65 results match your criteria atp8b1 deficiency


Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

Hepatology 2021 Mar 5. Epub 2021 Mar 5.

Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Mutations in ATP8B1 can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1 (PFIC1). The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide novel insights by using the largest genetically defined cohort of FIC1 deficiency patients to date. Read More

View Article and Full-Text PDF

Assessment of Adenosine Triphosphatase Phospholipid Transporting 8B1 (ATP8B1) Function in Patients With Cholestasis With ATP8B1 Deficiency by Using Peripheral Blood Monocyte-Derived Macrophages.

Hepatol Commun 2021 Jan 26;5(1):52-62. Epub 2020 Sep 26.

Laboratory of Molecular Pharmacokinetics Graduate School of Pharmaceutical Sciences University of Tokyo Tokyo Japan.

Adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) deficiency, an ultrarare autosomal recessive liver disease, includes severe and mild clinical forms, referred to as progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1), respectively. There is currently no practical method for determining PFIC1 or BRIC1 at an early disease course phase. Herein, we assessed the feasibility of developing a diagnostic method for PFIC1 and BRIC1. Read More

View Article and Full-Text PDF
January 2021

Long-term colestyramine treatment prevents cholestatic attacks in refractory benign recurrent intrahepatic cholestasis type 1 disease.

Hepatology 2020 Dec 5. Epub 2020 Dec 5.

Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive cholestatic disease characterized by intermittent cholestatic episodes of variable severity and duration. BRIC type 1 has been linked to gene mutations encoded in the hepatocanalicular transporter ATP8B1. It has been suggested that ATP8B1 affects the regulation of the farnesoid X receptor, and thus ATP8B1 deficiency could lead to an imbalance between intestinal absorption of bile acids and hepatic secretion, causing bile acid accumulation. Read More

View Article and Full-Text PDF
December 2020

Molecular Modelling and Evaluation of Hidden Information in ABCB11 Gene Mutations.

J Biomed Phys Eng 2019 Jun 1;9(3):303-316. Epub 2019 Jun 1.

MD, Genetic Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Background: Cholestatic disorders are divided in the extra and intra-hepatic that created due to the severe liver diseases. ABCB11 encodes the bile salt export pump and this gene is mutated in several forms of intrahepatic cholestasis. So far, some molecular features of this gene was studies. Read More

View Article and Full-Text PDF

In-silico Evaluation of Rare Codons and their Positions in the Structure of ATP8b1 Gene.

J Biomed Phys Eng 2019 Feb 1;9(1):105-120. Epub 2019 Feb 1.

MD, Genetic Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Background: Progressive familial intrahepatic cholestases (PFIC) are a spectrum of autosomal progressive liver diseases developing to end-stage liver disease. ATP8B1 deficiency caused by mutations in ATP8B1 gene encoding a P-type ATPase leads to PFIC1. The gene for PFIC1 has been mapped on a 19-cM region of 18q21-q22, and a gene defect in ATP8B1 can cause deregulations in bile salt transporters through decreased expression and/or activity of FXR. Read More

View Article and Full-Text PDF
February 2019

Progressive Familial Intrahepatic Cholestasis.

Clin Liver Dis 2018 11 3;22(4):657-669. Epub 2018 Aug 3.

Institute of Liver Studies, King's College London, King's College Hospital, Denmark Hill, London SE5 9RS, UK.

Genetic cholestasis has been dissected through genetic investigation. The major PFIC genes are now described. ATP8B1 encodes FIC1, ABCB11 encodes BSEP, ABCB4 encodes MDR3, TJP2 encodes TJP2, NR1H4 encodes FXR, and MYO5B encodes MYO5B. Read More

View Article and Full-Text PDF
November 2018

New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications.

Can J Gastroenterol Hepatol 2018 26;2018:2313675. Epub 2018 Jul 26.

Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute (CMHI), Warsaw 04-730, Poland.

Cholestasis is characterised by impaired bile secretion and accumulation of bile salts in the organism. Hereditary cholestasis is a heterogeneous group of rare autosomal recessive liver disorders, which are characterised by intrahepatic cholestasis, pruritus, and jaundice and caused by defects in genes related to the secretion and transport of bile salts and lipids. Phenotypic manifestation is highly variable, ranging from progressive familial intrahepatic cholestasis (PFIC)-with onset in early infancy and progression to end-stage liver disease-to a milder intermittent mostly nonprogressive form known as benign recurrent intrahepatic cholestasis (BRIC). Read More

View Article and Full-Text PDF
February 2019

Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies.

Hepatol Commun 2018 May 30;2(5):515-528. Epub 2018 Mar 30.

Institute of Liver Studies King's College London London United Kingdom.

Progressive familial intrahepatic cholestasis (PFIC) with normal circulating gamma-glutamyl transpeptidase levels can result from mutations in the gene (encoding familial intrahepatic cholestasis 1 [FIC1] deficiency) or the gene (bile salt export protein [BSEP] deficiency). We investigated the outcomes of partial external biliary diversion, ileal exclusion, and liver transplantation in these two conditions. We conducted a retrospective multicenter study of 42 patients with FIC1 deficiency (FIC1 patients) and 60 patients with BSEP deficiency (BSEP patients) who had undergone one or more surgical procedures (57 diversions, 6 exclusions, and 57 transplants). Read More

View Article and Full-Text PDF

Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2 gene variants analysis by high-throughput sequencing.

J Gastroenterol 2018 Aug 13;53(8):945-958. Epub 2017 Dec 13.

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

Background: Mutations in ATP-transporters ATPB81, ABCB11, and ABCB4 are responsible for progressive familial intrahepatic cholestasis (PFIC) 1, 2 and 3, and recently the gene for tight junction protein-2 (TJP2) has been linked to PFIC4.

Aim: As these four genes have been poorly studied in young people and adults, we investigated them in this context here.

Methods: In patients with cryptogenic cholestasis, we analyzed the presence of mutations by high-throughput sequencing. Read More

View Article and Full-Text PDF

Assessment of ATP8B1 Deficiency in Pediatric Patients With Cholestasis Using Peripheral Blood Monocyte-Derived Macrophages.

EBioMedicine 2018 Jan 7;27:187-199. Epub 2017 Oct 7.

Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Progressive familial intrahepatic cholestasis type 1 (PFIC1), a rare inherited recessive disease resulting from a genetic deficiency in ATP8B1, progresses to liver failure. Because of the difficulty of discriminating PFIC1 from other subtypes of PFIC based on its clinical and histological features and genome sequencing, an alternative method for diagnosing PFIC1 is desirable. Herein, we analyzed human peripheral blood monocyte-derived macrophages (HMDM) and found predominant expression of ATP8B1 in interleukin-10 (IL-10)-induced M2c, a subset of alternatively activated macrophages. Read More

View Article and Full-Text PDF
January 2018

Hepatic Tmem30a Deficiency Causes Intrahepatic Cholestasis by Impairing Expression and Localization of Bile Salt Transporters.

Am J Pathol 2017 Dec 15;187(12):2775-2787. Epub 2017 Sep 15.

Sichuan Provincial Key Laboratory for Human Disease Gene Study and School of Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China; Key Laboratory for NeuroInformation of Ministry of Education and Medicine Information Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. Electronic address:

Mutations in ATP8B1 or ATP11C (members of P4-type ATPases) cause progressive familial intrahepatic cholestasis type 1 in human or intrahepatic cholestasis in mice. Transmembrane protein 30A (TMEM30A), a β-subunit, is essential for the function of ATP8B1 and ATP11C. However, its role in the etiology of cholestasis remains poorly understood. Read More

View Article and Full-Text PDF
December 2017

Current and future therapies for inherited cholestatic liver diseases.

World J Gastroenterol 2017 Feb;23(5):763-775

Wendy L van der Woerd, Stan FJ van de Graaf, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, 1105 BK Amsterdam, The Netherlands.

Familial intrahepatic cholestasis (FIC) comprises a group of rare cholestatic liver diseases associated with canalicular transport defects resulting predominantly from mutations in , and . Phenotypes range from benign recurrent intrahepatic cholestasis (BRIC), associated with recurrent cholestatic attacks, to progressive FIC (PFIC). Patients often suffer from severe pruritus and eventually progressive cholestasis results in liver failure. Read More

View Article and Full-Text PDF
February 2017

ABCB4 missense mutations D243A, K435T, G535D, I490T, R545C, and S978P significantly impair the lipid floppase and likely predispose to secondary pathologies in the human population.

Cell Mol Life Sci 2017 07 20;74(13):2513-2524. Epub 2017 Feb 20.

Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, E1 2AT, London, UK.

Bile salts are natural detergents required to solubilise dietary fat and lipid soluble vitamins. They are synthesised in hepatocytes and secreted into the luminal space of the biliary tree by the bile salt export pump (BSEP), an ATP-binding cassette (ABC) transporter in the canalicular membrane. BSEP deficiency causes cytotoxic accumulation of bile salts in the hepatocyte that results in mild-to-severe forms of cholestasis. Read More

View Article and Full-Text PDF

Clinical Variability After Partial External Biliary Diversion in Familial Intrahepatic Cholestasis 1 Deficiency.

J Pediatr Gastroenterol Nutr 2017 03;64(3):425-430

*Division of Gastroenterology, Hepatology and Nutrition †Department of Transplant Surgery, Thomas E. Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA ‡Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX.

Objectives: Familial intrahepatic cholestasis 1 (FIC1) deficiency is caused by a mutation in the ATP8B1 gene. Partial external biliary diversion (PEBD) is pursued to improve pruritus and arrest disease progression. Our aim is to describe clinical variability after PEBD in FIC1 disease. Read More

View Article and Full-Text PDF

Osteopontin Deficiency Alters Biliary Homeostasis and Protects against Gallstone Formation.

Sci Rep 2016 08 3;6:30215. Epub 2016 Aug 3.

Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.

The precipitation of excess biliary cholesterol as solid crystals is a prerequisite for cholesterol gallstone formation, which occurs due to disturbed biliary homeostasis. Biliary homeostasis is regulated by an elaborate network of genes in hepatocytes. If unmanaged, the cholesterol crystals will aggregate, fuse and form gallstones. Read More

View Article and Full-Text PDF

The phospholipid flippase ATP8B1 mediates apical localization of the cystic fibrosis transmembrane regulator.

Biochim Biophys Acta 2016 09 11;1863(9):2280-8. Epub 2016 Jun 11.

Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. Electronic address:

Progressive familial intrahepatic cholestasis type 1 (PFIC1) is caused by mutations in the gene encoding the phospholipid flippase ATP8B1. Apart from severe cholestatic liver disease, many PFIC1 patients develop extrahepatic symptoms characteristic of cystic fibrosis (CF), such as pulmonary infection, sweat gland dysfunction and failure to thrive. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel essential for epithelial fluid transport. Read More

View Article and Full-Text PDF
September 2016

The Features of GGT in Patients with ATP8B1 or ABCB11 Deficiency Improve the Diagnostic Efficiency.

PLoS One 2016 6;11(4):e0153114. Epub 2016 Apr 6.

Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.

Background And Aims: Genetic defects in ATP8B1 or ABCB11 account for the majority of cholestasis with low GGT. But the ranges for GGT in patients with ATP8B1 or ABCB11 deficiency are unclear. This study tried to unravel the features of GGT in these patients that improve diagnostic efficiency. Read More

View Article and Full-Text PDF

ATP11C targets basolateral bile salt transporter proteins in mouse central hepatocytes.

Hepatology 2016 07 6;64(1):161-74. Epub 2016 Apr 6.

Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.

Unlabelled: ATP11C is a homolog of ATP8B1, both of which catalyze the transport of phospholipids in biological membranes. Mutations in ATP8B1 cause progressive familial intrahepatic cholestasis type1 in humans, which is characterized by a canalicular cholestasis. Mice deficient in ATP11C are characterized by a conjugated hyperbilirubinemia and an unconjugated hypercholanemia. Read More

View Article and Full-Text PDF

Rescue of defective ATP8B1 trafficking by CFTR correctors as a therapeutic strategy for familial intrahepatic cholestasis.

J Hepatol 2016 06 12;64(6):1339-47. Epub 2016 Feb 12.

Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands; Department of Gastroenterology & Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:

Background & Aims: ATP8B1 deficiency is an autosomal recessive liver disease characterized by intrahepatic cholestasis. ATP8B1 mutation p.I661T, the most frequent mutation in European patients, results in protein misfolding and impaired targeting to the plasma membrane. Read More

View Article and Full-Text PDF

Hypothyroidism Associated with ATP8B1 Deficiency.

J Pediatr 2015 Dec 15;167(6):1334-9.e1. Epub 2015 Sep 15.

Department of Pediatrics, Shanghai Medical College, Fudan University, Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China; Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China. Electronic address:

Objective: To examine whether hypothyroidism is an extrahepatic feature of ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) deficiency.

Study Design: Children with normal γ-glutamyltransferase cholestasis (n = 47; 13 patients with ATP8B1 deficiency, 19 with ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11) deficiency, and 15 without either ATP8B1 or ABCB11 mutations) were enrolled. Clinical information and thyroid function test results were retrospectively retrieved from clinical records and compared. Read More

View Article and Full-Text PDF
December 2015

ATP8B1 and ATP11C: Two Lipid Flippases Important for Hepatocyte Function.

Dig Dis 2015 27;33(3):314-8. Epub 2015 May 27.

Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands.

P4 ATPases are lipid flippases and transport phospholipids from the exoplasmic to the cytosolic leaflet of biological membranes. Lipid flipping is important for the biogenesis of transport vesicles. Recently it was shown that loss of the P4 ATPases ATP8B1 and ATP11C are associated with severe Cholestatic liver disease. Read More

View Article and Full-Text PDF

Analysis of aberrant pre-messenger RNA splicing resulting from mutations in ATP8B1 and efficient in vitro rescue by adapted U1 small nuclear RNA.

Hepatology 2015 Apr 23;61(4):1382-91. Epub 2015 Feb 23.

Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands; Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.

Unlabelled: ATP8B1 deficiency is a severe autosomal recessive liver disease resulting from mutations in the ATP8B1 gene characterized by a continuous phenotypical spectrum from intermittent (benign recurrent intrahepatic cholestasis; BRIC) to progressive familial intrahepatic cholestasis (PFIC). Current therapeutic options are insufficient, and elucidating the molecular consequences of mutations could lead to personalized mutation-specific therapies. We investigated the effect on pre-messenger RNA splicing of 14 ATP8B1 mutations at exon-intron boundaries using an in vitro minigene system. Read More

View Article and Full-Text PDF

Autoimmune BSEP disease: disease recurrence after liver transplantation for progressive familial intrahepatic cholestasis.

Clin Rev Allergy Immunol 2015 Jun;48(2-3):273-84

Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany,

Severe cholestasis may result in end-stage liver disease with the need of liver transplantation (LTX). In children, about 10 % of LTX are necessary because of cholestatic liver diseases. Apart from bile duct atresia, three types of progressive familial intrahepatic cholestasis (PFIC) are common causes of severe cholestasis in children. Read More

View Article and Full-Text PDF

The lipid flippase heterodimer ATP8B1-CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells.

Biochim Biophys Acta 2014 Dec 16;1842(12 Pt A):2378-86. Epub 2014 Sep 16.

Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.

Deficiency of the phospholipid flippase ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea. Read More

View Article and Full-Text PDF
December 2014

Hepatic cytochrome P450 deficiency in mouse models for intrahepatic cholestasis predispose to bile salt-induced cholestasis.

Lab Invest 2014 Oct 28;94(10):1103-13. Epub 2014 Jul 28.

Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.

Progressive familial intrahepatic cholestasis (PFIC) types 1 and 3 are severe cholestatic liver diseases caused by deficiency of ATB8B1 and ABCB4, respectively. Mouse models for PFIC display mild phenotypes compared with human patients, and this can be explained by the difference in bile salt pool composition. Mice, unlike humans, have the ability to detoxify hydrophobic bile salts by cytochrome P450-mediated (re)hydroxylation and thus have a less toxic bile salt pool. Read More

View Article and Full-Text PDF
October 2014

Altered expression and function of canalicular transporters during early development of cholestatic liver injury in Abcb4-deficient mice.

Am J Physiol Gastrointest Liver Physiol 2014 Apr 30;306(8):G670-6. Epub 2014 Jan 30.

Department of Internal Medicine and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut.

Deficiency of ABCB4 is associated with several forms of cholestasis in humans. Abcb4(-/-) mice also develop cholestasis, but it remains uncertain what role other canalicular transporters play in the development of this disease. We examined the expression of these transporters in Abcb4(-/-) mice compared with their wild-type littermate controls at ages of 10 days and 3, 6, and 12 wk. Read More

View Article and Full-Text PDF

Mutational analysis of ATP8B1 in patients with chronic pancreatitis.

PLoS One 2013 19;8(11):e80553. Epub 2013 Nov 19.

Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands ; Department of Metabolic Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Mutations in genes encoding cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor (SPINK1) and chymotrypsinogen C (CTRC) are associated with chronic pancreatitis. However, in many patients with a familial chronic pancreatitis pattern suggesting a genetic cause, no mutations in either of these genes can be found, indicating that other, still unknown, associated genes exist. In this respect ATP8B1 is an interesting candidate due to its strong expression in the pancreas, its supposed general function in membrane organization and the higher incidence of pancreatitis in patients with ATP8B1 deficiency. Read More

View Article and Full-Text PDF

Hepatotoxicity from anabolic androgenic steroids marketed as dietary supplements: contribution from ATP8B1/ABCB11 mutations?

Liver Int 2013 Sep 10;33(8):1266-70. Epub 2013 Jun 10.

Department of Gastroenterology and Hepatology, Brighton and Sussex University Hospitals, Brighton, UK.

Background: Though possession of androgenic anabolic steroids (AAS) is illegal, non-prescription use of AAS persists.

Methods: We describe two Caucasian males (aged 25 and 45 years) with cholestatic hepatitis following ingestion of the dietary supplement Mass-Drol ('Celtic Dragon') containing the AAS 2α-17α-dimethyl-etiocholan-3-one,17β-ol.

Results: Despite substantial hyperbilirubinaemia peak gamma-glutamyl transferase (GGT) remained normal. Read More

View Article and Full-Text PDF
September 2013

Polymorphisms in ABCB11 and ATP8B1 Associated with Development of Severe Intrahepatic Cholestasis in Hodgkin's Lymphoma.

J Clin Exp Hepatol 2013 Jun 7;3(2):159-61. Epub 2013 Feb 7.

Institute of Liver Studies and Transplantation, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, UK.

We report a young man presenting with jaundice and severe debilitating intrahepatic cholestasis 7 months before the diagnosis of Hodgkin's lymphoma. Serum gamma-glutamyl transferase (GGT) activity was not raised. Liver biopsy demonstrated deficiency of canalicular GGT and bile salt export pump expression, which suggested "benign" recurrent intrahepatic cholestasis. Read More

View Article and Full-Text PDF