References

nogr

Экспериментальная и клиническая гастроэнтерология

Experimental and Clinical Gastroenterology

1682-8658

«Global Media Technologies»

10.31146/1682-8658-ecg-230-10-71-83

nogr-3002

Research Article

ПРАКТИЧЕСКИЕ РЕКОМЕНДАЦИИ

PRACTICAL GUIDELINES

Неалкогольная жировая болезнь печени и беременность

Non-alcoholic fatty liver disease and pregnancy

https://orcid.org/0000-0001-5922-2271

Сарсенбаева

А. С.

Sarsenbayeva

A. S.

aiman-ss@yandex.ru

https://orcid.org/0000-0002-8844-2465

Туркина

С. В.

Turkina

S. V.

noemail@neicon.ru

Федеральное государственное бюджетное образовательное учреждение высшего образования «Южно-Уральский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияSouth Ural State Medical University” Ministry of Health of the Russian FederationRussian Federation

ФГБОУ ВО «Волгоградский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияVolgograd State Medical UniversityRussian Federation

2024

10122024

0107183

2024

Сарсенбаева А.С., Туркина С.В.

Sarsenbayeva A.S., Turkina S.V.

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/3002

Цель - провести обзор актуальной научной литературы по проблеме неалкогольной жировой болезни печени и беременности Материалы и методы: осуществлен литературный обзор отечественных и зарубежных научных публикаций. Поиск исследований проводился с помощью базы данных PubMed с использованием запросов по темам Non-alcoholic fatty liver disease and pregnancy; pathology of the liver during pregnancy, с использованием данных научной электронной библиотеки elibrary.ru Результаты: проведена систематизация данных о роли печени в обмене эстрогенов в организме женщины в норме и при патологии, об экзогенных и эндогенных влияниях на метаболизм эстрогенов вне беременности и при беременности. Сведения, изложенные в статье, помогут практическому врачу своевременно выявить факторы риска поражения печени, определить признаки поражения печени и тактику ведения женщины в процессе подготовки к беременности и во время беременности, правильно построить диагностический алгоритм и провести дифференциальный диагноз.

The purpose is to review the current scientific literature on the problem of non-alcoholic fatty liver disease and pregnancy Materials and methods: a literary review of domestic and foreign scientific publications has been carried out. The research was searched using the PubMed database using queries on the topics of Non-alcoholic fatty liver disease and pregnancy; pathology of the liver during pregnancy, using data from the scientific electronic library elibrary.ru Results: the data on the role of the liver in the metabolism of estrogens in the body of a woman in normal and pathological conditions, on exogenous and endogenous effects on the metabolism of estrogens outside pregnancy and during pregnancy were systematized. The information presented in the article will help the practitioner to identify risk factors for liver damage in a timely manner, identify signs of liver damage and management tactics of a woman in preparation for pregnancy and during pregnancy, correctly build a diagnostic algorithm and make a differential diagnosis.

печеньэстрогеныбеременностьнеалкогольная жировая болезнь печени

liverestrogenspregnancynon-alcoholic fatty liver disease

References1

Dovzhikova I.V., Lutsenko M.T. Modern concepts of estrogens role at pregnancy (review). Bulletin. 2016;(61):120-127. (in Russ.)@@ Довжикова И.В., Луценко М.Т. Современные представления о роли эстрогенов во время беременности (обзор литературы). Бюллетень. 2016;(61):120-127.

Eremina E.Y., Syatkin S.V. Drug-induced liver injury in pregnancy. journalHandG [Internet]. 2025Jan.31];2(2): 116-21. (in Russ.) Available at: http://hepatogastro.grsmu.by/index.php/journalHandG/article/view/73 (Accessed: 05.09.2024)@@ Еремина Е.Ю., Сяткин С.В. Лекарственные поражения печени у беременных. Гепатология и гастроэнтерология, 2018 № 2С. 116-121.

Novruzova D.R., Sosnova E.A. Peculiarities of the state of the hepatobiliary system in the physiological course of pregnancy and against the background of drug administration. V.F. Snegirev Archives of Obstetrics and Gynecology. 2018;5(2):60-64. (in Russ.) doi: 10.18821/2313-8726-2018-5-2-60-64.@@ Новрузова Д.Р., Соснова Е.А. Особенности состояния гепатобилиарной системы при физиологическом течении беременности и на фоне приёма лекарственных препаратов. Архив акушерства и гинекологии им. В.Ф. Снегирёва. 2018; 5(2): 60-64. doi: 10.18821/2313-8726-2018-5-2-60-64.

Tran T.T., Ahn J., Reau N.S. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111(2):176-94; quiz 196. doi: 10.1038/ajg.2015.430. Epub 2016 Feb 2. Erratum in: Am J Gastroenterol. 2016 Nov;111(11):1668. doi: 10.1038/ajg.2016.462.

Order of the Ministry of Health of the Russian Federation No. 803n of July 31, 2020 [On the procedure for using assisted reproductive technologies, contraindications and restrictions on their use]. (in Russ.)@@ Приказ Минздрава Российской Федерации № 803н от 31.07.2020 г «О порядке использования вспомогательных репродуктивных технологий, противопоказаниях и ограничениях к их применению».

Primak A.V. Metabolizm ehstrogenov u zhenshchin (obshchie predstavleniya i klinicheskaya praktika) [Estrogen metabolism in women (General concepts and clinical practice)]. EHsteticheskaya medicina - [Aesthetic medicine]. 2006, vol. 2, pp 208-214. (in Russ.)@@ Примак А.В. Метаболизм эстрогенов у женщин (общие представления и клиническая практика). Эстетическая медицина. - 2006. - № 2. - С. 208-214.

Tkacheva O.N, Bevz A. Yu., Ushkalova E.A., Chukhareva N.A. The first All-Russian pharmacoepidemiological study «Epidemiology of drug use in pregnant women»: basic results. Obstetrics and Gynegology. 2011; (4): 112-7. (in Russ.)@@ Ткачёва О.Н., Бевз А.Ю., Ушкалова Е.А., Чухарева Н.А. Первое Всероссийское фармакоэпидемиологическое исследование «Эпидемиология использования лекарственных средств у беременных»: основные результаты. Акушерство и гинекология. 2011; (4): 112-7.

Uspenskaya Yu.B. Hepatoprotection in gynecological practice. Effective pharmacotherapy. Obstetrics and Gynecology. 2015;5: 70-76. (in Russ.) doi: 10.4103/0300-1652.170385 12.@@ Успенская Ю.Б. Гепатопротекция в гинекологической практике. Эффективная фармакотерапия. Акушерство и гинекология» 2015;5: 70-76. doi: 10.4103/0300-1652.170385 12.

Uspenskaya Yu.B. [Clinical features. Diagnostics and treatment of diseases of the hepatobiliary system during pregnancy]. Diss. Doc of Med. Moscow. 2019, 46 p. (in Russ.)@@ Успенская Ю.Б. Особенности клиники. Диагностики и лечения заболеваний гепатобилиарной системы во время беременности Автореферат диссертации на соискание ученой степени доктора медицинских наук, 46 с, Москва. 2019 г

Uspenskaya Yu.B., Kuznetsova I.V. Impaired liver function in first half of pregnancy in practice of obstetrician-gynecologist. Medical alphabet. 2020;(4):33-38. (In Russ.) doi: 10.33667/2078-5631-2020-4-33-38.@@ Успенская Ю.Б., Кузнецова И.В. Нарушения функции печени в первой половине беременности в практике акушера-гинеколога. Медицинский алфавит. 2020;(4):33-38. doi: 10.33667/2078-5631-2020-4-33-38.

Hobkirk R. Steroid sulfation Current concepts. Trends Endocrinol Metab. 1993 Mar;4(2):69-74. doi: 10.1016/s1043-2760(05)80018-9.

Yakushevskaya O.V., Yureneva S.V., Protasova A.E. Estrogen metabolism: why it’s so crucial to keep the balance? Gynecology. 2019; 21 (6): 31-35. (in Russ.) doi: 10.26442/20795696.2019.6.190752.@@ Якушевская О.В., Юренева С.В., Протасова А.Э. Метаболизм эстрогенов: почему так важно сохранять равновесие? Гинекология. 2019; 21 (6): 31-35. doi: 10.26442/20795696.2019.6.190752.

ACOG Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol. 2002 Jan;99(1):159-67. doi: 10.1016/s0029-7844(01)01747-1.

Aithal G.P., Watkins P.B., Andrade R.J. et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89(6):806-815. doi: 10.1038/clpt.2011.58.

Alvaro D. Estrogens and the pathophysiology of the biliary tree. World J Gastroenterol. (2006) 12:3537. doi: 10.3748/wjg.v12.i22.3537.

Alvaro D., Invernizzi P., Onori P. et al. Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis. J Hepatol. (2004) 41:905-12. doi: 10.1016/j.jhep.2004.08.022.

Arment V.T., Redomski T.S., Moritz M. et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl. 2005:69-83.

Ballestri S., Nascimbeni F., Baldelli E., Marrazzo A., Romagnoli D., Lonardo A. NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk. Adv Ther. 2017 Jun;34(6):1291-1326. doi: 10.1007/s12325-017-0556-1.

Bar Oz. B., Hackman R., Einarson T., Koren G. Pregnancy outcome after cyclosporine therapy during pregnancy: a meta analysis. Transplantation. 2001 Apr 27;71(8):1051-5. doi: 10.1097/00007890-200104270-00006.

Bacak S.J., Thornburg L.L. Liver Failure in Pregnancy. Crit. Care Clin. 2016; 32(1): 61-72. doi: 10.1016/j.ccc.2015. 08.005

Beninchou C. Criteria of drug-induced liver disorder. Report of an international consensus meeting. J. Hepatol. 1990;11(2):272-276.

Bjornsson E., Jerlstad P., Bergqvist A., Olsson R. Fulminant druginduced hepatic failure leading to death or liver transplantation in Sweden. Scand. J. Gastroenterol. 2005; 40: 1095-101.

Bjornsson E., Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology. 2005;42(2):481-489. doi: 10.1002/hep.20800.

Bougarne N., Weyers B., Desmet S.J. et al. Molecular actions of PPARα in lipid metabolism and inflammation. Endocr Rev. 2018 Oct 1;39(5):760-802. doi: 10.1210/er.2018-00064.

Buratti S., Lavine J.E. Drugs and the liver: advances in metabolism, toxicity, and therapeutics. Curr. Opin. Pediatr. 2002 Oct;14(5):601-7. doi: 10.1097/00008480-200210000-00007.

Cao H., Zhu B., Qu Y., Zhang W. Abnormal Expression of ERα in Cholangiocytes of Patients With Primary Biliary Cholangitis Mediated Intrahepatic Bile Duct Inflammation. Front Immunol. 2019 Dec 5;10:2815. doi: 10.3389/fimmu.2019.02815.

Carey E.J., White P. Ursodeoxycholic acid for intrahepatic cholestasis of pregnancy: good for the mother, not bad for the baby. Evid Based Med. 2013 Dec;18(6): e55. doi: 10.1136/eb-2013-101298.

CDC. Hepattis C. PAQs for Health Professionals. Avallable at hitp//www.cdc.gov/hepatrus/HCV/H.CVIaq.him (accessed: 10 june 2014)

Chalasani N., Fontana R.J., Bonkovsky H.L., Watkins P.B., Davern T., Serrano J., Yang H., Rochon J.; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008 Dec;135(6):1924-34, 1934.e1-4. doi: 10.1053/j.gastro.2008.09.011.

Ch’ng C.L., Morgan M., Hainsworth I., Kingham J.G. Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut. 2002 Dec;51(6):876-80. doi: 10.1136/gut.51.6.876.

Christopher V., Al-Chalabi T., Richardson P.D. et al. Pregnancy outcome after liver transplantation: a single-center experience of 71 pregnancies in 45 recipients. Liver Transpl. 2006 Jul;12(7):1138-43. doi: 10.1002/lt.20810.

Churchill D., Duley L., Thornton J.G. et al.Interventiontst versus expectant care for severe pre-eclampsta between 24 and 34 weeks’ gestation. Cochrane Database Syst Rev. 2013 Jul 26;(7): CD003106. doi: 10.1002/14651858.CD003106.pub2.

Cundy T.F., O’Grady J.G., Williams R. Recovery of menstruation and pregnancy after liver transplantation. Gut. 1990 Mar;31(3):337-8. doi: 10.1136/gut.31.3.337.

Date R.S., Kaushal M., Ramesh A. A review of the management of gallstone disease and its complications in pregnancy. Am J Surg. 2008 Oct;196(4):599-608. doi: 10.1016/j.amjsurg.2008.01.015.

DeLeve L.D., Maretti-Mira A.C. Liver Sinusoidal Endothelial Cell: An Update. Semin Liver Dis. 2017 Nov;37(4):377-387. doi: 10.1055/s-0037-1617455.

Della Torre S., Maggi A. Sex Differences: A Resultant of an Evolutionary Pressure? Cell Metab. 2017 Mar 7;25(3):499-505. doi: 10.1016/j.cmet.2017.01.006.

Della Torre S., Mitro N., Meda C. et al. Short-Term Fasting Reveals Amino Acid Metabolism as a Major Sex-Discriminating Factor in the Liver. Cell Metab. 2018 Aug 7;28(2):256-267.e5. doi: 10.1016/j.cmet.2018.05.021.

Della Torre S., Rando G., Meda C. et al. Amino acid-dependent activation of liver estrogen receptor alpha integrates metabolic and reproductive functions via IGF-1. Cell Metab. 2011 Feb 2;13(2):205-14. doi: 10.1016/j.cmet.2011.01.002.

Deshpande N.A., James N.T., Kucirka L.M. et al. Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis. Liver Transpl. 2012 Jun;18(6):621-9. doi: 10.1002/lt.23416.

Dixon L.J., Barnes M., Tang H., Pritchard M.T., Nagy L.E. Kupffer cells in the liver.Compr Physiol. 2013 Apr;3(2):785-97. doi: 10.1002/cphy.c120026.

Efe C., Kahramanoğlu-Aksoy E., Yilmaz B. et al. Pregnancy in women with primary biliary cirrhosis. Autoimmun Rev. 2014 Sep;13(9):931-5. doi: 10.1016/j.autrev.2014.05.008.

Einarson T.R., Piwko C., Koren G. Quantifying the global rates of nausea and vomiting of pregnancy a meta analysis. J Popul Ther Clin Pharmacol. 2013;20(2): e171-83.

Farrell G.C. Drugs and steatohepatitis. Semin Liver Dis. 2002;22(2):185-194. doi: 10.1055/s-2002-30106.

Fitzpatrick K.E., Hinshaw K., Kurinczuk II. et al. Risk factors, management, and outcomes ofhemolysts, elevated liver enzymes, and low platelets syndrome and elevated liver enzymes, low platelets syndrome. Obstet Gynecol. 2014 Mar;123(3):618-627. doi: 10.1097/AOG.0000000000000140.

Fontana R.1. Should acidovir be given to all pattents presenting with acute liver fallure of unknown etology? Nat Clin Pract Gastro Hep. 2008 Jun;5(6):298-9. doi: 10.1038/ncpgasthep1128.

Fontana R., Torre S. The deep correlation between energy metabolism and reproduction: a view on the effects of nutrition for women fertility. Nutrients. 2016 Feb 11;8(2):87. doi: 10.3390/nu8020087.

Fukui M., Senmaru T., Hasegawa G. et al. 17β-Estradiol attenuates saturated fatty acid diet-induced liver injury in ovariectomized mice by up-regulating hepatic senescence marker protein-30. Biochem Biophys Res Commun. 2011 Nov 18;415(2):252-7. doi: 10.1016/j.bbrc.2011.10.025.

Garcia-Flores J., Canamares M., Cruseura M. et al. Clinical value of maternal bile acid quantification in intrahepatic cholestasis of pregnancy as an adversy perinatal outcome predictor. Gynecol Obstet Invest. 2015;79(4):222-8. doi: 10.1159/000370003.

Gernketmer T., James A.H., Stast R. How I treat thrombocytopenta in pregnancy. Blood. 2013 Jan 3;121(1):38-47. doi: 10.1182/blood-2012-08-448944.

Gilinsky N.H., Muthunyagam N. Gastrointestinal endosopy in pregnant and lactating women: emerging standard of care to guide desisionmarking. Obstet and Gynecol survey. 2006 Dec;61(12):791-9. doi: 10.1097/01.ogx.0000248745.10232.bb.

Glorloso D.V., Molloy P.J., Van Thiel D.H. et al. Successful empiric treatment of HSV hepatius in pregnancy. Case report and review of the literature. Dig Dis Sci. 1996 Jun;41(6):1273-5. doi: 10.1007/BF02088248.

Crand Matson S., Sauve N., Weber F. et al. Hepatic rupture in hemolyss. elevated liver enzymes, low platelets syndrome. Obstet Gynecol. 2012 Mar;119(3):617-25. doi: 10.1097/AOG.0b013e318245c283.

Gueldlines for diagnosis imaging during pregnansi. ACOG Committee Opinion No.299. American College of Obstetretricians and Gynecolojists. Obstet Gynecol. 2004; 104:647-51.

Han G.R., Cao M.K., Zhao W. et al. A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection. J Hepatol. 2011 Dec;55(6):1215-21. doi: 10.1016/j.jhep.2011.02.032.

Hecker M., Park J.W., Murphy M.B. et al. Effects of atrazine on CYP19 gene expression and aromatase activity in testes and on plasma sex steroid concentrations of male African clawed frogs (Xenopus laevis). Toxicol Sci. 2005 Aug;86(2):273-80. doi: 10.1093/toxsci/kfi203.

Hu Y., Chen J., Wen J., Xu C., Zhang S., Xu B., Zhou Y.H. Effect of elective cesarean section on the risk of mother-to-child transmission of hepatitis B virus. BMC Pregnancy Childbirth. 2013 May 24;13:119. doi: 10.1186/1471-2393-13-119.

Ibdah J.A., Bennett M.J., Rinaldo P., Zhao Y., Gibson B., Sims H.F., Strauss A.W. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med. 1999 Jun 3;340(22):1723-31. doi: 10.1056/NEJM199906033402204.

Ikejima K., Enomoto N., Iimuro Y. et al. Estrogen increases sensitivity of hepatic Kupffer cells to endotoxin. Am J Physiol Gastrointest Liver Physiol. (1998) 274: G669-76. doi: 10.1152/ajpgi.1998.274.4.G669.

Kamada Y., Kiso S., Yoshida Y. et al. Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet. Am J Physiol-Gastrointest Liver Physiol. 2011 Dec;301(6): G1031-43. doi: 10.1152/ajpgi.00211.2011.

Kao T.L., Kuan Y.P., Cheng W.C., Chang W.C., Jeng L.B., Yeh S., Ma W.L. Estrogen receptors orchestrate cell growth and differentiation to facilitate liver regeneration. Theranostics. 2018 Apr 9;8(10):2672-2682. doi: 10.7150/thno.23624.

Katz D., Beilin Y. Disorders of coagulation in pregnancy. Br.J. Anaesth. 2015;115 (Suppl. 2): ii75-ii88. doi: 10.1093/bja/aev374.

Kazankov K., Jørgensen S.M.D., Thomsen K.L. et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2019 Mar;16(3):145-159. doi: 10.1038/s41575-018-0082-x.

Keshava S.N., Mammen T., Surendrababu N., Moses V. Transjugular liver biopsy: What to do and what not to do. Indian J Radiol Imaging. 2008 Aug;18(3):245-8. doi: 10.4103/0971-3026.41839.

Kim M., Rostas S., Gabardi S. Mycophenolate fetal toxicity and risk evaluation and mitigation strategies. Am J Transplant. 2013 Jun;13(6):1383-9. doi: 10.1111/ajt.12238.

Koopmans C.M., Bylenga D., Groen H. et al. Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks’ gestation (HYPITAT): a multicenter, open-label randomized controlled trial. Lancet. 2009 Sep 19;374(9694):979-988. doi: 10.1016/S0140-6736(09)60736-4.

Kozic J.R., Benton S.I., Hutcheon J.A. et al. Abnormal liver function tests as predictors of adverse maternal outcomes in women with preeclampsia. J Obstet Gynaecol Can. 2011 Oct;33(10):995-1004. doi: 10.1016/S1701-2163(16)35048-4.

Krenkel O., Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017 May;17(5):306-321. doi: 10.1038/nri.2017.11.

Krueger K.J., Hoffman B.J., Lee W.M. Hepatic infarction associated with eclampsia. Am J Gastroenterol. 1990 May;85(5):588-92.

Kuy S., Roman S.A., Desai R. et al. Outcomes following cholecystectomy in pregnant and nonpregnant women. Surgery. 2009 Aug;146(2):358-66. doi: 10.1016/j.surg.2009.03.033.

Labrique A.B., Stkder S.S., Krain L.I. el al. Hepatis E, a vaccine preventable cause of maternal deaths. Emerg Infect Dis. 2012 Sep;18(9):1401-4. doi: 10.3201/eid1809.120241.

Lamers M.M. van Olfen M.G., Pronk M. et. al. Treatm Art options for autoimmune hepatis: a systematic review of randomized controlled trials. J Hepatol. 2010 Jul;53(1):191-8. doi: 10.1016/j.jhep.2010.01.037.

Lindor K.D., Gershwin M.E., Poupon R., Kaplan M., Bergasa N.V., Heathcote E.J.; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology. 2009 Jul;50(1):291-308. doi: 10.1002/hep.22906.

Larrey D. Drug-induced liver diseases. J Hepatol. 2000;32(1 Suppl):77-88. doi: 10.1016/s0168-8278(00)80417-1.

Levitsky J., Duddempudi A.T., Lakeman F.D., Whitley R.J., Luby J.P., Lee W.M., Fontana R.J., Blei A.T., Ison M.G.; US Acute Liver Failure Study Group. ection and diagnosis of herpes simplex virus infection in adults with acute liver failure. Liver Transpl. 2008 Oct;14(10):1498-504. doi: 10.1002/lt.21567.

Lee S.D., Lo K.J., Tsai Y.T. et al. Role of caesarean section in prevention of mother-infant transmission of hepatitis B virus. Lancet. 1988 Oct 8;2(8615):833-4. doi: 10.1016/s0140-6736(88)92792-4.

Lucena M.I., Kaplowitz N., Hallal H. et al. Recurrent Drug-Induced Liver Injury (DILI) with different drugs in the Spanish Registry: The dilemma of the relationship to autoimmune hepatitis. J. Нepatol. 2011 Oct;55(4):820-7. doi: 10.1016/j.jhep.2010.12.041.

Marschall H.U., Wagner M., Zollner G., Trauner M. Clinical hepatotoxicity. Regulation and treatment with inducers of transport and cofactors. Mol Pharm. 2007 Nov-Dec;4(6):895-910. doi: 10.1021/mp060133c.

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