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Intrahepatic Cholestasis of Pregnancy
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
About 15–30% of women presenting with ICP have a family history of intrahepatic cholestasis (IC), but most cases are not related to known mutations of familial IC. Genetic predisposition is shown in high-prevalence regions such as Chile and Scandinavia. Family clustering, prevalence of ethnic and geographic variations, and recently demonstrated mutations in gene coding for hepatobiliary transport proteins further indicate a genetic predisposition in ICP. There are many genetic variations described, which occur at different chromosomal locations: ATP8B1 at 18q 21–22, ABCB4 at 7q21, and ABCB11 at 2q24 [11]. Genetic predisposition may lead to altered cell membrane composition of bile ducts and hepatocytes, as well as the subsequent dysfunction of biliary canalicular transporters. Mutations in the hepatic phospholipid transporter (MDR3/ABCB4), amniophospholipid transporter (ATP8B1/FIC1), and bile salt export pump (BSEP/ABCB11) have been found in patients with ICP. These genetic mutations are more frequent in women who developed severe ICP [4, 8].
Mouse Knockout Models of Biliary Epithelial Cell Formation and Disease
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
ATP8B1 encodes a P/type ATPase that is mutated in benign intrahepatic cholestasis (BRIC) as well as familial intrahepatic cholestasis (FIC1) The mice have a milder hepatic phenotype due to abnormalities in trans location of aminophospholipids between membrane leaflets resulting in aberrant intestinal bile salt absorption. Also known as BSEP (bile salt export protein), and SPGP (sister for P/glycoprotein), ABCBl 1 is an ATP/dependent membrane transporter expressed in the canalicular membrane of hepatocytes that functions in transporting bile acids out of hepatocyte into the canaliculus. Mouse mutants (or ABCB1 1 show mild cholestasis, reduced hepatic bile acid output and high amounts of tetra hydroxylated bile acids suggesting an alternative protective mechanism for bile acid export. 50–52
The gastrointestinal tract
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
There are three conditions caused by different variants in the gene ATP8B1: Benign recurrent cholestasis: Autosomal recessiveIntrahepatic cholestasis of pregnancyFamilial progressive cholestasis (Byler disease), often leading to hepatic failure before adulthood: Autosomal recessive
Improvement of cholestatic episodes in patients with benign recurrent intrahepatic cholestasis (BRIC) treated with rifampicin. A long-term follow-up
Published in Scandinavian Journal of Gastroenterology, 2023
Holmfridur Helgadottir, Geir Folvik, Mette Vesterhus
Five BRIC1 cases, all males with median age at the first cholestatic attack 22 years, were available for this case series. Characteristics of the patients are prescribed in Table 1. All cases presented in the same county in Western Norway and had the same homozygous mutation in the ATP8B1 gene: c1982T > C (p. Ile661Thr). Case 1 and 5 are monozygotic twin brothers and Case 5 has a son diagnosed with BRIC1 (<18 years of age; hence, not included). Case 2 had a grandmother who had icterus and abdominal pain occurring episodically without a diagnosis and lived to the age of 84. Case 2 and 4 are descendants of people who lived in the same small and isolated community and likely to have inherited the gene mutations form common ancestors born from consanguineous unions. Case 3 is not related to the other cases but his mother had a liver transplantation at the age of 39, presumably because of primary sclerosing cholangitis. Although the diagnosis of BRIC1 has been confirmed with gene testing in all cases today, the gene test was not available until 2006 and the first three cases underwent extensive workup before the diagnosis of BRIC1 was established, including liver biopsy and endoscopic retrograde cholangiopancreatography (ERCP).
Compound Heterozygous Myosin 5B (Myo5b) Mutation with Early Onset Progressive Cholestasis and No Intestinal Failure
Published in Fetal and Pediatric Pathology, 2022
Progressive familial intrahepatic cholestasis (PFIC) refers to a group of genetic diseases of autosomal recessive inheritance that are characterized by defects in the handling of bile acids and lipids [1]. Historically, such diseases were diagnosed based on recognition of unrelenting cholestasis without gene identification. Molecular studies have uncovered underlying molecular defects implicated in the PFIC etiopathogeneis including ATP8B1 (PFIC type 1), ABCB11 (PFIC type 2), and ABCB4 (PFIC type 3), TJP2 (PFIC type 4) and NR1H4 (PFIC type 5) [2–4]. Recently, other novel genes have also been reported causing progressive cholestasis including MYO5B, USP53, and LSR [5,6]. PFIC causes a multitude of clinical manifestations with variable severity often beginning in childhood leading to liver failure and end stage liver disease. Various mechanisms of cholestasis have been described in PFIC including disorders of canalicular transport, integrity of tight junctions, nuclear signaling, vesicular trafficking, and maintenance of hepatocyte membrane polarization [1]. We report an Indian child with novel compound heterozygous variants in MYO5B gene presenting with low gamma-glutamyl transferase (GGT), fluctuating jaundice and severe pruritus.
Unexplained cholestasis in adults and adolescents: diagnostic benefit of genetic examination
Published in Scandinavian Journal of Gastroenterology, 2018
Luise Aamann, Nikolaj Ørntoft, Ida Vogel, Henning Grønbaek, Naja Becher, Hendrik Vilstrup, Peter Ott, Dorte Launholt Lildballe
Genomic DNA was isolated from peripheral blood leukocytes using a magnetic-beads based method on automated Chemagic MSN1 following the manufacturer’s instructions (Chemagen, Germany). From 1 μg of DNA, a library for Illumina paired-end sequencing was constructed using the KAPA HTP Library Preparation Kit according to the manufacturer’s instructions (KAPA Biosystems Inc., Wilmington, MA, USA). The generated libraries were enriched for regions of interest using customized targeting probe set (SeqCap EZ Choise; Roche Nimblegen, Inc., Madison, WI, USA), and sequenced on a MiSeq Desktop Sequencer (Illumina, San Diego, CA, USA). The reads obtained from sequencing were aligned to the human genome (hg19; average read depths >400×) and variants were called using CLC Genomics Workbench v. 7.0.3 software (CLC bio-Qiagen, Aarhus, Denmark). The analyzed genes [reference sequences] were: ATP8B1 [NM_005603.4]; ABCB11 [NM_003742.2]; ABCB4 [NM_000443.3]; ABCG5 [NM_022436.2]; ABCC2 [NM_000392.3]; JAG1 [NM_000214.2]; NOTCH2 [NM_024408.3]; UGT1A1 [NM_000463.2].