ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population

Anzivino, Claudia; Odoardi, Maria Rosaria; Meschiari, Erica; Baldelli, Enrica; Facchinetti, Fabio; Neri, Isabella; Ruggiero, Giuseppe; Zampino, Rosa; Bertolotti, Marco; Loria, Paola; Carulli, Lucia

doi:10.1016/j.dld.2012.08.011

Cited by 51 publications

(40 citation statements)

References 32 publications

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“…56 Many cases of ICP are associated with mutations in the ABCB4 and ABCB11 genes. 57,58 Pruritus spontaneously resolves, and liver function test results typically normalize within 4 weeks after delivery. Thus, ICP is a self-limiting condition for the mother but increases the risk of preterm birth, fetal distress during labor, and intrauterine death.…”

Section: Intrahepatic Cholestasis Of Pregnancymentioning

confidence: 99%

Pathophysiology and Diseases of the Proximal Pathways of the Biliary System

Nakanishi¹,

Saxena

2015

Archives of Pathology &Amp; Laboratory Medicine

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Care of the patient with cholestasis hinges on identifying the etiology. Diagnostic steps in cholestatic conditions comprise a thorough patient history, abdominal imaging, distinct serological studies, and liver biopsy. Primary biliary cirrhosis is characterized by distinctive serological and histological findings. The small-duct variant of primary sclerosing cholangitis is very rare and difficult to diagnose; imaging of the bile ducts is not helpful. Graft-versus-host disease is characterized by damage and loss of intrahepatic bile ducts. Drugs can cause injury variably at the level of bile canaliculus or the interlobular bile duct. Loss of bile ducts may be seen with primary biliary cirrhosis, primary sclerosing cholangitis, graft-versus-host disease, and drug-induced liver injury. Progressive familial intrahepatic cholestasis and progressive familial intrahepatic cholestasis represent 2 extreme ends of the spectrum of abnormalities in transporters responsible for bile formation. Intrahepatic cholestasis of pregnancy has a variable incidence in different parts of the world and may be due to abnormalities in transporter molecules.

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Section: Intrahepatic Cholestasis Of Pregnancymentioning

confidence: 99%

Pathophysiology and Diseases of the Proximal Pathways of the Biliary System

Nakanishi¹,

Saxena

2015

Archives of Pathology &Amp; Laboratory Medicine

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“…The role of genetic variation at this locus in ICP susceptibility has recently been explored in detail, with several recurrent mutations identified, together with the confirmation of the p.444A variant as a population susceptibility allele (30). Further analysis of an Italian cohort has further established ABCB11 variation as playing a role in ICP susceptibility (31). …”

Section: Introductionmentioning

confidence: 99%

A Comprehensive Analysis of Common Genetic Variation Around Six Candidate Loci for Intrahepatic Cholestasis of Pregnancy

Dixon

Wadsworth

Chambers

et al. 2014

American Journal of Gastroenterology

109

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OBJECTIVES:Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19).METHODS:ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case–control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitage's trend test.RESULTS:Cochran–Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10−4 (rs3815676) and for ABCB4 it was 4.6×10−7(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings.CONCLUSIONS:Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility.

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“…ICP with elevated bile acids in serum and liver is a major cause for premature embryo development and embryonic death (Diken, Usta & Nassar, 2013). Genetic variations or mutations of farnesoid X receptor (FXR) (Van Mil et al, 2007), bile salt export pump (BSEP/ABCB11) (Dixon et al, 2009), and ATP-binding cassette, sub-family B (MDR/TAP), member 4 (ABCB4/MDR3) and ABCB11 (Dixon et al, 2000; Anzivino et al, 2013) contribute to the etiology of ICP. To fully understand bile acid synthesis, transport, and regulation in normal pregnancy would help us to shed light on the pathology of ICP.…”

Section: Introductionmentioning

confidence: 99%

Hepatic bile acids and bile acid-related gene expression in pregnant and lactating rats

Xie

Zhang

Liu

et al. 2013

PeerJ

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Background. Significant physiological changes occur during pregnancy and lactation. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease closely related to disruption of bile acid homeostasis. The objective of this study was to examine the regulation of bile acid synthesis and transport in normal pregnant and lactating rats.Materials and Methods. Livers from timed pregnant SD rats were collected on gestational days (GD) 10, 14 and 19, and postnatal days (PND) 1, 7, 14 and 21. Total bile acids were determined by the enzymatic method, total RNA was isolated and subjected to real time RT-PCR analysis. Liver protein was extracted for western-blot analysis.Results. Under physiological conditions hepatic bile acids were not elevated during pregnancy but increased during lactation in rats. Bile acid synthesis rate-limiting enzyme Cyp7a1 was unchanged on gestational days, but increased on PND14 and 21 at mRNA and protein levels. Expression of Cyp8b1, Cyp27a1 and Cyp7b1 was also higher during lactation. The mRNA levels of small heterodimer partner (SHP) and protein levels of farnesoid X receptor (FXR) were increased during pregnancy and lactation. Bile acid transporters Ntcp, Bsep, Mrp3 and Mrp4 were lower at gestation, but increased during lactation. Hepatic Oatp transporters were decreased during pregnancy and lactation.Conclusion. Hepatic bile acid homeostasis is maintained during normal pregnancy in rats, probably through the FXR-SHP regulation. The expression of bile acid synthesis genes and liver bile acid accumulation were increased during lactation, together with increased expression of bile acid efflux transporter Bsep, Mrp3 and Mrp4.

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ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population

Cited by 51 publications

References 32 publications

Pathophysiology and Diseases of the Proximal Pathways of the Biliary System

Pathophysiology and Diseases of the Proximal Pathways of the Biliary System

A Comprehensive Analysis of Common Genetic Variation Around Six Candidate Loci for Intrahepatic Cholestasis of Pregnancy

Hepatic bile acids and bile acid-related gene expression in pregnant and lactating rats

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