Alternative titles; symbols
ORPHA: 69665; DO: 0070228;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18q21.31 | Cholestasis, intrahepatic, of pregnancy, 1 | 147480 | Autosomal dominant | 3 | ATP8B1 | 602397 |
A number sign (#) is used with this entry because of evidence that intrahepatic cholestasis of pregnancy-1 (ICP1) can be caused by heterozygous mutation in the ATP8B1 gene (602397) on chromosome 18q21.
Mutation in the ATP8B1 gene can also cause progressive familial intrahepatic cholestasis-1 (PFIC1; 211600) and benign recurrent intrahepatic cholestasis-1 (BRIC1; 243300).
Intrahepatic cholestasis of pregnancy is a reversible form of cholestasis that occurs most often in the third trimester of pregnancy and recurs in 45 to 70% of subsequent pregnancies. Symptoms include pruritus, jaundice, increased serum bile salts, and abnormal liver enzymes, all of which resolve rapidly after delivery. However, the condition is associated with fetal complications, including placental insufficiency, premature labor, fetal distress, and intrauterine death. Some women with ICP may also be susceptible to oral contraceptive-induced cholestasis (OCIC) (summary by Pasmant et al., 2012).
Genetic Heterogeneity of Intrahepatic Cholestasis of Pregnancy
See also ICP3 (614972), caused by mutation in the ABCB4 gene (171060).
Intrahepatic cholestasis of pregnancy was reported in sisters by Svanborg and Ohlsson (1959), Cahill (1962), and Fast and Roulston (1964).
Holzbach and Sanders (1965) reported a mother and 2 daughters with recurrent ICP characterized by generalized itching, with or without jaundice, during pregnancy. The disorder began primarily in the third trimester and disappeared shortly postpartum. There was no biliary colic, no jaundice or pruritus between pregnancies, and no chronic liver disease. Holzbach et al. (1983) updated the pedigree. In all, there were 5 affected women in 4 sibships spanning 3 generations. The authors favored female-limited autosomal dominant inheritance. A male transmitted the disorder from his mother to his daughter. During periods between pregnancies, the trait could be demonstrated by an oral steroid hormone challenge test or by use of oral contraceptives.
Somayaji et al. (1968) reported sisters who developed cholestatic jaundice following the taking of an oral contraceptive agent. One of them had had pruritus during the latter part of each of 3 pregnancies. McKusick and Clayton (1968) observed that mothers of patients with PFIC1 had severe pruritus in late pregnancy, raising the possibility that cholestasis of pregnancy may be a manifestation of the heterozygous state of the gene which in the homozygote produces a fatal form of cholestasis.
Reyes et al. (1978) and Reyes (1982) reported that ICP is frequent in the Araucanian Indians of Chile. Reyes et al. (1976) reported a large kindred from Chile in which 10 of 32 multiparous women in the last 2 generations had ICP. There were 2 probable instances of males who transmitted the disorder to a daughter.
Hirvioja and Kivinen (1993) reported 3 sisters with ICP, which was observed in 5 successive generations of their family. Most of the patients also had cholelithiasis. Uniform expression, complete penetrance, and direct parent-to-child transmission supported dominant inheritance.
In 4 of 182 unrelated patients with ICP1, Mullenbach et al. (2005) identified heterozygous mutations in the ATP8B1 gene (602397.0010; 602397.0011).
Genetic Heterogeneity
Savander et al. (2003) prospectively interviewed 69 Finnish patients with ICP for a family history of the disorder; 11 of the patients were found to have familial ICP and 58 had sporadic ICP. The pedigree structures in 16% (11 of 69) patients suggested dominant inheritance. Patients with familial ICP had higher serum amino transferase levels and a higher recurrence risk (92% vs 40%). Haplotype and multipoint linkage analysis excluded the ABCB11 (603201), ATP8B1, and the ABCB4 genes in 2 pedigrees. Savander et al. (2003) concluded that ICP is genetically heterogeneous.
In a large screening of the ATP8B1 gene in 176 familial and sporadic patients with ICP, Painter et al. (2005) concluded that ATP8B1 is probably not a major gene contributing to the disorder.
ICP affects approximately 0.5 to 0.7% of all pregnancies in the UK (Mullenbach et al., 2005).
Cahill, K. M. Hepatitis in pregnancy. Surg. Gynec. Obstet. 114: 545-552, 1962. [PubMed: 13875565]
dePagter, A. G. F., vanBerge Henegouwen, G. P., ten Bokkel Huinink, J. A., Brandt, K.-H. Familial benign recurrent intrahepatic cholestasis: interrelation with intrahepatic cholestasis of pregnancy and from oral contraceptives? Gastroenterology 71: 202-207, 1976. [PubMed: 939378]
Fast, B. B., Roulston, T. M. Idiopathic jaundice of pregnancy. Am. J. Obstet. Gynec. 88: 314-321, 1964. [PubMed: 14123402] [Full Text: https://doi.org/10.1016/0002-9378(64)90425-9]
Hirvioja, M.-L., Kivinen, S. Inheritance of intrahepatic cholestasis of pregnancy in one kindred. Clin. Genet. 43: 315-317, 1993. [PubMed: 8370153] [Full Text: https://doi.org/10.1111/j.1399-0004.1993.tb03826.x]
Holzbach, R. T., Sanders, J. H. Recurrent intrahepatic cholestasis of pregnancy: observations on pathogenesis. JAMA 193: 542-544, 1965. [PubMed: 14326722] [Full Text: https://doi.org/10.1001/jama.1965.03090060132017]
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 85: 175-179, 1983. [PubMed: 6852450]
McKusick, V. A., Clayton, R. J. Cholestasis of pregnancy. (Letter) New Eng. J. Med. 278: 566 only, 1968. [PubMed: 5637248]
Mullenbach, R., Bennett, A., Tetlow, N., Patel, N., Hamilton, G., Cheng, F., Chambers, J., Howard, R., Taylor-Robinson, S. D., Williamson, C. ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy. Gut 54: 829-834, 2005. [PubMed: 15888793] [Full Text: https://doi.org/10.1136/gut.2004.058115]
Painter, J. N., Savander, M., Ropponen, A., Nupponen, N., Riikonen, S., Ylikorkala, O., Lehesjoki, A.-E., Aittomaki, K. Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy. Europ. J. Hum. Genet. 13: 435-439, 2005. [PubMed: 15657619] [Full Text: https://doi.org/10.1038/sj.ejhg.5201355]
Pasmant, E., Goussard, P., Baranes, L., Laurendeau, I., Quentin, S., Ponsot, P., Consigny, Y., Farges, O., Condat, B., Vidaud, D., Vidaud, M., Chen, J.-M., Parfait, B. First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis. Europ. J. Hum. Genet. 20: 277-282, 2012. [PubMed: 21989363] [Full Text: https://doi.org/10.1038/ejhg.2011.186]
Reyes, H. The enigma of intrahepatic cholestasis of pregnancy: lessons from Chile. Hepatology 2: 87-96, 1982. [PubMed: 7054071] [Full Text: https://doi.org/10.1002/hep.1840020114]
Reyes, H., Gonzalez, M. C., Ribalta, J., Aburto, H., Matus, C., Schramm, G., Katz, R., Medina, E. Prevalence of intrahepatic cholestasis of pregnancy in Chile. Ann. Intern. Med. 88: 487-493, 1978. [PubMed: 637428] [Full Text: https://doi.org/10.7326/0003-4819-88-4-487]
Reyes, H., Ribalta, J., Gonzalez-Ceron, M. Idiopathic cholestasis of pregnancy in a large kindred. Gut 17: 709-713, 1976. [PubMed: 976812] [Full Text: https://doi.org/10.1136/gut.17.9.709]
Savander, M., Ropponen, A., Avela, K., Weerasekera, N., Cormand, B., Hirvioja, M.-L., Riikonen, S., Ylikorkala, O., Lehesjoki, A.-E., Williamson, C., Aittomaki, K. Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy. Gut 52: 1025-1029, 2003. [PubMed: 12801961] [Full Text: https://doi.org/10.1136/gut.52.7.1025]
Somayaji, B. N., Paton, A., Price, J. H., Harris, A. W., Flewett, T. H. Norethisterone jaundice in two sisters. Brit. Med. J. 2: 281-283, 1968. [PubMed: 4296504] [Full Text: https://doi.org/10.1136/bmj.2.5600.281]
Svanborg, A., Ohlsson, S. Recurrent jaundice of pregnancy: a clinical study of twenty-two cases. Am. J. Med. 27: 40-49, 1959. [PubMed: 13661186] [Full Text: https://doi.org/10.1016/0002-9343(59)90059-2]