Principles of treatment of intrahepatic cholestasis of pregnant women

Abstract

BACKGROUND: Intrahepatic cholestasis of pregnancy occupies a leading place in the structure of hepatoses associated with pregnancy. As with many other diseases that debut during gestation, all the symptoms of intrahepatic cholestasis of pregnancy disappear after delivery and have no consequences for the mother, unlike, for example, acute fatty degeneration of the liver. However, the fetal prognosis remains serious due to the high incidence of preterm birth and the toxic effect of bile components on the developing fetus, which both lead to perinatal complications. Especially fatal is the situation when intrahepatic cholestasis of pregnancy is combined with intrauterine infection, placental insufficiency, severe preeclampsia, diabetes mellitus, or other extragenital pathology. Until recently, it was believed that the only correct solution for intrahepatic cholestasis of pregnancy development was early delivery. Only in recent decades, attempts have been made to therapeutic correction of this pathology in order to prolong pregnancy to full term and reduce the frequency of perinatal complications. So far, tangible results have been achieved with the use of ursodeoxycholic acid preparations and the introduction of efferent methods of therapy into obstetric practice.

AIM: The aim of this study was to develop optimal schemes for pathogenetic therapy of intrahepatic cholestasis of pregnancy using hepatoprotectors from the ursodeoxycholic acid group, as well as ademetionine, essential phospholipids, and membrane plasmapheresis.

MATERIALS AND METHODS: This study included 150 pregnant women with intrahepatic cholestasis of pregnancy. Group I (n = 50) comprised patients who were treated only with ursodeoxycholic acid. Group II (n = 50) included individuals who were given combined drug therapy with ursodeoxycholic acid, ademetionine, and essential phospholipids. Group III (n = 50) consisted of women whose treatment included efferent therapies (membrane plasmapheresis) in combination with ursodeoxycholic acid or ademetionine preparations. All pregnant women before the start of therapy were determined the blood levels of bile acids, total and direct bilirubin, and transaminases (alanine aminotransferase, aspartate aminotransferase). Blood parameters were monitored once every seven days. All the patients were also monitored for the condition of the fetus (fetometry, dopplerometry, cardiotocography).

RESULTS: The use of ursodeoxycholic acid not combined with other hepatoprotectors (group I) was possible only in cases of increased blood levels of bile acids of not more than 40 mmol/L, preparations of ademetionine and essential phospholipids as monotherapy being ineffective. With an increase in the blood levels of bile acids of more than 40 mmol/L and transaminases by two to three or more times from the upper limit of the norm (group II), the most effective was the combined use of ursodeoxycholic acid, ademetionine and essential phospholipid preparations. The most significant decrease in the blood levels of bile acids and hepatic cytolysis parameters (transaminases) was observed when plasmapheresis was used in combination with ursodeoxycholic acid or ademetionine (group III).

CONCLUSIONS: The choice of treatment regimen depends on the level of increase in bile acids and the severity of cytolytic syndrome. With an increase in the level of bile acids to 40 mmol/L, ursodeoxycholic acid preparations can be used only. With an increase in bile acid level of more than 40 mmol/L, the complex use of the above hepatoprotectors is necessary. The most effective treatment regimen is the use of membrane plasmapheresis in combination with ursodeoxycholic acid or ademetionine.

Keywords

intrahepatic cholestasis / bile acids / ursodeoxycholic acid / plasmapheresis

References

[1] Lineva OI, Osadchenko EYu, Nesterenko SA, et al. Clinic and treatment of cholestatic hepatosis. Obstetrics and Gynecology. 2000;(2):15–17. (In Russ.)

[2] Линева О.И., Осадченко Е.Ю., Нестеренко С.А. и др. Клиника и лечение холестатического гепатоза // Акушерство и гинекология. 2000. № 2. С. 15–17.

[3] Lineva OI, Romanova EYu, Zhelnova TI. Cholestatic hepatosis of pregnant women. Samara: Perspektiva; 2002. (In Russ.)

[4] Линева О.И., Романова Е.Ю., Желнова Т.И. Холестатический гепатоз беременных. Самара: Перспектива, 2002.

[5] Maev IV, Andreev DN, Dicheva DT, et al. Intrahepatic cholestasis of pregnancy: the state-of-the-art. Klinicheskaya meditsina. 2015;93(6):25–30. (In Russ.)

[6] Маев И.В., Андреев Д.Н., Дичева Д.Т., и др. Внутрипеченочный холестаз беременных: современное состояние проблемы // Клиническая медицина. 2015. Т. 93. № 6. С. 25–30.

[7] Lammert F, Marschall HU, Glantz A, et al. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol. 2000;33(6):1012–1021. DOI: 10.1016/s0168-8278(00)80139-7

[8] Lammert F., Marschall H.U., Glantz A., et al. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management // J. Hepatol. 2000. Vol. 33. No. 6. P. 1012–1021. DOI: 10.1016/s0168-8278(00)80139-7

[9] Wong LF, Shallow H, O’Connell MP. Comparative study on the outcome of obstetric cholestasis. J Matern Fetal Neonatal Med. 2008;21(5):327–330. DOI: 10.1080/14767050802034446

[10] Wong L.F., Shallow H., O’Connell M.P. Comparative study on the outcome of obstetric cholestasis // J. Matern. Fetal. Neonatal. Med. 2008. Vol. 21. No. 5. P. 327–330. DOI: 10.1080/14767050802034446

[11] Brouwers L, Koster MP, Page-Christiaens GC, et al. Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels. Am J Obstet Gynecol. 2015;212(1):100.e1–100.e1007. DOI: 10.1016/j.ajog.2014.07.026

[12] Brouwers L., Koster M.P., Page-Christiaens G.C., et al. Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels // Am. J. Obstet. Gynecol. 2015. Vol. 212. No. 1. P. 100.e1–100.e1007. DOI: 10.1016/j.ajog.2014.07.026

[13] Voinov VA, Zhestkova NV, Karchevskiy KS, et al. Membrannyi plazmaferez pri kholestaticheskom gepatoze beremennykh. Bulletin of Almazov Federal Heart, Blood and Endocrinology Centre. (Zdorovaya zhenshchina — zdorovyi novorozhdennyi: tezisy VIII mezhdistsiplinarnoi konferentsii po akusherstvu, perinatologii, neonatologii, posvyashchenoi 200-letiyu so dnya rozhdeniya Aleksandra Aleksandrovicha Kitera (1813–1879). 15-16 november, 2013). 2013;(2):29. (In Russ.)

[14] Воинов В.А., Жесткова Н.В., Карчевский К.С., и др. Мембранный плазмаферез при холестатическом гепатозе беременных // Бюллетень Федерального центра сердца, крови и эндокринологии им. В.А. Алмазова. (Здоровая женщина — здоровый новорожденный: тезисы VIII междисциплинарной конференции по акушерству, перинатологии, неонатологии, посвященой 200-летию со дня рождения Александра Александровича Китера (1813–1879). 15–16 ноября 2013 г.). 2013. Прилож. № 2. С. 29.

[15] Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis. 2007;2:26. DOI: 10.1186/1750-1172-2-26

[16] Pusl T., Beuers U. Intrahepatic cholestasis of pregnancy // Orphanet. J. Rare Dis. 2007. Vol. 2. P. 26. DOI: 10.1186/1750-1172-2-26

[17] Beuers U, Pusl T. Intrahepatic cholestasis of pregnancy – a heterogeneous group of pregnancy-related disorders? Hepatology. 2006;43(4):647–649. DOI: 10.1002/hep.21156

[18] Beuers U., Pusl T. Intrahepatic cholestasis of pregnancy – a heterogeneous group of pregnancy-related disorders? // Hepatology. 2006. Vol. 43. No. 4. P. 647–649. DOI: 10.1002/hep.21156

[19] Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology. 2004;40(2):467–474. DOI: 10.1002/hep.20336

[20] Glantz A., Marschall H.U., Mattsson L.A. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates // Hepatology. 2004. Vol. 40. No. 2. P. 467–474. DOI: 10.1002/hep.20336

[21] 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

[22] Kondrackiene J., Beuers U., Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy // Gastroenterology. 2005. Vol. 129. No. 3. P. 894–901. DOI: 10.1053/j.gastro.2005.06.019

[23] Glantz A, Marschall HU, Lammert F, et al. Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid. Hepatology. 2005;42(6):1399–1405. DOI: 10.1002/hep.20952

[24] Glantz A., Marschall H.U., Lammert F., et al. Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid // Hepatology. 2005;42(6):1399–1405. DOI: 10.1002/hep.20952

[25] Zapata R, Sandoval L, Palma J, et al. Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy. A 12-year experience. Liver Int. 2005;25(3):548–554. DOI: 10.1111/j.1478-3231.2004.0996.x

[26] Zapata R., Sandoval L., Palma J., et al. Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy. A 12-year experience // Liver Int. 2005;25(3):548–554. DOI: 10.1111/j.1478-3231.2004.0996.x

[27] Patent RF No. 2 610536 / 13.02.2017 Byul. No. 5. Petrosyan MA, Zhestkova NV, Balashova NN, et al. Sposob modelirovaniya ostrogo zhirovogo gepatoza beremennykh. (In Russ.) [cited 2023 Feb 12]. Available from: https://patents.s3.yandex.net/RU2610536C1_20170213.pdf.

[28] Патент РФ на изобретение № 2 610536 / 13.02.2017 Бюл. № 5. Петросян М.А., Жесткова Н.В., Балашова Н.Н., и др. Способ моделирования острого жирового гепатоза беременных [дата обращения 12.02.2023]. Доступ по ссылке: https://patents.s3.yandex.net/RU2610536C1_20170213.pdf

[29] Petrosyan MA, Zhestkova NV, Tumasova ZN, et al. Effects of S-adenosyl methionine and essential phospholipids on serum biochemical parameters in simulated acute liver disease in late pregnancy. Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):65–70. (In Russ.) DOI: 10.17816/RCF19165-70

[30] Петросян М.А., Жесткова Н.В., Тумасова Ж.Н., и др. Влияние препаратов S-аденозилметионина и эссенциальных фосфолипидов на биохимические показатели сыворотки крови крыс в модели острого поражения печени на позднем сроке беременности // Обзоры по клинической фармакологии и лекарственной терапии. 2021. Т. 19. № 1. C. 65–70. DOI: 10.17816/RCF19165-70

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Zhestkova N.V., Aylamazyan E.K., Kuzminykh T.U., Marchenko N.V.