- Case report
- Open Access
- Open Peer Review
Successful management of severe intrahepatic cholestasis of pregnancy: report of a first Japanese case
- Kenya Kamimura†1Email author,
- Hiroyuki Abe†1,
- Naomi Kamimura†2,
- Masayuki Yamaguchi2,
- Maiko Mamizu1,
- Kanna Ogi2,
- Yoshifumi Takahashi1,
- Ken-ichi Mizuno1,
- Hiroteru Kamimura1,
- Yuji Kobayashi1,
- Manabu Takeuchi1,
- Kunihiko Yoshida2,
- Kyoko Yamada2,
- Takayuki Enomoto2,
- Koichi Takakuwa3,
- Minoru Nomoto1,
- Miki Obata4,
- Yoshinori Katsuragi4,
- Yukio Mishima4,
- Ryo Kominami4,
- Tomoteru Kamimura5 and
- Yutaka Aoyagi1
© Kamimura et al.; licensee BioMed Central Ltd. 2014
- Received: 27 May 2014
- Accepted: 11 September 2014
- Published: 13 September 2014
Intrahepatic cholestasis of pregnancy (ICP) is a cholestasis condition caused by elevated levels of serum bile acids that mainly occurs in the third trimester of pregnancy. Maternal symptoms include pruritus; elevation of transaminases, biliary enzymes, and bilirubin levels; and abnormal liver function tests. Fetal symptoms include spontaneous preterm labor, fetal distress, and intrauterine death. It is more prevalent in the Caucasians and is rarely found in Asian countries, including Japan. The etiology of ICP has been reported as involving various factors such as, environmental factors, hormone balance, and genetic components. The genetic factors include single-nucleotide polymorphisms (SNPs) in the genes of canalicular transporters, including ABCB4 and ABCB11. It has also been reported that the combination of these SNPs induces severe cholestasis and liver dysfunction.
Here, we report for the first time a 24-year Japanese case of severe ICP diagnosed by typical symptoms, serum biochemical analysis, and treated with the administration of ursodeoxycholic acid which improved cholestasis and liver injury and prevented fetal death. The sequence analysis showed SNPs reported their association with ICP in the ABCB11 (rs2287622, V444A) and ABCB4 (rs1202283, N168N) loci.
The risk of ICP has been reported to be population-specific, and it is rare in the Japanese population. Our case was successfully treated with ursodeoxycholic acid and the genetic sequence analysis has supported the diagnosis. Because genetic variation in ABCB4 and ABCB11 has also been reported in the Japanese population, we need to be aware of potential ICP cases in pregnant Japanese women although further studies are necessary.
- Intrahepatic cholestasis of pregnancy
- Bile acid
- Ursodeoxycholic acid
- Single-nucleotide polymorphism
The etiology of intrahepatic cholestasis of pregnancy (ICP) involves various factors such as environmental factors, hormonal balance, and genetic components. The relation of the genetic factors lead to the various prevalence rates among different ethnic groups. It has been reported that the prevalence in Caucasians in Europe, United States, Canada, and Australia ranges from 0.1% to 1.5% . On the other hand, much fewer number of cases have been reported in Asian countries . Symptoms include itching, particularly of the palms and feet, and jaundice. Fetal consequences of ICP include spontaneous preterm labor, fetal distress, and intrauterine death due to increased levels of serum bile acids [1–5]. Biochemical analysis shows a mild increase in transaminases, bilirubin, other biliary enzymes, and serum bile acids levels of >10 μmol/L [6, 7]. In addition, the level of cytotoxic bile acids, such as chenodeoxycholic acid, increases 10-100 times higher than the normal level. Symptoms and serum abnormalities abate after delivery; however, recently, reviews have reported that ICP is also related to an increased risk of developing hepatobiliary diseases later in life . More recently, results of comprehensive analysis of genetic variation in ICP have been reported, and common variations around ABCB4 and ABCB11 encoding multidrug resistance protein 3 (MDR3) and bile salt export pump (BSEP), respectively, have been reported as key factors [1, 6]. Similar results have been reported that ABCB4[9–13] and ABCB11 have significant relationships with the etiology of ICP. The combination of these mutations has been reported to be related to severe ICP. For example, the combination of homozygous polymorphisms in ABCB11 at the complementary DNA position 1331 with a thymine replaced by a cytosine (1331 T > C, rs2287622), leading to an exchange from valine to alanine (V444A), and in ABCB4 at position 959 in exon 9 with a cytosine replaced by a thymine (959 C > T), leading to an exchange of serine to phenylalanine (S320F), and some other synonymous SNPs are considered to be related to the etiology of severe type of ICP . Further analysis has shown that the association of 1331 T > C (rs2287622) was also driven by other SNP (rs3815676) . Therefore, these genetic variations may contribute to the difference of the occurrence in ethnic groups and further studies will clarify the more accurate contributions of each variation, since these SNPs have also been found in general population [16–18]. Here, we report the first case of a Japanese woman diagnosed with ICP based on severe pruritis, increased levels of bile acid and hepatobiliary enzymes, and successfully treated with ursodeoxycholic acid (UDCA) preventing fetal death and clinical symptoms as well. The genetic sequence analysis showed a homozygous polymorphism in ABCB11 at 1331 T > C leading to V444A that is often reported in the conditions [1, 15]. Furthermore, another synonymous single-nucleotide polymorphism in ABCB4 (504 C > T, rs1202283, N168N) was combined in our patient that have never been reported the association with this disease. Based on these results, we concluded our case as a first Japanese case of severe ICP with mutations in ABCB11 and ABCB4. Further study will help us to find and appropriately treat patients preventing fetal death and clinical symptoms.
Results of laboratory investigation
Viral hepatitis, autoimmune liver injury, hyperemesis gravidarum, acute fatty liver of pregnancy, HELLP (hemolysis, elevated liver enzyme levels, and low platelet levels) syndrome, preeclampsia, and ICP are known to be involved in the etiology of liver injury found during pregnancy [1, 6]. Among these diseases, ICP is frequently found in Caucasians, and the difference in the prevalence rate of ICP among the populations is due to genetic variation in the genes encoding ATP-Binding Cassette (ABC) transporters . The most common symptom is pruritis, which typically presents in the third trimester of pregnancy, but early disease onset can be observed in ~20% of cases . Symptoms disappear after delivery; however, it has been reported that ICP is associated with an increased risk of developing various hepatobiliary diseases, including gallstones and cirrhosis, later in life . Biochemical analysis revealed increased levels of transaminases, bilirubin, and serum bile acids (>10 μmol/l). However, clinical jaundice is detected in 10%-15% of patients, and bile acid levels rarely exceed 100 μmol/l [2, 5]. The symptoms and the level of serum enzymes ranged variously, and the severe type was reported with an early onset, severe pruritis, significant elevation of the hepatobiliary enzymes .
Recent large cohort studies and reviews reported that common variations around ABCB4 and ABCB11 as key factors for developing ICP [1–6]. In addition, it has been reported that the SNP in ABCB11 (1331 T > C), leading to an exchange from valine to alanine (V444A), is related to severe type of ICP . These genetic backgrounds might affect the expression of transporters and their structures that transport sulphated progesterone metabolites which significantly increases during pregnancy leading to the clinical symptoms . Our case showed significant pruritis and increased levels of total and cytotoxic bile acids at the time of admission that was first trimester of pregnancy. Her serum markers showed no evidence of other hepatic diseases, such as HELLP syndrome, acute fatty liver of pregnancy, autoimmune liver diseases, or viral chronic hepatitis. The major SNP in ABCB11 (1331 T > C, rs2287622) and the additional synonymous mutation in ABCB4 (504 C > T, rs1202283) were confirmed by the genomic sequencing strategy. These results are indicating the potential relationship with the disease  and its severity , however since these variations have also been found in general population [16–18], the diagnosis of the disease based on the clinical symptoms and exclusion of other liver diseases like our case. Although a standard therapeutic method has not been established, two recent studies encouraged the administration of UDCA for ICP to reduce pruritis and improve hepatobiliary enzyme levels to reduce the risk of fetal death [20, 21]. The therapeutic effect of UDCA has been reported from various aspects. It replaces cytotoxic bile acid, such as chenodeoxycholic acid into UDCA, directly. In addition, it increases the membrane transport expression, such as MDR3 and BSEP, leading to the stimulation of hepatobiliary excretion of progesterone disulphates that ameliorate pruritus and liver injury . These effects contribute for the treatment of ICP [20, 21]. In our case, UDCA was effective for improving symptoms, i.e., led to decreases in levels of hepatobiliary enzymes and the C/BA ratio, and prevented intrauterine death and meconium passage. The C/BA ratio was used to define the level of bile acid toxicity because the total bile acid level increased after the administration of UDCA followed by replacement with cytotoxic chenodeoxycholic acid. Further studies will help the understandings and the genetic diagnosis, because no need exists to perform liver biopsy as an interventional method to diagnose the disease. In addition, as it is also known that ICP recurs in subsequent pregnancy , it is important to be aware of the disease and its therapeutic options.
The risk of ICP has been reported to be population-specific, and it is rare in the Japanese population. Here, we report the first Japanese case of ICP with severe symptoms and successfully treated with UDCA. The genetic sequence analysis also supported the diagnosis. Because genetic variation in ABCB4 and ABCB11 has also been reported in the Japanese population, we need to be aware of potential ICP cases in pregnant Japanese women although further studies are necessary.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
We acknowledge Enago for the English language review.
- Dixon PH, Wadsworth CA, Chambers J, Donnelly J, Cooley S, Buckley R, Mannino R, Jarvis S, Syngelaki A, Geenes V, Paul P, Sothinathan M, Kubitz R, Lammert F, Tribe RM, Ch’ng CL, Marschall HU, Glantz A, Khan SA, Nicolaides K, Whittaker J, Geary M, Williamson C: A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy. Am J Gastroenterol. 2014, 109: 76-84. 10.1038/ajg.2013.406.View ArticlePubMedGoogle Scholar
- Geenes V, Williamson C: Intrahepatic cholestasis of pregnancy. World J Gastroenterol. 2009, 15: 2049-2066. 10.3748/wjg.15.2049.View ArticlePubMedPubMed CentralGoogle Scholar
- Schutt VA, Minuk GY: Liver diseases unique to pregnancy. Best Pract Res Clin Gastroenterol. 2007, 21: 771-792. 10.1016/j.bpg.2007.05.004.View ArticlePubMedGoogle Scholar
- Joshi D, James A, Quaglia A, Westbrook RH, Heneghan MA: Liver disease in pregnancy. Lancet. 2010, 375: 594-605. 10.1016/S0140-6736(09)61495-1.View ArticlePubMedGoogle Scholar
- Bacq Y: Liver diseases unique to pregnancy: a 2010 update. Clin Res Hepatol Gastroenterol. 2011, 35: 182-193. 10.1016/j.clinre.2010.11.011.View ArticlePubMedGoogle Scholar
- Ahmed KT, Almashhrawi AA, Rahman RN, Hammoud GM, Ibdah JA: Liver diseases in pregnancy: diseases unique to pregnancy. World J Gastroenterol. 2013, 19: 7639-7646. 10.3748/wjg.v19.i43.7639.View ArticlePubMedPubMed CentralGoogle Scholar
- Geenes V, Chappell LC, Seed PT, Steer PJ, Knight M, Williamson C: Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: A prospective population-based case–control study. Hepatology. 2014, 59: 1482-1491. 10.1002/hep.26617.View ArticlePubMedPubMed CentralGoogle Scholar
- Marschall HU, Wikstrom Shemer E, Ludvigsson JF, Stephansson O: Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study. Hepatology. 2013, 58: 1385-1391. 10.1002/hep.26444.View ArticlePubMedGoogle Scholar
- Schneider G, Paus TC, Kullak-Ublick GA, Meier PJ, Wienker TF, Lang T, van de Vondel P, Sauerbruch T, Reichel C: Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy. Hepatology. 2007, 45: 150-158. 10.1002/hep.21500.View ArticlePubMedGoogle Scholar
- Floreani A, Carderi I, Paternoster D, Soardo G, Azzaroli F, Esposito W, Montagnani M, Marchesoni D, Variola A, Rosa Rizzotto E, Braghin C, Mazzella G: Hepatobiliary phospholipid transporter ABCB4, MDR3 gene variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy. Dig Liver Dis. 2008, 40: 366-370. 10.1016/j.dld.2007.10.016.View ArticlePubMedGoogle Scholar
- Trauner M, Fickert P, Wagner M: MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Semin Liver Dis. 2007, 27: 77-98. 10.1055/s-2006-960172.View ArticlePubMedGoogle Scholar
- Floreani A, Carderi I, Paternoster D, Soardo G, Azzaroli F, Esposito W, Variola A, Tommasi AM, Marchesoni D, Braghin C, Mazzella G: Intrahepatic cholestasis of pregnancy: three novel MDR3 gene mutations. Aliment Pharmacol Ther. 2006, 23: 1649-1653. 10.1111/j.1365-2036.2006.02869.x.View ArticlePubMedGoogle Scholar
- Pauli-Magnus C, Lang T, Meier Y, Zodan-Marin T, Jung D, Breymann C, Zimmermann R, Kenngott S, Beuers U, Reichel C, Kerb R, Penger A, Meier PJ, Kullak-Ublick GA: Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics. 2004, 14: 91-102. 10.1097/00008571-200402000-00003.View ArticlePubMedGoogle Scholar
- Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F, Kubitz R, Keitel V, Glantz A, Mattsson LA, Marschall HU, Molokhia M, Moore GE, Linton KJ, Williamson C: Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut. 2009, 58: 537-544. 10.1136/gut.2008.159541.View ArticlePubMedGoogle Scholar
- Keitel V, Vogt C, Haussinger D, Kubitz R: Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy. Gastroenterology. 2006, 131: 624-629. 10.1053/j.gastro.2006.05.003.View ArticlePubMedGoogle Scholar
- Kim SR, Saito Y, Itoda M, Maekawa K, Kawamoto M, Kamatani N, Ozawa S, Sawada J: Genetic variations of the ABC transporter gene ABCB11 encoding the human bile salt export pump (BSEP) in a Japanese population. Drug Metab Pharmacokinet. 2009, 24: 277-281. 10.2133/dmpk.24.277.View ArticlePubMedGoogle Scholar
- Lang T, Haberl M, Jung D, Drescher A, Schlagenhaufer R, Keil A, Mornhinweg E, Stieger B, Kullak-Ublick GA, Kerb R: Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11). Drug Metab Dispos. 2006, 34: 1582-1599. 10.1124/dmd.105.008854.View ArticlePubMedGoogle Scholar
- Meier Y, Pauli-Magnus C, Zanger UM, Klein K, Schaeffeler E, Nussler AK, Nussler N, Eichelbaum M, Meier PJ, Stieger B: Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology. 2006, 44: 62-74.View ArticlePubMedGoogle Scholar
- Glantz A, Reilly SJ, Benthin L, Lammert F, Mattsson LA, Marschall HU: Intrahepatic cholestasis of pregnancy: Amelioration of pruritus by UDCA is associated with decreased progesterone disulphates in urine. Hepatology. 2008, 47: 544-551.View ArticlePubMedGoogle Scholar
- Chappell LC, Gurung V, Seed PT, Chambers J, Williamson C, Thornton JG: Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial. BMJ. 2012, 344: e3799-10.1136/bmj.e3799.View ArticlePubMedPubMed CentralGoogle Scholar
- Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T, Nicastri PL, Locatelli A, Floreani A, Hernandez I, Di Martino V: Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology. 2012, 143: 1492-1501. 10.1053/j.gastro.2012.08.004.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/14/160/prepub
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