The many facets of bile acids in the physiology and pathophysiology of the human liver.

Bile acids perform vital functions in the human liver and are the essential component of bile. It is therefore not surprising that the biology of bile acids is extremely complex, regulated on different levels, and involves soluble and membrane receptors as well as transporters. Hereditary disorders of these proteins manifest in different pathophysiological processes that result in liver diseases of varying severity.

Platelets Boost Recruitment of CD133 Bone Marrow Stem Cells to Endothelium and the Rodent Liver-The Role of P-Selectin/PSGL-1 Interactions.

We previously demonstrated that clinical administration of mobilized CD133 bone marrow stem cells (BMSC) accelerates hepatic regeneration. Here, we investigated the potential of platelets to modulate CD133BMSC homing to hepatic endothelial cells and sequestration to warm ischemic livers. Modulatory effects of platelets on the adhesion of CD133BMSC to human and mouse liver-sinusoidal- and micro- endothelial cells (EC) respectively were evaluated in in vitro co-culture systems.

Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset.

Genetic variants in the adenosine triphosphate-binding cassette subfamily B member 4 () gene, which encodes hepatocanalicular phosphatidylcholine floppase, can lead to different phenotypes, such as progressive familial intrahepatic cholestasis (PFIC) type 3, low phospholipid-associated cholelithiasis, and intrahepatic cholestasis of pregnancy. The aim of this multicenter project was to collect information on onset and progression of this entity in different age groups and to assess the relevance of this disease for the differential diagnosis of chronic liver disease. Clinical and laboratory data of 38 patients (17 males, 21 females, from 29 families) with homozygous or (compound) heterozygous mutations were retrospectively collected.

Post-transplant Recurrent Bile Salt Export Pump Disease: A Form of Antibody-mediated Graft Dysfunction and Utilization of C4d.

Recurrent bile salt export pump (rBSEP) disease has been reported in progressive familial intrahepatic cholestasis type 2 (PFIC2) patients following liver transplantation (LT) and is often refractory to standard anti-cellular rejection immunosuppressants. The mechanism of rBSEP disease is proposed to be a form of type II hypersensitivity reaction with de novo anti-BSEP antibodies blocking the function of allograft BSEP. Utilization of C4d has not been evaluated in rBSEP.

Partial external biliary diversion in bile salt export pump deficiency: Association between outcome and mutation.

Aim: To investigate the relation of two different mutations to the outcome of partial external biliary diversion (PEBD) in severe bile salt export pump (BSEP) deficiency.

Methods: Mutations in the gene encoding BSEP leading to severe BSEP deficiency in two unrelated patients were identified by genomic sequencing. Native liver biopsies and transiently transfected human embryonic kidney (HEK) 293 cells expressing either wild-type or mutated BSEP were subjected to immunofluorescence analysis to assess BSEP transporter localization.

Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants.

Background & Aims: The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity.

Methods: Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause.

Recurrence of Progressive Familial Intrahepatic Cholestasis Type 2 Phenotype After Living-donor Liver Transplantation: A Case Report.

Background: Progressive familial intrahepatic cholestasis 2 (PFIC2) is the result of mutations in the ABCB11, which encodes for bile salt export pump (BSEP). An absence of BSEP in the canalicular membrane causes cholestasis and leads to the development of end-stage liver disease in the first decade of life. Liver transplantation (LT) has been considered curative for BSEP disease.

Exon-skipping and mRNA decay in human liver tissue: molecular consequences of pathogenic bile salt export pump mutations.

The bile salt export pump BSEP mediates bile formation. Over 150 BSEP mutations are associated with progressive familial intrahepatic cholestasis type 2 (PFIC-2), with few characterised specifically. We examined liver tissues from two PFIC-2 patients compound heterozygous for the splice-site mutation c.

Bile salt export pump-reactive antibodies form a polyclonal, multi-inhibitory response in antibody-induced bile salt export pump deficiency.

Unlabelled: Progressive familial intrahepatic cholestasis type 2 (PFIC-2) is caused by mutations in ABCB11, encoding the bile salt export pump (BSEP). In 2009, we described a child with PFIC-2 who developed PFIC-like symptoms after orthotopic liver transplantation (OLT). BSEP-reactive antibodies were demonstrated to account for disease recurrence.

TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro.

Objective: Cholestatic liver diseases in humans as well as bile acid (BA)-feeding and common bile duct ligation (CBDL) in rodents trigger hyperplasia of cholangiocytes within the portal fields. Furthermore, elevation of BA levels enhances proliferation and invasiveness of cholangiocarcinoma (CCA) cells in animal models, thus promoting tumour progression. TGR5 is a G-protein coupled BA receptor, which is highly expressed in cholangiocytes and postulated to mediate the proliferative effects of BA.

Two Case Reports of Successful Treatment of Cholestasis With Steroids in Patients With PFIC-2.

Mutations in the gene encoding the canalicular bile salt export pump (BSEP) can result in progressive familial intrahepatic cholestasis type 2 (PFIC-2). Treatment options are limited, and PFIC-2 often necessitates liver transplantation. We report on a young woman and a boy who clinically presented with PFIC-2 phenotypes and dramatically improved with steroid treatment.

Severe liver fibrosis caused by Schistosoma mansoni: management and treatment with a transjugular intrahepatic portosystemic shunt.

Liver diseases are common in inhabitants and migrants of tropical countries, where the liver can be exposed not only to toxins but also to many viral, bacterial, fungal, and parasitic infections. Schistosomiasis--a common parasitic infection that affects at least 240 million people worldwide, mostly in Africa--is regarded as the most frequent cause of liver fibrosis worldwide. We present a case of a 19-year-old male refugee from Guinea with recurrent oesophageal variceal bleeding due to schistosomal liver fibrosis refractory to endoscopic therapy.

TIPS geometry influences patency.

Objective: The purpose of this study was to evaluate potential causes of Transjugular intrahepatic portosystemic shunt (TIPS) dysfunction.

Material And Methods: We retrospectively evaluated 26 patients who required TIPS revision (group I) and 24 patients who did not require any further intervention (group II) within the first two years following TIPS implantation. The distance of the distal end of the stent to the hepatocaval junction was measured.

Anaphylactic shock ensuing therapeutic puncture of an echinococcal cyst.

Cystic echinococcosis (CE) is a widespread zoonosis. For treating single echinococcal cysts during the last decades, therapeutic puncture of the cyst, aspiration, injection of a scolicide, and re-aspiration (PAIR) has been established as a minimal-invasive alternative method to surgery. A recent review on the complications of therapeutic cyst punctures has shown that dangerous complications occur much less frequently than previously assumed.

A mutation within the extended X loop abolished substrate-induced ATPase activity of the human liver ATP-binding cassette (ABC) transporter MDR3.

The human multidrug resistance protein 3 (MDR3/ABCB4) belongs to the ubiquitous family of ATP-binding cassette (ABC) transporters and is located in the canalicular membrane of hepatocytes. There it flops the phospholipids of the phosphatidylcholine (PC) family from the inner to the outer leaflet. Here, we report the characterization of wild type MDR3 and the Q1174E mutant, which was identified previously in a patient with progressive familial intrahepatic cholestasis type 3 (PFIC-3).

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

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.

Conjugated bilirubin triggers anemia by inducing erythrocyte death.

Unlabelled: Hepatic failure is commonly associated with anemia, which may result from gastrointestinal bleeding, vitamin deficiency, or liver-damaging diseases, such as infection and alcohol intoxication. At least in theory, anemia during hepatic failure may result from accelerated clearance of circulating erythrocytes. Here we show that bile duct ligation (BDL) in mice leads to severe anemia despite increased reticulocyte numbers.

Strategies to inhibit entry of HBV and HDV into hepatocytes.

Although there has been much research into the pathogenesis and treatment of hepatitis B virus (HBV) and hepatitis D virus (HDV) infections, we still do not completely understand how these pathogens enter hepatocytes. This is because in vitro infection studies have only been performed in primary human hepatocytes. Development of a polarizable, HBV-susceptible human hepatoma cell line and studies of primary hepatocytes from Tupaia belangeri have provided important insights into the viral and cellular factors involved in virus binding and infection.

A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy.

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.

Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes.

Background & Aims: Hepatitis B and D viruses (HBV and HDV) are human pathogens with restricted host ranges and high selectivity for hepatocytes; the HBV L-envelope protein interacts specifically with a receptor on these cells. We aimed to identify this receptor and analyze whether it is the recently described sodium-taurocholate co-transporter polypeptide (NTCP), encoded by the SLC10A1 gene.

Methods: To identify receptor candidates, we compared gene expression patterns between differentiated HepaRG cells, which express the receptor, and naïve cells, which do not.

A dileucine motif is involved in plasma membrane expression and endocytosis of rat sodium taurocholate cotransporting polypeptide (Ntcp).

The sodium taurocholate cotransporting polypeptide (Ntcp) is the major uptake transporter for bile salts into liver parenchymal cells, and PKC-mediated endocytosis was shown to regulate the number of Ntcp molecules at the plasma membrane. In this study, mechanisms of Ntcp internalization were analyzed by flow cytometry, immunofluorescence, and Western blot analyses in HepG2 cells. PKC activation induced endocytosis of Ntcp from the plasma membrane by ~30%.