medigraphic.com
Órgano Oficial de la Asociación Mexicana de Hepatología

2002, Number 1

<< Back Next >>

Ann Hepatol 2002; 1 (1)

Intrahepatic cholestasis of pregnancy: Changes in maternal-fetal bile acid balance and improvement by ursodeoxycholic acid

Brites D

Language: English
References: 105
Page: 20-28
PDF size: 209.49 Kb.


Text Extraction

Intrahepatic cholestasis of pregnancy (ICP) is a disease characterized by generalized pruritus and biochemical cholestasis that appears typically during the last trimester of gestation. The most predictive and accurate markers for diagnosis and follow-up of ICP are increased total bile acid levels (above 11,0 μmol/L), enhanced cholic acid percentage (above 42%) and decreased glycine/taurine bile acid ratio (below 1.0). Although essentially benign for the mother, evidence associates ICP with fetal poor prognosis resulting from increased transfer of bile acids from mother to fetus, who showed reduced ability to eliminate bile acids across the placenta. Those conditions lead to an accumulation of bile acids in the cord blood serum, meconium and amniotic fluid that may account for a diminished fetal well-being and sudden intra-uterine death by ICP. Ursodeoxycholic acid (UDCA) treatment was shown to reduce the bile acid content in the fetal compartment, while restoring the ability of the placenta to carry out vectorial transfer of these compounds towards the mother, decreasing bile acid levels in maternal serum and its passage to the fetus. In addition, UDCA administered to the mother also lowers the amount of bile acids present in colostrum without either increasing the UDCA concentration or causing major changes in lithocholic acid levels, further supporting the safety of UDCA in late pregnancy. Therefore, it is tempting to indicate UDCA as a first choice therapy for ICP as much as relevant aspects of fetal outcome may also be improved. This review focuses on the altered bile acid profiles in maternal and fetal compartments during ICP and its recovery by UDCA administration. Further elucidation of the precise mechanisms of action of UDCA and its therapeutic potential in improving fetal prognosis could result in the approval of UDCA for ICP treatment.


REFERENCES

  1. Heikkinen J, Mäentausta O, Ylöstalo P, Jänne O. Changes in serum bile acids concentrations during normal pregnancy, in patients with intrahepatic cholestasis of pregnancy and in pregnant women with itching. Br J Obstet Gynaecol 1981; 88: 240-5.

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

  3. Brites D, Rodrigues CM, Cardoso MC, Graça LM. Unusual case of severe cholestasis of pregnancy with early onset, improved by ursodeoxycholic acid administration. Eur J Obstet Gynecol Reprod Biol 1998; 76: 165-8.

  4. Reyes H. The spectrum of liver and gastrointestinal disease seen in cholestasis of pregnancy. In: Riely CA, Abell TL, eds. Gastroenterology Clinics of North America. Gastrointestinal and Liver Problems in Pregnancy. Philadelphia: WB Saunders, 1992: 905-21.

  5. Brites D, Rodrigues CM, van-Zeller H, Brito A, Silva R. Relevance of serum bile acid profile in the diagnosis of intrahepatic cholestasis of pregnancy in an high incidence area: Portugal. Eur J Obstet Gynecol Reprod Biol 1998; 80: 31-8.

  6. Heikkinen J. Serum bile acids in the early diagnosis of intrahepatic cholestasis of pregnancy. Obstet Gynecol 1983; 61: 581-7.

  7. Bacq Y, Sapey T, Brechot MC, Pierre F, Fignon A, Dubois F. Intrahepatic cholestasis of pregnancy: a French prospective study. Hepatology 1997; 26: 358-64.

  8. Davidson KM. Intrahepatic cholestasis of pregnancy. Semin Perinatol 1998; 22: 104-11.

  9. Shaw D, Frohlich J, Wittmann BAK, Willms M. A prospective study of 18 patients with cholestasis of pregnancy. Am J Obstet Gynecol 1982; 142: 621-5.

  10. Carter J. Serum bile acids in normal pregnancy. Br J Obstet Gynaecol 1991; 98: 540-3.

  11. Van Dyke RW. The liver in pregnancy. In: Zakim D, Boyer TD, eds. Hepatology. A Textbook of Liver Disease. Volume 2. Philadelphia: WB Saunders, 1990: 1438-59.

  12. Lammert F, Marschall HU, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 2000; 33: 1012-21.

  13. Läatikainen T, Tulenheimo A. Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy. Int J Gynaecol Obstet 1984; 22: 91-4.

  14. Davies MH, Ngong JM, Yucesoy M, Acharya SK, Mills CO, Weaver JB, Waring RH, Elias E. The adverse influence of pregnancy upon sulphation: a clue to the pathogenesis of intrahepatic cholestasis of pregnancy? J Hepatol 1994; 21: 1127-34.

  15. Leslie KK, Reznikov L, Simon FR, Fennessey PV, Reyes H, Ribalta J. Estrogens in intrahepatic cholestasis of pregnancy. Obstet Gynecol 2000; 95: 372-6.

  16. Meng LJ, Reyes H, Axelson M, Palma J, Hernandez I, Ribalta J, Sjovall J. Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: effect of ursodeoxycholic acid therapy. Hepatology 1997; 26: 1573-9.

  17. Sjövall J, Reyes H. Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy. Ann Med 2000; 32: 94-106.

  18. Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Semin Liver Dis 2001; 21: 551-62.

  19. Jacquemin E, Cresteil D, Manouvrier S, Boute O, Hadchouel M. Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy. Lancet 1999; 353: 210-1.

  20. Dixon PH, Weerasekera N, Linton KJ, Donaldson O, Chambers J, Egginton E, Weaver J, et al. Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Hum Mol Genet 2000; 9: 1209-17.

  21. Laatikainen T, Ikonen E. Fetal prognosis in obstetric hepatosis. Ann Chir Gynecol Fenn 1975; 64: 155-64.

  22. Kauppila A, Korpela H, Makila UM, Yrjanheikki E. Low serum selenium concentration and glutathione peroxidase activity in intrahepatic cholestasis of pregnancy. Br Med J 1987; 294: 150-2.

  23. Reyes H, Baez ME, Gonzalez MC, Hernandez I, Palma J, Ribalta J, Sandoval L, Zapata R. Selenium, zinc and copper plasma levels in intrahepatic cholestasis of pregnancy, in normal pregnancies and in healthy individuals, in Chile. J Hepatol 2000; 32: 542-9.

  24. Reyes H, Gonzalez MC, Ribalta J, Aburto H, Matus C, Schramm G, Katz R, et al. Prevalence of intrahepatic cholestasis of pregnancy in Chile. Ann Intern Med 1978; 88: 487-93.

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

  26. Reyes H, Radrigan ME, Gonzalez MC, Latorre R, Ribalta J, Segovia N, Alvarez C, et al. Steatorrhea in patients with intrahepatic cholestasis of pregnancy. Gastroenterology 1987; 93: 584-90.

  27. Fisk NM, Storey GNB. Fetal outcome in obstetric cholestasis. Br J Obstet Gynaecol 1988; 95: 1137-43.

  28. Alsulyman OM, Ouzounian JG, Ames-Castro M, Goodwin TM. Intrahepatic cholestasis of pregnancy: perinatal outcome associated with expectant management. Am J Obstet Gynecol 1996; 175: 957-60.

  29. Laatikainen T. Effect of cholestyramine and phenobarbital on pruritus and serum bile acid levels in cholestasis of pregnancy. Am J Obstet Gynecol 1978; 132: 501-6.

  30. Heikkinen J, Maentausta O, Ylostalo P, Janne O. Serum bile acid levels in intrahepatic cholestasis of pregnancy during treatment with phenobarbital or cholestyramine. Eur J Obstet Gynecol Reprod Biol 1982; 14: 153-62.

  31. Frezza M, Pozzato G, Chiesa L, Stramentinoli G, Di Padova C. Reversal of intrahepatic cholestasis of pregnancy in women after high dose S-adenosyl-L-methione administration. Hepatology 1984; 4: 274-8.

  32. Almasio P, Bortolini M, Pagliaro L, Coltorti M. Role of S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis [Supplement]. Drugs 1990; 40: 111-23.

  33. Ribalta J, Reyes H, Gonzalez MC, Iglesias J, Arresse M, Poniachik J, Molina C, et al. S-Adenosyl-L-methionine in the treatment of patients with intrahepatic cholestasis of pregnancy: a randomized, double-blind, placebo controlled study with negative results. Hepatology 1991; 13: 1084-9.

  34. Hirvioja ML, Tuimala R, Vuori J. The treatment of intrahepatic cholestasis of pregnancy by dexamethasone. Br J Obstet Gynaecol 1992; 99: 109-11.

  35. Gonzalez MC, Iglesias J, Tiribelli C, Ribalta J, Reyes H, Hernandez I, Bianchi N, et al. Epomediol ameliorates pruritus in patients with intrahepatic cholestasis of pregnancy [Letter]. J Hepatol 1992; 16: 241-2.

  36. Palma J, Reyes H, Ribalta J, Iglesias J, Gonzalez MC, Hernandez I, Alvarez C, et al. Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy. Hepatology 1992; 15: 1043-7.

  37. Marpeau L, Chazouillière D, Rhimi Z, Poupon R, Pigne A, Barrat J. Pregnancy-associated idiopathic intrahepatic cholestasis. Hypotheses of physiopathology: a therapeutic case report. Fetal Diagn Ther 1991; 6: 120-5.

  38. Mazzella G, Rizzo N, Salzetta A, Iampieri R, Bovicelli L, Roda E. Management of intrahepatic cholestasis in pregnancy. Lancet 1991; 338: 1594-5.

  39. Brites D, Poeiras J, Rodrigues C. Colestase intra-hepática da gravidez. Etiopatogénese, prognóstico e terapêutica. Acta Med Port 1994; 7: 181-8.

  40. Floreani A, Paternoster D, Grella V, Sacco S, Gangemi M, Chiaramonte M. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy. British J Obstet Gynaecol 1994; 101: 64-5.

  41. Davies MH, da Silva RCMA, Jones SR, Weaver JB, Elias E. Fetal mortality associated with cholestasis of pregnancy and the potential benefit of therapy with ursodeoxycholic acid. Gut 1995; 37: 580-4.

  42. Mazzella G, Nicola R, Francesco A, Patrizia S, Luciano B, Anna M, Giuliana S, et al. Ursodeoxycholic acid administration in patients with cholestasis of pregnancy: effects on primary bile acids in babies and mothers. Hepatology 2001; 33: 504-8.

  43. Colombo C, Roda A, Roda E, Buscaglia M, dell’Agnola CA, Filippetti P, Ronchi M, Sereni F. Correlation between fetal and maternal serum bile acid concentrations. Pediatr Res 1985; 19: 227-31.

  44. Monte MJ, Rodriguez-Bravo T, Macias RI, Bravo P, el-Mir MY, Serrano MA, Lopez-Salva A, Marin JJG. Relationship between bile acid transplacental gradients and transport across the fetal-facing plasma membrane of the human trophoblast. Pediatr Res 1995; 38: 156-63.

  45. Serrano MA, Brites D, Larena MG, Monte MJ, Bravo MP, Oliveira N, Marin JJ. Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta. J Hepatol 1998; 28: 829-39.

  46. Laatikainen T, Tulenheimo A. Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy. Int J Gynaecol Obstet 1984; 22: 91-4.

  47. Heikkinen J, Ylöstalo P, Mäentausta O, Jänne O. Bile acids in maternal serum, umbilical cord serum and amniotic fluid of healthy women, women with pruritus and patients with intrahepatic cholestasis of pregnancy. J Obstet Gynaecol 1983; 4: 17-20.

  48. Sepulveda WH, Gonzalez C, Cruz MA, Rudolph MI. Vasoconstrictive effect of bile acids on isolated human placental chorionic veins. Eur J Obstet Gynecol Reprod Biol 1991; 42: 211-5.

  49. Altshuler G, Hyde S. Meconium-induced vasocontraction: a potential cause of cerebral and other fetal hypoperfusion and of poor pregnancy outcome. J Child Neurol 1989; 4: 137-42.

  50. Altshuler G, Arizawa M, Molnar-Nadasdy G. Meconium-induced umbilical cord vascular necrosis and ulceration: apotential link between the placenta and poor pregnancy outcome. Obstet Gynecol 1992; 79: 760-6.

  51. Williamson C, Gorelik J, Eaton BM, Lab M, de Swiet M, 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: 363-9.

  52. Palma J, Reyes H, Ribalta J, Hernandez I, Sandoval L, Almuna R, Liepins J, Lira F, Sedano M, Silva O, Toha D, Silva JJ. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo. J Hepatol 1997; 27: 1022-8.

  53. Poupon RE, Balkau B, Eschwege E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med 1991; 324: 1548-54.

  54. Maggiore G, de Giacomo C. Efficacy of ursodeoxycholic acid in preventing cholestatic episodes in a patient with benign recurrent intrahepatic cholestasis. Hepatology 1992; 16: 504.

  55. Jacquemin E, Hermans D, Myara A, Habes D, Debray D, Hadchouel M, Sokal EM, Bernard O. Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis. Hepatology 1997; 25: 519-23.

  56. Lazaridis KN, Gores GJ, Lindor KD. Ursodeoxycholic acid ‘mechanisms of action and clinical use in hepatobiliary disorders’. J Hepatol 2001; 35: 134-46.

  57. Calmus Y, Gane P, Rouger P, Poupon R. Hepatic expression of class I and class II major histocompatibility complex molecules in primary biliary cirrhosis: effect of ursodeoxycholic acid. Hepatology 1990; 11: 12-5.

  58. Rodrigues CM, Steer CJ. The therapeutic effects of ursodeoxycholic acid as an anti-apoptotic agent. Expert Opin Investig Drugs 2001; 10: 1243-53.

  59. Rodrigues CM, Fan G, Ma X, Kren BT, Steer CJ. A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation. J Clin Invest 1998; 101: 2790-9.

  60. Beuers U, Boyer JL, Paumgartner G. Ursodeoxycholic acid in cholestasis: potential mechanisms of action and therapeutic applications. Hepatology 1998; 28: 1449-53.

  61. Stiehl A, Raedsch R, Rudolph G. Acute effects of ursodeoxycholic and chenodeoxycholic acid on the small intestinal absorption of bile acids. Gastroenterology 1990; 98: 424-8.

  62. Marteau P, Chazouilleres O, Myara A, Jian R, Rambaud JC, Poupon R. Effect of chronic administration of ursodeoxycholic acid on the ileal absorption of endogenous bile acids in man. Hepatology 1990; 12: 1206-8.

  63. Bouchard G, Yousef IM, Tuchweber B. Influence of oral treatment with ursodeoxycholic and tauroursodeoxycholic acids on estrogen-induced cholestasis in rats: effects on bile formation and liver plasma membranes. Liver 1993; 13: 193-202.

  64. Meng LJ, Reyes H, Palma J, Hernandez I, Ribalta J, Sjovall J. Effects of ursodeoxycholic acid on conjugated bile acids and progesterone metabolites in serum and urine of patients with intrahepatic cholestasis of pregnancy. J Hepatol 1997; 27: 1029-40.

  65. Beuers U, Bilzer M, Chittattu A, Kullak-Ublick GA, Keppler D, Paumgartner G, Dombrowski F. Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver. Hepatology 2001; 33: 1206-16.

  66. Floreani A, Paternoster D, Melis A, Grella PV. S-adenosylmethionine versus ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy: preliminary results of a controlled trial. Eur J Obstet Gynecol Reprod Biol 1996; 67: 109-13.

  67. Brites D, Rodrigues CMP, Oliveira N, Cardoso MC, Graça LM. Correction of maternal serum bile acid profile during ursodeoxycholic acid therapy in cholestasis of pregnancy. J Hepatol 1998; 28: 91-8.

  68. Lunzer M, Barnes P, Byth K, O’Halloran M. Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis. Gastroenterology 1986; 91: 825-9.

  69. Laatikainen T, Lehtonen P, Hesso A. Biliary bile acids in uncomplicated pregnancy and in cholestasis of pregnancy. Clin Chim Acta 1978; 85: 145-50.

  70. Bacq Y, Myara A, Brechot MC, Hamon C, Studer E, Trivin F, Metman EH. Serum conjugated bile acid profile during intrahepatic cholestasis of pregnancy. J Hepatol 1995; 22: 66-70.

  71. Sjovall K, Sjovall J. Serum bile acid levels in pregnancy with pruritus (bile acids and steroids 158). Clin Chim Acta 1966; 13: 207-11.

  72. Hofmann AF. Bile acid hepatotoxicity and the rationale of UDCA therapy in chronic cholestatic liver disease: some hypotheses. In: Paumgartner G, Stiehl A, Barbara L, Roda E, editors. Strategies for the Treatment of Hepatobiliary Diseases. Dordrecht: Kluwer Academic, 1990: 13-34.

  73. Roszkowski I, Pisarek-Miedzinska D. Jaundice in pregnancy. II. Clinical course of pregnancy and delivery and condition of neonate. Am J Obstet Gynecol 1968; 101: 500-3.

  74. Ward A, Brogden RN, Heel RC, Speight TM, Avery GS. Ursodeoxycholic acid: a review of its pharmacological properties and therapeutic efficacy. Drugs 1984; 27: 95-131.

  75. Zimber A, Zusman I. Effects of secondary bile acids on the intrauterine development in the rat. Teratology 1990; 42: 215-24.

  76. Balistreri WF, Heubi JE, Suchy FJ. Immaturity of the enterohepatic circulation in early life: factors predisposing to “physiologic” maldigestion and cholestasis. J Pediatr Gastroenterol Nutr 1983; 2: 346-54.

  77. Lester R. Physiologic cholestasis. Gastroenterology 1980; 78: 864-5.

  78. de Belle RC, Vaupshas V, Vitullo BB, Haber LR, Shaffer E, Mackie GG, Owen H, et al. Intestinal absorption of bile salts: immature development in the neonate. J Pediatr 1979; 94: 472-6.

  79. Suchy FJ, Balistreri WF, Heubi HE, Searcy JE, Levin RS. Physiologic cholestasis: elevation of the primary serum bile acid concentrations in normal infants. Gastroenterology 1981; 80: 1037-41.

  80. Brites D, Rodrigues CMP. Elevated levels of bile acids in colostrum of patients with cholestasis of pregnancy are decreased following ursodeoxycholic acid therapy. J Hepatol 1998; 29: 743-51.

  81. Forsyth JS, Ross PE, Bouchier IAD. Bile salts in breast milk. Eur J Pediatr 1983; 140: 126-7.

  82. Forsyth JS, Donnet L, Ross PE. A study of the relationship between bile salts, bile salt-stimulated lipase, and free fatty acids in breast milk: normal infants and those with breast milk jaundice. J Pediatr Gastroenterol Nutr 1990; 11: 205-10.

  83. Rodrigues CMP, Marín JJG, Brites D. Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid treatment. Gut 1999, 45: 446-452.

  84. Lester R, Pyrek Jst, Little JM, Adcock EW. Nature of bile acids in the fetus and newborn infant. J Ped Gastroenterol Nutr 1983; 2: S197-206.

  85. Sewell RB, Hardy KJ, Smallwood RA, Hoffman NE. Fetal bile salt metabolism: placental transfer of dihydroxy bile salts in sheep. Am J Physiol 1982; 243: G172-5.

  86. Heikkinen J, Mäentausta O, Tuimala R, Ylöstalo P, Jänne O. Amniotic fluid bile acids in normal and pathologic pregnancy. Obstet Gynecol 1980; 56: 60-4.

  87. Back P, Walter K. Developmental pattern of bile acid metabolism as revealed by bile acid analysis of meconium. Gastroenterology 1980; 78: 671-6.

  88. Murai T, Mahara R, Kurosawa T, Kimura A, Tohma M. Determination of fetal bile acids in biological fluids from neonates by gas chromatography-negative ion chemical ionization mass spectrometry. J Chromatogr B Biomed Sci Appl 1997; 28: 13-22.

  89. Colombo C, Zuliani G, Ronchi M, Breidenstein J, Setchell KDR. Biliary bile acid composition of the human fetus in the early gestation. Pediatr Res 1987; 21: 197-200.

  90. Setchell KD, Dumaswala R, Colombo C, Ronchi M. Hepatic bile acid metabolism during early development revealed from the analysis of human fetal gallbladder bile. J Biol Chem 1988; 263: 16637-44.

  91. Shoda J, Mahara R, Osuga T, Tohma M, Ohnishi S, Miyazaki H, Tanaka N, Matsuzaki Y. Similarity of unusual bile acids in human umbilical cord blood and amniotic fluid from newborns and in sera and urine from adult patients with cholestatic liver diseases. J Lipid Res 1988; 29: 847-58.

  92. Jönsson G, Midtvedt A-C, Norman A, Midtvedt T. Intestinal microbial bile acid transformation in healthy infants. J Pediatr Gastroenterol Nutr 1995; 20: 394-402.

  93. Sharp HL, Peller J, Carey JB. Primary and secondary bile acids in meconium. Pediatr Res 1971; 5: 274-9.

  94. Laatikainen TJ, Lehtonen PJ, Hesso AE. Fetal sulfated and nonsulfated bile acids in intrahepatic cholestasis of pregnancy. J Lab Clin Med 1978; 92: 185-93.

  95. Brites D, El-Mir MY, Oliveira N, Marín JJG. Amniotic fluid bile acid changes in the course of ursodeoxycholic acid therapy in intrahepatic cholestasis of pregnancy [Abstract]. J Hepatol 1997; 26: 164A.

  96. Brites D, El-Mir MY, Rodrigues CMP, van-Zeller H, Marín JJG. Bile acid composition of amniotic fluid and maternal serum in cholestasis of pregnancy and effect of ursodeoxycholic acid [Abstract]. J Hepatol 1998; 28: 125A.

  97. Laatikainen TJ. Fetal bile acid levels in pregnancies complicated by maternal intrahepatic cholestasis. Am J Obstet Gynecol 1975; 122: 852-6.

  98. Barbara L, Lazzari R, Roda A, Aldini R, Festi D, Sama C, Morselli AM, Collina A, Bazzoli F, Mazzella G, Roda E. Serum bile acids in newborns and children. Pediatr Res 1980; 14: 1222-5.

  99. Barnes S, Berkowitz G, Hirschowitz BI, Wirtschafter D, Cassady G. Postnatal physiologic hypercholemia in both premature and full-term infants. J Clin Invest 1981; 68: 775-82.

  100. Heikura S, Simila S, Finni K, Maentausta O, Janne O. Cholic acid and chenodeoxycholic acid concentrations in serum during infancy and childhood. Acta Paediatr Scand 1980; 69: 659-62.

  101. Brites D, Oliveira N, van-Zeller H, Rodrigues CMP, Brito A. Correction of fetal cord serum bile acid profile by maternal ursodeoxycholic acid therapy in cholestasis of pregnancy [Abstract]. J Hepatol 1997; 26: 163A.

  102. Arrese M, Ananthananarayanan M, Suchy FJ. Hepatobiliary transport: molecular mechanisms of development and cholestasis. Pediatr Res 1999; 44: 1-13.

  103. Kullak-Ublick GA, Beuers U, Paumgartner G. Hepatobiliary transport. J Hepatol 2000; 32: 3-18.

  104. Zollner G, Fickert P, Zenz R, Fuchsbichler A, Stumptner C, Kenner L, Ferenci P, et al. Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 2001; 33: 633-46.

  105. Marin JJ, Serrano MA, el-Mir MY, Eleno N, Boyd CA. Bile acid transport by basal membrane vesicles of human term placental trophoblast. Gastroenterology 1990; 99: 1431-8.




2020     |     www.medigraphic.com