Intrahepatic Cholestasis of Pregnancy: An Intriguing Pregnancy-Specific Disorder

Abstract

Objective: To review animal and human data available regarding the etiology, maternal and fetal impact, and treatment of intrahepatic cholestasis of pregnancy (ICP).

Methods: Pertinent studies on human and animal models of ICP were selected through a MEDLINE database search, focusing on etiology and clinical impact of the disease. Analytic and descriptive studies were included, and the data were analyzed looking for crude numbers.

Results: Intrahepatic cholestasis of pregnancy is a pregnancy-specific disorder. Its prevalence is higher in Chile and Sweden compared with any other population. Its etiology is largely unknown, although endocrine, genetic, and environmental factors have been postulated as responsible for the appearance of the disease. Maternal effects of ICP are mild; however, there is a clear association between ICP and poor perinatal outcome, including a higher frequency of fetal distress, preterm labor and delivery, and unexplained fetal death. The treatment is mainly symptomatic. Recent data suggest that oral use of ursodeoxycholic acid improves maternal condition and might prevent the fetal complications of ICP.

Conclusions: Intrahepatic cholestasis of pregnancy should be considered a high-risk condition, and careful fetal assessment and appropriate medical intervention might improve perinatal outcome.

Keywords

Intrahepatic cholestasis of pregnancy genetic basis of disease preterm birth fetal death

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References

1. Reyes H . Review: Intrahepatic cholestasis. A puzzling disorder of pregnancy. J Gastroenterol Hepatol 1997;12:211-216.

2. Bacq Y , Sapey T , Brechot MC , Pierre F , Fignon A , Dubois F . Intrahepatic cholestasis of pregnancy: A French prospective study. Hepatology 1997;26:358-364.

3. Heikkinen J , Maentausta O , Ylostalo P , Janne O . Changes in serum bile acid concentrations during normal pregnancy, in patients with intrahepatic cholestasis of pregnancy and in pregnant women with itching. Br J Obstet Gynaecol 1981;88:240-245.

4. Heikkinen J . Serum bile acidsin the early diagnosis of intrahepatic cholestasis of pregnancy. Obstet Gynecol 1983;61:581-587.

5. Reyes H . The enigma of intrahepatic cholestasis of pregnancy: Lessons from Chile, Hepatology 1982;2:87-96.

6. Reyes H , Simon FR . Intrahepatic cholestasis of pregnancy: An estrogen-related disease. Semin Liver Dis 1993;13:289-301.

7. Reyes H , Ribalta J , Gonzalez MC , Segovia N , Oberhauser E . Sulfobromophthalein clearance tests before and after ethinyl estradiol administration, in women and men with familial history of intrahepatic cholestasis of pregnancy. Gastroenterology 1981;81:226-231.

8. King PD , Blitzer BL . Drug-induced cholestasis: Pathogenesis and clinical features. Semin Liver Dis 1990;10:316-321.

9. Schreiber AJ , Simon FR . Estrogen-induced cholestasis: Clues to pathogenesis and treatment. Hepatology 1983;3:607-613.

10.

10. Germain A , Kato S , Carvajal J , et al. Intrahepatic cholestasis of pregnancy. A model of premature initiation of parturition. J Soc Gynecol Invest 1999;6:204A-204A.

11.

11. Leslie KK , Reznikov L , Simon FR , Fennessey PV , Reyes H , Ribalta J . Estrogens in intrahepatic cholestasis of pregnancy. Obstet Gynecol 2000;95:372-376.

12.

12. Meng LJ , Reyes H , Palma J , Hernandez I , Ribalta J , Sjovall J . Profiles of bile acids and progesterone metabolites in the urine and serum of women with intrahepatic cholestasis of pregnancy. J Hepatol 1997;27:346-357.

13.

13. Reyes H , Gonzalez MC , Ribalta J , et al. Prevalence of intrahepatic cholestasis of pregnancy in Chile. Ann Intern Med 1978;88:487-493.

14.

14. Berg B , Helm G , Petersohn L , Tryding N . Cholestasis of pregnancy. Clinical and laboratory studies. Acta Obstet Gynecol Scand 1986;65:107-113.

15.

15. Hirvioja ML , Kivinen S . Inheritance of intrahepatic cholestasis of pregnancy in one kindred. Clin Genet 1993;43:315-317.

16.

16. Holzbach RT , Sivak DA , Braun WE . Familial recurrent intrahepatic cholestasis of pregnancy: A genetic study providing evidence for transmission of a sex-limited, dominant trait. Gastroenterology 1983;85:175-179.

17.

17. Jacquemin E , Cresteil D , Manouvrier S , Boute O , Hadchouel M . Heterozygous non-sense muation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy. Lancet 1999;353:210-211.

18.

18. Bull LN , Carlton VE , Stricker NL , et al. Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PEIC-1] and Byler syndrome): Evidence for heterogeneity. Hepatology 1997;26:155-164.

19.

19. de Vree JM , Jacquemin E , Sturm E , et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci U S A 1998;95:282-287.

20.

20. Maggiore G , Bernard O , Hadchouel M , Lemonnier A , Alagille D . Diagnostic value of serum gamma-glutamyl transpeptidase activity in liver diseases in children. J Pediatr Gastroenterol Nutr 1991;12:21-26.

21.

21. Dixon PH , Weerasekera N , Linton KJ , et al. Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: Evidence for a defect in protein trafficking. Hum Mol Genet 2000;9:1209-1217.

22.

22. Reyes H , Wegmann ME , Segovia N , et al. HLA in Chileans with intrahepatic cholestasis of pregnancy. Hepatology 1982;2:463-466.

23.

23. Mella JG , Rochmann E , Glasinovic JC , Alvarado A , Scrivanti M , Volk BA . Exploring the genetic role of the HLA-DPB1 locus in Chileans with intrahepatic cholestasis of pregnancy. J Hepatol 1996;24:320-323.

24.

24. Ribalta J , Reyes H , Hernandez I , et al. Can a selenium deficiency affect the pathogenesis of cholestasis in pregnancy? Gastroenterol Hepatol 1995;18:114-120.

25.

25. Ranta T , Unnerus HA , Rossi J , Seppala M . Elevated plasma prolactin concentration in cholestasis of pregnancy. Am J Obstet Gynecol 1979;134:1-3.

26.

26. Wojcicka-Jagodzinska J , Kuczynska-Sicinska J , Osobka-Morawski W , Siekierski BP , Smolarczyk R . [Evaluation of renal tubular function in pregnant women with cholestasis]. Ginekol Pol 1987;58:680-684.

27.

27. Wojcicka-Jagodzinska J , Kuczynska-Sicinska J , Czajkowski K , Smolarczyk R . Carbohydrate metabolism in the course of intrahepatic cholestasisin pregnancy. Am J Obstet Gynecol 1989;161:959-964.

28.

28. Israel EJ , Guzman ML , Campos GA . Maximal response to oxytocin of the isolated myometrium from pregnant patients with intrahepatic cholestasis. Acta Obstet Gynecol Scand 1986;65:581-582.

29.

29. Costoya AL , Leontic EA , Rosenberg HG , Delgado MA . Morphological study of placental terminal villi in intrahepatic cholestasis of pregnancy: Histochemistry, light and electron microscopy. Placenta 1980;1:361-368.

30.

30. Pasanen M , Helin-Martikainen HL , Pelkonen O , Kirkinen P . Intrahepatic cholestasis of pregnancy impairs the activities of human placental xenobiotic and steroid metabolizing enzymes in vitro. Placenta 1997;18:37-41.

31.

31. Johnston WG , Baskett TF . Obstetric cholestasis. A 14 year review. Am J Obstet Gynecol 1979;133:299-301.

32.

32. Rioseco AJ , Ivankovic MB , Manzur A , et al. Intrahepatic cholestasis of pregnancy: A retrospective case-control study of perinatal outcome. Am J Obstet Gynecol 1994;170:890-895.

33.

33. Ahlfeld F. Berichte und Arbeiten aus der Geburtshilflich-Gynaekologischen Klinik zu Giessen 1881-1882, mit Beiträgen von F. Marchand. Leipzig: Grunow, 1883:148.

34.

34. Jiang ZH , Qiu ZD , Liu WW , et al. Intrahepatic cholestasis of pregnancy and its complications. Analysis of 100 cases in Chongqing area. Chin Med J (Engl) 1986;99:957-960.

35.

35. Fisk NM , Storey GN . Fetal outcome in obstetric cholestasis. Br J Obstet Gynaecol 1988;95:1137-1143.

36.

36. Campos GA , Guerra FA , Israel EJ . Effects of cholic acid infusion in fetal lambs. Acta Obstet Gynecol Scand 1986;65:23-26.

37.

37. Campos GA , Castillo RJ , Toro FG . [Effect of bile acids on the myometral contractility of the isolated pregnant uterus]. Rev Chil Obstet Ginecol 1988;53:229-233.

38.

38. Perez R , Garcia M , Ulloa N , Jara C , Bardisa L , Rudolph MI . A single intravenous high dose of cholic acid to a pregnant ewe does not affect fetal well-being. Res Exp Med (Berl) 1994;194:63-67.

39.

39. Alsulyman OM , Ouzounian JG , Ames-Castro M , Goodwin TM . Intrahepatic cholestasis of pregnancy: Perinatal outcome associated with expectant management [see comments]. Am J Obstet Gynecol 1996;175:957-960.

40.

40. Sepulveda WH , Gonzalez C , Cruz MA , Rudolph MI . Vasoconstrictive effectof bile acids on isolated human placental chorionic veins. Eur J Obstet Gynecol Reprod Biol 1991;42:211-215.

41.

41. Kafkasli A , Belfort MA , Giannina G , Vedernikov YP , Schaffner DL , Popek EJ . Histopathologic effects of meconium on human umbilical artery and vein: In vitro study. J Matem Fetal Med 1997;6:356-361.

42.

42. Sienko A , Altshuler G . Meconium-induced umbilical vascular necrosis in abortuses and fetuses: A histopathologic study for cytokines. Obstet Gynecol 1999;94:415-420.

43.

43. Guerra F , Guzman S , Campos G . [Evaluation of maternal and fetal blood flow indices in intrahepatic cholestasis of pregnancy]. Rev Chil Obstet Ginecol 1994;59:17-21.

44.

44. Zimmermann P , Koskinen J , Vaalamo P , Ranta T . Doppler umbilical artery velocimetry in pregnancies complicated by intrahepatic cholestasis. J Perinat Med 1991;19:351-355.

45.

45. Kretowicz E , McIntyre HD . Intrahepatic cholestasis of pregnancy, worsening after dexamethasone. Aust N Z J Obstet Gynaecol 1994;34:211-213.

46.

46. Hirvioja ML , Tuimala R , Vuori J . The treatment of intrahepatic cholestasis of pregnancy by dexamethasone. Br J Obstet Gynaecol 1992;99:109-111.

47.

47. Laifer SA , Stiller RJ , Siddiqui DS , Dunston-Boone G , Whetham JC . Ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy. J Matern Fetal Med 2001;10:131-135.

48.

48. Mazzella G , Nicola R , Francesco A , et al. Ursodeoxycholic acid administration in patients with cholestasis of pregnancy: Effects on primary bile acids in babies and mothers. Hepatology 2001;33:504-508.

49.

49. Berkane N , Cocheton JJ , Brehier D , et al. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy. A retrospective study of 19 cases. Acta Obstet Gynecol Scand 2000;79:941-946.

50.

50. Nicastri PL , Diaferia A , Tartagni M , Loizzi P , Fanelli M . A randomised placebo-controlled trial of ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol 1998;105;1205-1207.

51.

51. Serrano MA , Brites D , Larena MG , et al. Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy inbile acid transport across the human placenta. J Hepatol 1998;28:829-839.

52.

52. Brites D , Rodrigues CM , Oliveira N , Cardoso M , Graca LM . Correction of maternal serum bile acid profile during ursodeoxycholic acid therapy in cholestasis of pregnancy. J Hepatol 1998;28:91-98.

53.

53. Palma J , Reyes H , Ribalta J , et al. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: A randomized, double-blind study controlled with placebo. J Hepatol 1997;27:1022-1028.

54.

54. Van de Meeberg PC , van Erpecum KJ , van Berge-Henogouwen GP . Therapy with ursodeoxycholic acid in cholestatic liver disease. Scand J Gastroenterol 1993;200(Suppl):15-20.

55.

55. Pares A , Rodes J . [Ursodeoxycholic acid: An alternative in the treatment of chronic cholestasis]. Gastroenterol Hepatol 1996;19:58-67.