of nonalcoholic fatty liver disease (NAFLD). The article describes the results of research at the development of new directions in the treatment of this disease and rates the of the most promising drugs. Conclusions. There are several new drugs for treatment of nonalcoholic fatty liver disease under clinical trials today, but further research is needed to assess their long-term efficacy and safety. One of the more pathogenetically grounded drugs for the treatment of NAFLD is ademetionine.

неалкогольная жировая болезнь печенинеалкогольный стеатогепатиттерапияновые препаратыадеметионинnonalcoholic fatty liver diseasenonalcoholic steatohepatitistreatmentS-adenosylmethionineademetioninenew drugsReferencesИвашкин В. Т., Драпкина О. М., Маев И. В. и соавт. Распространенность неалкогольной жировой болезни печени у пациентов амбулаторно-поликлинической практики в российской федерации: результаты исследования DIREG 2. Российский журнал гастроэнтерологии, гепатологии, колопроктологии, 2015, № 6, С. 31-41.Ивашкин В. Т., Драпкина О. М., Маев И. В. и соавт. Распространенность неалкогольной жировой болезни печени у пациентов амбулаторно-поликлинической практики в российской федерации: результаты исследования DIREG 2. Российский журнал гастроэнтерологии, гепатологии, колопроктологии, 2015, № 6, С. 31-41.Charlton M. R., Burns J. M., Pedersen R. A. et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology, 2011, vol.141, pp. 1249-1253.Charlton M. R., Burns J. M., Pedersen R. A. et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology, 2011, vol.141, pp. 1249-1253.Wong R. J. Aguilar M., Cheung R. et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology, 2015, vol.148, no. 36 pp. 547-555.Wong R. J. Aguilar M., Cheung R. et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology, 2015, vol.148, no. 36 pp. 547-555.Younossi Z. M., Koenig A. B., Abdelatif D. et al. Global epidemiology of nonalcoholic fatty liver disease - Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology, 2016, vol.64, no.1, pp.73-84.Younossi Z. M., Koenig A. B., Abdelatif D. et al. Global epidemiology of nonalcoholic fatty liver disease - Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology, 2016, vol.64, no.1, pp.73-84.EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Journal of Hepatology, 2016, vol. 64, no. 6, pp.1388-1402.EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Journal of Hepatology, 2016, vol. 64, no. 6, pp.1388-1402.Практические рекомендации Всемирной Гастроэнтерологической Организации: неалкогольная жировая болезнь печени и неалкогольный стеатогепатит [Электронный ресурс]. Режим доступа: http://www.worldgastroenterology.org/guidelines/global-guidelines/nafld-nash (последнее обращение 21.02.2017).Практические рекомендации Всемирной Гастроэнтерологической Организации: неалкогольная жировая болезнь печени и неалкогольный стеатогепатит [Электронный ресурс]. Режим доступа: http://www.worldgastroenterology.org/guidelines/global-guidelines/nafld-nash (последнее обращение 21.02.2017).Chalasani N., Younossi Z., Lavine J. E. et al. 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, vol. 55, no. 6, pp. 2005-2023.Chalasani N., Younossi Z., Lavine J. E. et al. 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, vol. 55, no. 6, pp. 2005-2023.Ивашкин В. Т., Маевская М. В., Павлов Ч. С. и соавт. Клинические рекомендации по диагностике и лечению неалкогольной жировой болезни печени Российского Общества по Изучению Печени и Российской Гастроэнтерологической Ассоциации. Российский Журнал Гастроэнтерологии, Гепатологии, Колопроктологии, 2016, Т. 26, № 2, С. 24-42.Ивашкин В. Т., Маевская М. В., Павлов Ч. С. и соавт. Клинические рекомендации по диагностике и лечению неалкогольной жировой болезни печени Российского Общества по Изучению Печени и Российской Гастроэнтерологической Ассоциации. Российский Журнал Гастроэнтерологии, Гепатологии, Колопроктологии, 2016, Т. 26, № 2, С. 24-42.McTigue K.M., Harris R., Hemphill B. et al. Screening and interventions for obesity in adults: summary of the evidence for the U. S. Preventive Services Task Force. Annals of International Medicine, 2003, vol.139, pp. 933-949.McTigue K.M., Harris R., Hemphill B. et al. Screening and interventions for obesity in adults: summary of the evidence for the U. S. Preventive Services Task Force. Annals of International Medicine, 2003, vol.139, pp. 933-949.Trappoliere M., Tuccillo C., Federico A. et al. The treatment of NAFLD. European Review for Medical and Pharmacological Sciences, 2005, vol. 9, no. 5, pp. 299-304.Trappoliere M., Tuccillo C., Federico A. et al. The treatment of NAFLD. European Review for Medical and Pharmacological Sciences, 2005, vol. 9, no. 5, pp. 299-304.Vilar-Gomez E., Martinez-Perez Y., Calzadilla-Bertot L. et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology, 2015, vol. 149, no. 2, pp. 367-378.Vilar-Gomez E., Martinez-Perez Y., Calzadilla-Bertot L. et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology, 2015, vol. 149, no. 2, pp. 367-378.Dansinger M. L., Tatsioni A., Wong J. B. et al. Meta- analysis: the effect of dietary counseling for weight loss. Annals of International Medicine, 2007, vol.147, pp. 41-50.Dansinger M. L., Tatsioni A., Wong J. B. et al. Meta- analysis: the effect of dietary counseling for weight loss. Annals of International Medicine, 2007, vol.147, pp. 41-50.The Look AHEAD Research Group. The look AHEAD study: a description of the lifestyle intervention and the evidence supporting it. Obesity (Silver Spring), 2006, vol.14, no. 5, pp. 737-752.The Look AHEAD Research Group. The look AHEAD study: a description of the lifestyle intervention and the evidence supporting it. Obesity (Silver Spring), 2006, vol.14, no. 5, pp. 737-752.Vilar-Gomez E., Yasells-Garcia A., Martinez-Perez Y. et al. Development and validation of a noninvasive prediction model for nonalcoholic steatohepatitis resolution after lifestyle intervention. Hepatology, 2016, vol. 63, pp. 1875-1887.Vilar-Gomez E., Yasells-Garcia A., Martinez-Perez Y. et al. Development and validation of a noninvasive prediction model for nonalcoholic steatohepatitis resolution after lifestyle intervention. Hepatology, 2016, vol. 63, pp. 1875-1887.Lavine J. E., Schwimmer J. B., Van Natta M. L. et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA, 2011, vol. 305, pp. 1659-1668.Lavine J. E., Schwimmer J. B., Van Natta M. L. et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA, 2011, vol. 305, pp. 1659-1668.Sanyal A. J., Chalasani N., Kowdley K. V. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. The New England Journal of Medicine, 2010, vol. 362, pp. 1675-1685.Sanyal A. J., Chalasani N., Kowdley K. V. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. The New England Journal of Medicine, 2010, vol. 362, pp. 1675-1685.Bjelakovic G., Nikolova D., Gluud L. L. et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA, 2007, vol. 297, pp. 842-857.Bjelakovic G., Nikolova D., Gluud L. L. et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA, 2007, vol. 297, pp. 842-857.Klein E. A., Thompson Jr I. M., Tangen C. M. et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA, 2011, vol. 306, pp. 1549-1556.Klein E. A., Thompson Jr I. M., Tangen C. M. et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA, 2011, vol. 306, pp. 1549-1556.Leuschner U. F., Lindenthal B., Herrmann G. et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology, 2010, vol. 52, pp. 472-479.Leuschner U. F., Lindenthal B., Herrmann G. et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology, 2010, vol. 52, pp. 472-479.Argo C. K., Patrie J. T., Lackner C. et al. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. Journal of Hepatology, 2015, vol. 62, pp. 190-197.Argo C. K., Patrie J. T., Lackner C. et al. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. Journal of Hepatology, 2015, vol. 62, pp. 190-197.Dongiovanni P., Petta S., Mannisto V. et al. Statin use and nonalcoholic steatohepatitis in at risk individuals. Journal of Hepatology, 2015, vol. 63, pp. 705-712.Dongiovanni P., Petta S., Mannisto V. et al. Statin use and nonalcoholic steatohepatitis in at risk individuals. Journal of Hepatology, 2015, vol. 63, pp. 705-712.Carbone L. J., Angus P. W., Yeomans N. D. Incretin-based therapies for the treatment of non-alcoholic fatty liver disease: a systematic review and meta- analysis. Journal of Gastroenterology and Hepatology, 2016, vol. 31, pp.23-31.Carbone L. J., Angus P. W., Yeomans N. D. Incretin-based therapies for the treatment of non-alcoholic fatty liver disease: a systematic review and meta- analysis. Journal of Gastroenterology and Hepatology, 2016, vol. 31, pp.23-31.Musso G., Gambino R., Cassader M., Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology, 2010, vol. 52, pp. 79-104.Musso G., Gambino R., Cassader M., Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology, 2010, vol. 52, pp. 79-104.Rotman Y., Sanyal A. J. Current and upcoming pharmacotherapy for non- alcoholic fatty liver disease. Gut, 2016, vol. 66, no. 1, pp. 180-190.Rotman Y., Sanyal A. J. Current and upcoming pharmacotherapy for non- alcoholic fatty liver disease. Gut, 2016, vol. 66, no. 1, pp. 180-190.Ratziu V., Harrison S. A., Francque S. et al. Elafibranor, an agonist of the peroxisome proliferator activated receptor alpha and delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology, 2016, vol. 150, pp. 1147-1159.Ratziu V., Harrison S. A., Francque S. et al. Elafibranor, an agonist of the peroxisome proliferator activated receptor alpha and delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology, 2016, vol. 150, pp. 1147-1159.ClinicalTrials.gov [Электронный ресурс]. Режим доступа: http://www. clinicaltrials.gov (последнее обращение 21.02.2017).ClinicalTrials.gov [Электронный ресурс]. Режим доступа: http://www. clinicaltrials.gov (последнее обращение 21.02.2017).Neuschwander-Tetri B.A., Loomba R., Sanyal A. J. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet, 2015, vol. 385, no. 9972, pp. 956-965.Neuschwander-Tetri B.A., Loomba R., Sanyal A. J. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet, 2015, vol. 385, no. 9972, pp. 956-965.Safadi R., Konikoff F. M., Mahamid M.et al. The fatty acid-bile acid conjugate aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clinical Gastroenterology and Hepatology, 2014, vol. 12, no. 12, pp. 2085-2091.Safadi R., Konikoff F. M., Mahamid M.et al. The fatty acid-bile acid conjugate aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clinical Gastroenterology and Hepatology, 2014, vol. 12, no. 12, pp. 2085-2091.Mukhopadhyay P., Horvath B., Rajesh M. et al. PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis. Journal of Hepatology, 2017, vol. 66, no. 3, pp. 589-600.Mukhopadhyay P., Horvath B., Rajesh M. et al. PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis. Journal of Hepatology, 2017, vol. 66, no. 3, pp. 589-600.Balistreri W. F. Eschewing the Fat: What’s on the Horizon for Treating NASH? 2015 [Электронный ресурс]. Режим доступа: / http://www.medscape.com/viewarticle/841001 (последнее обращение 21.02.2017).Balistreri W. F. Eschewing the Fat: What’s on the Horizon for Treating NASH? 2015 [Электронный ресурс]. Режим доступа: / http://www.medscape.com/viewarticle/841001 (последнее обращение 21.02.2017).Copple B. L., Jaeschke H., Klaassen C. D. Oxidative stress and the pathogenesis of cholestasis. Seminars in Liver Disease, 2010, vol. 30, no. 2, pp. 195-204.Copple B. L., Jaeschke H., Klaassen C. D. Oxidative stress and the pathogenesis of cholestasis. Seminars in Liver Disease, 2010, vol. 30, no. 2, pp. 195-204.Avila M. A., Berasain C., Torres L. et al. Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. Journal of Hepatology, 2000, vol. 33, no. 6, pp. 907-914.Avila M. A., Berasain C., Torres L. et al. Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. Journal of Hepatology, 2000, vol. 33, no. 6, pp. 907-914.Colell A., Garcia-Ruiz C., Miranda M. et al. Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology, 1998, vol. 115, no. 6, pp. 1541-1551.Colell A., Garcia-Ruiz C., Miranda M. et al. Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology, 1998, vol. 115, no. 6, pp. 1541-1551.Song Z., Zhou Z., Chen T. et al. S-adenosylmethionine (SAMe) protects against acute alcohol induced hepatotoxicity in mice. The Journal of Nutritional Biochemistry, 2003, vol. 14, no. 10, pp. 591-597.Song Z., Zhou Z., Chen T. et al. S-adenosylmethionine (SAMe) protects against acute alcohol induced hepatotoxicity in mice. The Journal of Nutritional Biochemistry, 2003, vol. 14, no. 10, pp. 591-597.Vendemiale G., Altomare E., Trizio T. et al. Effects of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease. Scandinavian Journal of Gastroenterology, 1989, vol. 24, no. 4, pp. 407-415.Vendemiale G., Altomare E., Trizio T. et al. Effects of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease. Scandinavian Journal of Gastroenterology, 1989, vol. 24, no. 4, pp. 407-415.Martinez-Chantar M.L., Corrales F. J., Martinez-Cruz L.A. et al. Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. The FASEB Journal, 2002, vol. 16, no. 10, pp. 1292-1294.Martinez-Chantar M.L., Corrales F. J., Martinez-Cruz L.A. et al. Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. The FASEB Journal, 2002, vol. 16, no. 10, pp. 1292-1294.Webster C. R., Boria P., Usechak P., Anwer M. S. S-adenosylmethionine and cAMP confer differential cytoprotection against bile acid-induced apoptosis in canine renal tubular cells and primary rat hepatocytes. Journal of Veterinary Pharmacology and Therapeutics, 2002, vol. 3, no. 4, pp. 474-484.Webster C. R., Boria P., Usechak P., Anwer M. S. S-adenosylmethionine and cAMP confer differential cytoprotection against bile acid-induced apoptosis in canine renal tubular cells and primary rat hepatocytes. Journal of Veterinary Pharmacology and Therapeutics, 2002, vol. 3, no. 4, pp. 474-484.Huang X. F., Zhao W. Y., Huang W. D. et al. FXR and liver carcinogenesis. Acta Pharmacologica Sinica: English edition, 2015, vol. 36, no. 1, pp. 37-43.Huang X. F., Zhao W. Y., Huang W. D. et al. FXR and liver carcinogenesis. Acta Pharmacologica Sinica: English edition, 2015, vol. 36, no. 1, pp. 37-43.Anstee Q. M., Goldin R. D. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. International Journal of Experimental Pathology, 2006, vol. 87, no. 1, pp. 1-16.Anstee Q. M., Goldin R. D. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. International Journal of Experimental Pathology, 2006, vol. 87, no. 1, pp. 1-16.Cano A., Buque X., Martinez-Una M. et al. Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice. Hepatology, 2011, vol. 54, no. 6, pp. 1975-1986.Cano A., Buque X., Martinez-Una M. et al. Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice. Hepatology, 2011, vol. 54, no. 6, pp. 1975-1986.Kalhan S. C., Edmison J., Marczewski S. et al. Methionine and protein metabolism in non-alcoholic steatohepatitis: evidence for lower rate of transmethylation of methionine. Clinical Science, 2011, vol. 121, no. 4, pp. 179-189.Kalhan S. C., Edmison J., Marczewski S. et al. Methionine and protein metabolism in non-alcoholic steatohepatitis: evidence for lower rate of transmethylation of methionine. Clinical Science, 2011, vol. 121, no. 4, pp. 179-189.Tao Guo, Lei Chang, Yusha Xiao, Quanyan Liu. S-Adenosyl-L-Methionine for the Treatment of Chronic Liver Disease: A Systematic Review and Meta-Analysis. PLOS ONE, 2015, vol. 10, no. 3, e0122124.Tao Guo, Lei Chang, Yusha Xiao, Quanyan Liu. S-Adenosyl-L-Methionine for the Treatment of Chronic Liver Disease: A Systematic Review and Meta-Analysis. PLOS ONE, 2015, vol. 10, no. 3, e0122124.Барановский А. Ю., Райхельсон К. Л., Марченко Н. В. Применение S-аденозилметионина (Гептрала®) в терапии больных неалкогольным стеатогепатитом. Клинические перспективы гастроэнтерологии, гепатологии, 2010. Т. 9, № 1, C. 3-10.Барановский А. Ю., Райхельсон К. Л., Марченко Н. В. Применение S-аденозилметионина (Гептрала®) в терапии больных неалкогольным стеатогепатитом. Клинические перспективы гастроэнтерологии, гепатологии, 2010. Т. 9, № 1, C. 3-10.Virukalpattigopalratnam M. P., Singh T., Ravishankar A. C. Heptral (ademetionin) in patients with intrahepatic cholestasis in chronic liver diseases due to non-alcoholic liver disease: results of a multicenter observational study in India. Journal of the Indian Medical Association, 2013, vol. 111, no. 12, pp. 856-859.Virukalpattigopalratnam M. P., Singh T., Ravishankar A. C. Heptral (ademetionin) in patients with intrahepatic cholestasis in chronic liver diseases due to non-alcoholic liver disease: results of a multicenter observational study in India. Journal of the Indian Medical Association, 2013, vol. 111, no. 12, pp. 856-859.Prospective multicenter observational program to characterize the patient population with cholestasis in chronic liver disease due to non-alcoholic liver disease (hepatic steatosis) receiving Heptral in the Russian Federation / Abbott Laboratories (Abbott) / Program Report R&D/13/766 / Protocol P12-715 (информация предоставляется по запросу компании Abbott LLC)Prospective multicenter observational program to characterize the patient population with cholestasis in chronic liver disease due to non-alcoholic liver disease (hepatic steatosis) receiving Heptral in the Russian Federation / Abbott Laboratories (Abbott) / Program Report R&D/13/766 / Protocol P12-715 (информация предоставляется по запросу компании Abbott LLC)

The authors declare that there are no conflicts of interest present.