Gebeliğin İntrahepatik Kolestazı

Abstract

Gebeliğin intrahepatik kolestazı (GİK); gebeliğin 2. Trimestr’ından sonra gelişen, karakteristik olarak serum safra asidi yüksekliği ve kaşıntı ile seyreden gebeliğe özgü bir karaciğer hastalığıdır. Prevelansı; etnik köken, genetik ve çevresel faktörlere bağlı değişkenlik göstermekle birlikte ülkemizdeki sıklığı %0.45 olarak bildirilmiştir. Genetik faktörlerden özellikle hepatositlerde fosfolipid transportunda görevli ABCB4 geni üzerinde durulmaktadır. Risk faktörleri arasında geçirilmiş GİK öyküsü, ileri maternal yaş (>35), multiparite, oral kontraseptif kullanımı ile birliktelik gösteren kolestaz öyküsü, yardımcı üreme teknikleri ile gebe kalmak, ovaryan hiperstimulasyon sendromu, çoğul gebelik, kronik Hepatit C hastası olmak yer almaktadır. En sık semptomu kaşıntıdır ve genelikle avuç içi ve ayak tabanında izlenir. Serum safra asidi yüksekliği (>10 µmol/L) etkilenen gebelerin %90’ında görülür. Serum aminotransferazları hastaların %60’ında artış göstermektedir. Bu artış çoğunlukla normalin 2 katını geçmemektedir. GİK olan hastalarda intrauterin fetal kayıp, mekonyumlu amnion mayi, spontan ve iatrojenik preterm doğum, yenidoğan yoğun bakım ihtiyacı artmış olarak izlenmiştir. Bu komplikasyonlardan fetal dolaşımda artan safra asidi sorumlu tutulmaktadır. Tedavinin amacı maternal biyokimyasal değerlerin normal referans aralığı yakın tutulması, maternal kaşıntı başta olmak üzere semptomların azaltılması ve fetal komplikasyonların önlenmesidir. Ursodeoksikolik asit (UDCA) diğer yöntemlerle karşılaştırıldığında serum safra asidi düzeylerinde ve karaciğer enzimlerinde daha belirgin düzelme sağlamaktadır. İntrauterin fetal kayıp GİK’te ani olarak gelişmekte ve bu nedenle NST, USG ve doppler USG değerlendirmelerinin takipteki yeri sınırlıdır. Gebelerin hangi sıklıkta izleneceği konusunda bir fikir birliği yoktur. Preterm doğum beklenen hastalarda akciğer matürasyonu için kortikosteroid önerilmektedir. GİK olan hastalarda fetal mortalitenin 36. haftada doğumu gerçekleştirilenlerde daha düşük olduğu bildirilmiştir.

Keywords

• Kolestaz
• Safra Asitleri
• Ursodeoksikolik Asit

Intrahepatic Cholestasis of Pregnancy

Abstract

Intrahepatic cholestasis of pregnancy; is a pregnancy-specific liver disorder developing after the second trimester of pregnancy, characteristically coursing with high serum bile acid level and maternal pruritus. Its prevalence shows a chance depending on environmental factors, genetics and ethnic origin and at the same time it is reported that the frequency of this disease is 0.45% in our country. In all genetic factors, especially ABCB4 gene, which is in charge with transporting phospholipid in hepatocytes is dwelled on. Risk factors include previous presence of NCBI, advanced maternal age (˃35), multiparity, history of cholestasis with the use of oral contraceptive, becoming pregnant with assisted reproductive techniques, ovarian hyperstimulation syndrome, multiple pregnancy, being a patient with chronic hepatitis C. The most frequent symptom is pruritus and it is generally seen on palm and soles. It is seen among 90% of pregnant impressed by the high level of serum bile acid (˃10 umol/L). Serum aminotransferases show increase among 60% of the patients. This increase generally isn’t two times more than normal. Intrauterine fetal loss among the patients with NCBI, is seen as amnion liquid with meconium, spontaneous and iatrogenic preterm birth, increased need in neonatal intensive care. Bile acid increasing in fetal circulation is hold responsible for these complications. The aim of the cure is to keep the maternal biochemical values close to the normal reference range, decrease the symptoms; especially maternal pruritus, prevent fetal complications. When it is compared with the other methods, ursodeoxycholic acid (UDCA) provides more apparent improvement in the liver enzymes and the levels of serum bile acid. Intrauterine fetal loss with NCBI occurs suddenly so NST, USG and doppler USG evaluations are limited in the place of follow up. There isn’t a consensus on how often a pregnant should be screening. Among the patients who are expected to have preterm birth, corticosteroid is suggested for lung maturation. It is stated that fetal mortality is lower among the patients with NCBI than who gives birth at the 36th week.

Keywords

• Cholestasis
• Bile Acid
• Ursodeoxycholic Acid

References

1. 1. Beuers U, Pusl T. Intrahepatic cholestasis of pregnancy-A heterogeneous group of pregnancy‐related disorders? Hepatology. 2006;43(4):647-9.
2. 2. Schmid R, Haemmerli U. Der Schwangerschaftsikterus. Ikterus Stuttgart: Schattauer. 1968:227-31.
3. 3. Svanborg A. A study of recurrent jaundice in pregnancy. Acta Obstet Gynecol Scan. 1954;33(4):434-44.
4. 4. Lee R, Goodwin T, Greenspoon J, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol. 2006;26(9):527-32.
5. 5. Jacquemin E, Cresteil D. Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy. The Lancet. 1999;353(9148):210-1.
6. 6. Reyes H, Gonzalez MC, Rıbalta J, et al. Prevalence of intrahepatic cholestasis of pregnancy in Chile. Ann Internal Med. 1978;88(4):487-93.
7. 7. Yıldırım G, Aslan H, Asar E, et al. İntrahepatik Kolestazda Gebelik Sonuçları. J Turk Obstet Gynecol Soc. 2007;4(4):250-3.
8. 8. Lo T, Lau W, Lam HS, Leung W, Chin RK. Obstetric cholestasis in Hong Kong-local experience with eight consecutive cases. Hong Kong Med J. 2007;13(5):387.

9. 9. Berg B, Helm G, Petersohn L, Tryding N. Cholestasis of pregnancy: clinical and laboratory studies. Acta Obstet Gynecol Scan. 1986;65(2):107-13.
10. 10. Reyes H, Simon FR, editors. Intrahepatic cholestasis of pregnancy: an estrogen-related disease. Seminars in liver disease; 1993: © 1993 by Thieme Medical Publishers, Inc.
11. 11. Bacq Y, Sapey T, Brechot M, Pierre F, Fignon A, Dubois F. Intrahepatic cholestasis of pregnancy: a French prospective study. Hepatology. 1997;26(2):358-64.
12. 12. Yılmaz S, Üstün Y, Hızlı D, Deveer R. Gebeliğin İntrahepatik Kolestazı. Gazi Med J. 2012;23:138-44.
13. 13. Glantz A, Reilly SJ, Benthin L, Lammert F, Mattsson LÅ, Marschall HU. Intrahepatic cholestasis of pregnancy: amelioration of pruritus by UDCA is associated with decreased progesterone disulphates in urine. Hepatology. 2008;47(2):544-51.
14. 14. Reyes H, Báez ME, González MC, Hernández I, Palma J, Ribalta J, et al. Selenium, zinc and copper plasma levels in intrahepatic cholestasis of pregnancy, in normal pregnancies and in healthy individuals, in Chile. J Hepatol. 2000;32(4):542-9.
15. 15. Locatelli A, Roncaglia N, Arreghini A, Bellini P, Vergani P, Ghidini A. Hepatitis C virus infection is associated with a higher incidence of cholestasis of pregnancy. BJOG: Int J Obstet Gynaecol. 1999;106(5):498-500.
16. 16. Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol. 2014;124(1):120-33.
17. 17. Kenyon AP, Piercy CN, Girling J, Williamson C, Tribe R, Shennan A. Pruritus may precede abnormal liver function tests in pregnant women with obstetric cholestasis: a longitudinal analysis. Brit J Obstet Gynaecol. 2001;108(11):1190-2.
18. 18. Kondrackiene J, Kupcinskas L. Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems. World J Gastroenterol. 2008;14(38):5781.
19. 19. Ropponen A, Sund R, Riikonen S, Ylikorkala O, Aittomäki K. Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: a population‐based study. Hepatology. 2006;43(4):723-8.
20. 20. Glantz A, Marschall HU, Mattsson LÅ. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology. 2004;40(2):467-74.
21. 21. Manzotti C, Casazza G, Stimac T, Nikolova D, Gluud C. Total serum bile acids or serum bile acid profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev. 2019;7(7):CD012546.
22. 22. Lee NM, Brady CW. Liver disease in pregnancy. World J Gastroenterol. 2009;15(8):897.
23. 23. Lammert F, Marschall H-U, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol. 2000;33(6):1012-21.
24. 24. Ovadia C, Seed PT, Sklavounos A, Geenes V, Di Ilio C, Chambers J, et al. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. The Lancet. 2019;393(10174):899-909.
25. 25. Sepulveda W, Gonzalez C, Cruz M, Rudolph M. Vasoconstrictive effect of bile acids on isolated human placental chorionic veins. Eur J Obstet Gynecol Reprod Biol. 1991;42(3):211-5.
26. 26. Perez MJ, Macias RI, Duran C, Monte MJ, Gonzalez-Buitrago JM, Marin JJ. Oxidative stress and apoptosis in fetal rat liver induced by maternal cholestasis. Protective effect of ursodeoxycholic acid. J Hepatol. 2005;43(2):324-32.
27. 27. Wıllıamson C, Gorelık J, Eaton BM, Lab M, Swıet Md, Korchev Y. The bile acid taurocholate impairs rat cardiomyocyte function: a proposed mechanism for intra-uterine fetal death in obstetric cholestasis. Clin Sci. 2001;100(4):363-9.
28. 28. Lee RH, Kwok KM, Ingles S, Wilson ML, Mullin P, Incerpi M, et al. Pregnancy outcomes during an era of aggressive management for intrahepatic cholestasis of pregnancy. Am J Perinatol. 2008;25(06):341-5.
29. 29. Germain AM, Kato S, Carvajal JA, Valenzuela GJ, Valdes GL, Glasinovic JC. Bile acids increase response and expression of human myometrial oxytocin receptor. Am J Obstet Gynecol. 2003;189(2):577-82.
30. 30. Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T, et al. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology. 2012;143(6):1492-501.
31. 31. Bicocca MJ, Sperling JD, Chauhan SP. Intrahepatic cholestasis of pregnancy: review of six national and regional guidelines. Eur J Obstet Gynecol Reprod Biol. 2018;231:180-7.
32. 32. Bacq Y, le Besco M, Lecuyer A-I, Gendrot C, Potin J, Andres CR, et al. Ursodeoxycholic acid therapy in intrahepatic cholestasis of pregnancy: Results in real-world conditions and factors predictive of response to treatment. Digest Liver Dis. 2017;49(1):63-9.
33. 33. Liu J, Murray AM, Mankus EB, Ireland KE, Acosta OM, Ramsey PS. Adjuvant use of rifampin for refractory intrahepatic cholestasis of pregnancy. Obstet Gynecol. 2018;132(3):678-81.
34. 34. Pathak B, Sheibani L, Lee RH. Cholestasis of pregnancy. Obstet Gynecol Clin. 2010;37(2):269-82.
35. 35. Puljic A, Kim E, Page J, Esakoff T, Shaffer B, LaCoursiere DY, et al. The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age. Am J Obstet Gynecol. 2015;212(5):667.
36. 36. Brouwers L, Koster MP, Page-Christiaens GC, Kemperman H, Boon J, Evers IM, et al. Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels. Am J Obstet Gynecol. 2015;212(1):100.
37. 37. Oztekin D, Aydal I, Oztekin O, Okcu S, Borekci R, Tinar S. Predicting fetal asphyxia in intrahepatic cholestasis of pregnancy. Arch Gynecol Obstet. 2009;280(6):975.
38. 38. Williamson C, Hems LM, Goulis DG, Walker I, Chambers J, Donaldson O, et al. Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. BJOG: Inter J Obstet Gynaecol. 2004;111(7):676-81.
39. 39. Curtis KM, Tepper NK, Jatlaoui TC, Berry-Bibee E, Horton LG, Zapata LB, et al. US medical eligibility criteria for contraceptive use, 2016. MMWR Recomm Rep. 2016;65(3):1-103.