Diagnosis and Therapy of Intrahepatic Cholestasis of Pregnancy

Zusammenfassung

Die intrahepatische Schwangerschaftscholestase (ISC) bezeichnet ein Syndrom, das durch Pruritus in der Spätschwangerschaft gekennzeichnet ist. Die Diagnose der ISC erfolgt durch Ausschluss pruritogener Hauterkrankungen und den Nachweis von erhöhten Gesamtgallensäuren-Serumkonzentrationen. Es gibt Hinweise auf eine genetische Prädisposition. Zahlreiche Studien haben den Stellenwert von Mutationen in bekannten Cholestase-Genen wie ABCB4 (auch MDR3 genannt), ABCB11 (BSEP) und ATP8B1 (FIC1) für die Entwicklung einer ISC untersucht. Die bisher vorliegenden Daten weisen auf eine heterogene Ätiologie des Syndroms hin. Die ISC scheint mit einem erhöhten Risiko von Früh- und Totgeburten des Kindes vergesellschaftet zu sein. Weiterhin kann die Symptomatik in Einzelfällen sehr stark sein und eine frühzeitige Entbindung mit den dazugehörigen Risiken für Mutter und Kind erzwingen. Schwangerschaften von Patientinnen mit ISC sind daher als Risikoschwangerschaften einzuschätzen. Therapien zur Verminderung des Pruritus oder der Cholestase durch Antihistaminika, Phenobarbital, Anionenaustauscher, Dexamethason und S-Adenosylmethionin sind nur begrenzt wirksam oder werden wegen ihrer Nebenwirkungen nur selten eingesetzt. Neuere kontrollierte Studien zeigen, dass Ursodeoxycholsäure (UDCA) einen positiven Effekt auf Juckreiz und laborchemische Veränderungen bei ISC hat. Die weitere Aufklärung der molekularen Ursachen der ISC wird in Zukunft eventuell zur gezielteren und wirkungsvolleren Therapie des Krankheitsbildes beitragen.

Abstract

Intrahepatic cholestasis of pregnancy (ICP) is characterized by the occurrence of pruritus mostly in the third trimenon. Diagnosis is based on the presence of pruritus and elevated levels of serum bile acids in the absence of pruritic skin diseases. There is strong evidence of a genetic predisposition for ICP. Numerous studies have investigated the association of known cholestasis genes such as ABCB4 (also designated MDR3), ABCB11 (BSEP) and ATP8B1 (FIC1) with ICP. The results of these studies implicate a heterogeneous etiology of this syndrome. ICP increases the risk of preterm delivery and fetal loss. Furthermore, intense pruritus may necessitate premature induction of labor with its known higher frequency of complications for mother and child. Therefore, ICP pregnancies should be managed as high-risk pregnancies. Pharmaceuticals to alleviate pruritus or improve cholestasis like antihistamines, phenobarbital, anion exchange resins, dexamethasone or S-adenosylmethionine are not widely accepted because of questionable efficacy or side effects. Recent randomized studies have shown beneficial effects of ursodeoxycholic acid (UDCA) on laboratory data and pruritus in patients with ICP. Improved knowledge about the diagnostic classification of different types and pathophysiological mechanisms of ICP may allow for a more targeted treatment of this disease in future.

Schlüsselwörter

Intrahepatische Schwangerschaftscholestase - pruritogene Hauterkrankungen - Gallensäuren-Serumkonzentration - progressive familial intrahepatishe Cholestase - low-phospholipid-assoziierte Cholelithiasis - ABCB4 Gen - ABCB11 Gen - ATP8B1 Gen

Key words

Intrahepatic cholestasis of pregnancy - pruritus - serum bile acids - progressive familial intrahepatic cholestasis - low phospholipid-associated cholelithiasis - ABCB4 gene - ABCB11 gene - ATP8B1 gene

References

• 1 Ahlfeld F. Berichte und Arbeiten aus der Geburtshilflich-Gynäkologischen Klinik zu Gießen 1881 - 1882. Leipzig; Grunow 1883
• 2 Bacq Y. Intrahepatic cholestasis of pregnancy.  Clinics Liver Dis. 1999;  3 1-13
• 3 Savander M, Ropponen A, Avela K. Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy.  Gut. 2003;  52 1025-1029
• 4 Bacq Y, Sapey T, Brechot M C. et al . Intrahepatic cholestasis of pregnancy: a French prospective study.  Hepatology. 1997;  26 358-364
• 5 Rioseco A J, Ivankovic M B, Manzur A. et al . Intrahepatic cholestasis of pregnancy: a retrospective case-control study of perinatal outcome.  Am J Obstet Gynecol. 1994;  170 890-895
• 6 Shaw D, Frohlich J, Wittmann B A. et al . A prospective study of 18 patients with cholestasis of pregnancy.  Am J Obstet Gynecol. 1982;  142 (6 Pt 1) 621-625
• 7 Alsulyman O M, Ouzounian J G, Ames-Castro M. et al . Intrahepatic cholestasis of pregnancy: perinatal outcome associated with expectant management.  Am J Obstet Gynecol. 1996;  175 (4 Pt 1) 957-960
• 8 Berg B, Helm G, Petersohn L. et al . Cholestasis of pregnancy. Clinical and laboratory studies.  Acta Obstet Gynecol Scand. 1986;  65 107-113
• 9 Laatikainen T, Tulenheimo A. Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy.  Int J Gynaecol Obstet. 1984;  22 91-94
• 10 Jacquemin E, Cresteil D, Manouvrier S. et al . Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy.  Lancet. 1999;  353 (9148) 210-211
• 11 Dixon P H, Weerasekera N, Linton K 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 1209-1217
• 12 Lucena J F, Herrero J I, Quiroga J. et al . A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis.  Gastroenterology. 2003;  124 1037-1042
• 13 De Vree J M, Jacquemin E, Sturm E. et al . Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.  Proc Natl Acad Sci USA. 1998;  95 282-287
• 14 Jacquemin E, De Vree J M, Cresteil D. et al . The wide spectrum of multidrug resistance 3 deficiency: From neonatal cholestasis to cirrhosis of adulthood.  Gastroenterology. 2001;  120 1448-1458
• 15 Simon E, Marschall H U, Glantz A. et al . Mutations of hepatocanalicular ABC transporters in intrahepatic cholestasis of pregnancy (ICP).  Hepatology. 2002;  36 (4 Pt. 2) 687
• 16 Glantz A, Marschall H U, Lammert F. et al . Intrahepatic cholestasis of pregnancy: A placebo-controlled randomised trial of ursodeoxycholic acid vs dexamethasone on maternal and fetal outcome and metabolism. Abstract from: Bile acids: From genomics to disease and therapy. XVII International Bile Acid Meeting 2002, Falk Symposium No. 129. 
• 17 Huchzermeyer H. Leber und Schwangerschaft. Bern; Huber 1978
• 18 Olsson R, Tysk C, Aldenborg F. et al . Prolonged postpartum course of intrahepatic cholestasis of pregnancy.  Gastroenterology. 1993;  105 267-271
• 19 Brites D, Rodrigues C M, Oliveira N. et al . Correction of maternal serum bile acid profile during ursodeoxycholic acid therapy in cholestasis of pregnancy.  J Hepatol. 1998;  28 91-98
• 20 Carter J. Serum bile acids in normal pregnancy.  Br J Obstet Gynaecol. 1991;  98 540-543
• 21 Heikkinen J. Serum bile acids in the early diagnosis of intrahepatic cholestasis of pregnancy.  Obstet Gynecol. 1983;  61 581-587
• 22 Lunzer M, Barnes P, Byth K. et al . Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis.  Gastroenterology. 1986;  91 825-829
• 23 Van Dyke R W. The liver in pregnancy. In: Zakim D, Boyer TD (eds). Hepatology. A Textbook of Liver Disease. Philadelphia; WB Saunders 1996: 1734-1759
• 24 Roger D, Vaillant L, Fignon A. et al . Specific pruritic diseases of pregnancy. A prospective study of 3192 pregnant women.  Arch Dermatol. 1994;  130 734-739
• 25 Braun-Falco O, Plewig G, Wolff H H. Dermatologie und Venerologie. Berlin, Heidelberg, New York; Springer 1997
• 26 Kreek M J. Female sex steroids and cholestasis.  Semin Liver Dis. 1987;  7 8-23
• 27 Samsioe G, Svendsen P, Johnson P. et al . Studies in cholestasis of pregnancy. V. Gallbladder disease, liver function tests, serum lipids and fatty acid composition of serum lecithin in the non-pregnant state.  Acta Obstet Gynecol Scand. 1975;  54 417-423
• 28 Glasinovic J C. et al .Pregnancy and gallstones. In: Reyes HB, Leuschner U, Arias I (eds). Pregnancy, Sex Hormones and the Liver. Dordrecht; Kluwer 1996: 267-281
• 29 Stieger B, Fattinger K, Madon J. et al . Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver.  Gastroenterology. 2000;  118 422-430
• 30 Bossard R, Stieger B, O‘Neill B. et al . Ethinylestradiol treatment induces multiple canalicular membrane transport alterations in rat liver.  J Clin Invest. 1993;  91 2714-2720
• 31 Kullak-Ublick G A, Stieger B, Hagenbuch B. et al . Hepatic transport of bile salts.  Semin Liver Dis. 2000;  20 273-292
• 32 Trauner M, Meier P J, Boyer J L. Molecular pathogenesis of cholestasis.  N Engl J Med. 1998;  339 1217-1227
• 33 Sjovall J, Sjovall K. Steroid sulphates in plasma from pregnant women with pruritus and elevated plasma bile acid levels.  Ann Clin Res. 1970;  2 321-337
• 34 Meng L J, Reyes H, Axelson M. et al . Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: effect of ursodeoxycholic acid therapy.  Hepatology. 1997;  26 1573-1579
• 35 Holzbach R T, Sivak D A, Braun W E. Familial recurrent intrahepatic cholestasis of pregnancy: a genetic study providing evidence for transmission of a sex-limited, dominant trait.  Gastroenterology. 1983;  85 175-179
• 36 Dalen E, Westerholm B. Occurrence of hepatic impairment in women jaundiced by oral contraceptives and in their mothers and sisters.  Acta Med Scand. 1974;  195 459-463
• 37 Hirvioja M L, Kivinen S. Inheritance of intrahepatic cholestasis of pregnancy in one kindred.  Clin Genet. 1993;  43 315-317
• 38 Mella J G, Roschmann E, Glasinovic J C. et al . Exploring the genetic role of the HLA-DPB1 locus in Chileans with intrahepatic cholestasis of pregnancy.  J Hepatol. 1996;  24 320-333
• 39 Deleuze J F, Jacquemin E, Dubuisson C. et al . Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis.  Hepatology. 1996;  23 904-908
• 40 Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis.  Gastroenterology. 2001;  120 1459-1467
• 41 Rosmorduc O, Hermelin B, Boelle P Y. et al . ABCB4 gene mutation-associated cholelithiasis in adults.  Gastroenterology. 2003;  125 452-459
• 42 Lammert F, Carey M C, Paigen B. Chromosomal organization of candidate genes involved in cholesterol gallstone formation: a murine gallstone map.  Gastroenterology. 2001;  120 221-238
• 43 De Pagter A G, van Berge Henegouwen GP. et al .
• 44 Whitington P F, Freese D K, Alonso E M. et al . Clinical and biochemical findings in progressive familial intrahepatic cholestasis.  J Pediatr Gastroenterol Nutr. 1994;  18 134-341
• 45 Stieger B. FIC1: another bile salt carrier within the enterohepatic circulation?.  J Hepatol. 2001;  35 522-524
• 46 Jansen P L, Strautnieks S S, Jacquemin E. et al . Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis.  Gastroenterology. 1999;  117 1370-1379
• 47 Nishida T, Gatmaitan Z, Che M. et al . Rat liver canalicular membrane vesicles contain an ATP-dependent bile acid transport system.  Proc Natl Acad Sci USA. 1991;  88 6590-6594
• 48 Eloranta M L, Hakli T, Hiltunen M. et al . Association of single nucleotide polymorphisms of the bile salt export pump gene with intrahepatic cholestasis of pregnancy.  Scand J Gastroenetrol. 2003;  38 648-652
• 49 Sadler L C, Lane M, North R. Severe fetal intracranial haemorrhage during treatment with cholestyramine for intrahepatic cholestasis of pregnancy.  Br J Obstet Gynaecol. 1995;  102 169-170
• 50 Heikkinen J, Maentausta O, Ylostalo P. et al . Serum bile acid levels in intrahepatic cholestasis of pregnancy during treatment with phenobarbital or cholestyramine.  Eur J Obstet Gynecol Reprod Biol. 1982;  14 153-162
• 51 Frezza M, Surrenti C, Manzillo G. et al . Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis. A double-blind, placebo-controlled study.  Gastroenterology. 1990;  99 211-215
• 52 Ribalta J, Reyes H, Gonzales M 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 1084-1089
• 53 Hirvioja M L, Tuimala R, Vuori J. The treatment of intrahepatic cholestasis of pregnancy by dexamethasone.  Br J Obstet Gynaecol. 1992;  99 109-111
• 54 Floreani A, Paternoster D, Melis A. et al . 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;  67 109-113
• 55 Palma J, Reyes H, Axelson M. 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
• 56 Schmid R, Haemmerli U P. Der Schwangerschaftsikterus. In: Beck K (ed). Ikterus. Stuttgart; Schattauer 1968: 227-231