Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families
ABSTRACT Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy.
Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome.
Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]).
With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential.
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ABSTRACT: Introduction: The liver is the central place for the metabolism of drugs and other xenobiotics. In the liver cell, oxidation and conjugation of compounds take place, and at the same time, bile formation helps in extrusion of these compounds via the biliary route. A large number of transporters are responsible for drug uptake into the liver cell and excretion into bile or efflux to the sinusoidal blood.Areas covered: Genetic variants of these transporters and their transactivators contribute to changes in drug handling and are also responsible for cholestatic syndromes of different severity. This review summarizes the current knowledge regarding the influence of these genetic changes. The review covers progressive hereditary cholestatic syndromes as well as recurrent or transient cholestatic syndromes such as drug-induced liver injury, intrahepatic cholestasis of pregnancy, and benign recurrent intrahepatic cholestasis.Expert opinion: Polymorphisms in transporter genes are frequent. For clinically relevant cholestatic syndromes, it often requires a combination of genetic variants or acquired triggers such as pregnancy or drug treatment. In combination with other pathogenetic aspects, genetic variants in drug transporters may contribute to our understanding of not only cholestatic diseases such as primary sclerosing cholangitis or primary biliary cirrhosis, but also the natural course of chronic liver disease in general.Expert Opinion on Drug Metabolism & Toxicology 09/2014; 10(11). DOI:10.1517/17425255.2014.963553 · 2.93 Impact Factor
Article: FXR and liver carcinogenesis[Show abstract] [Hide abstract]
ABSTRACT: Farnesoid X receptor (FXR) is a member of the nuclear receptor family and a ligand-modulated transcription factor. In the liver, FXR has been considered a multi-functional cell protector and a tumor suppressor. FXR can suppress liver carcinogenesis via different mechanisms: 1) FXR maintains the normal liver metabolism of bile acids, glucose and lipids; 2) FXR promotes liver regeneration and repair after injury; 3) FXR protects liver cells from death and enhances cell survival; 4) FXR suppresses hepatic inflammation, thereby preventing inflammatory damage; and 5) FXR can directly increase the expression of some tumor-suppressor genes and repress the transcription of several oncogenes. However, inflammation and epigenetic silencing are known to decrease FXR expression during tumorigenesis. The reactivation of FXR function in the liver may be a potential therapeutic approach for patients with liver cancer.Acta Pharmacologica Sinica 12/2014; 36(1). DOI:10.1038/aps.2014.117 · 2.50 Impact Factor
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ABSTRACT: Objectives: Partial external bile diversion (PEBD) is an established therapy for low-GGT Progressive Familial Intrahepatic Cholestasis (PFIC). This study sought to determine if the dynamics of the cholic acid (CA) and chenodeoxycholic acid (CDCA) pools in low-GGT-PFIC subjects with successful PEBD were equivalent to those achieved with successful liver transplantation (LTX). Methods: The kinetics of CA and CDCA metabolism were measured by stable isotope dilution in plasma samples in 5 PEBD subjects all with intact canalicular BSEP expression and compared to low-GGT-PFIC subjects with successful LTX. Stomal loss of bile acids was measured in PEBD subjects. Results: The fractional turnover rate for CA in the PEBD group ranged from 0.5 to 4.2 d-1 (LTX group, range 0.2 - 0.9 d-1, p = 0.076) and for CDCA from 0.7 to 4.5 d-1 (LTX group 0.3 - 0.4 d-1, p = 0.009). The CA and CDCA pool sizes were equivalent between groups; however pool composition in PEBD was somewhat more hydrophilic. The CA/CDCA ratio in PEBD ranged from 0.9 to 19.5, whereas in LTX it ranged from 0.5 to 2.6. Synthesis rates computed from isotope dilution correlated well with timed output for both CA: r2 = 0.760, p = 0.024 and CDCA: r2 = 0.690, p = 0.021. Conclusions: PEBD results in bile acid fractional turnover rates greater than LTX, pool sizes equivalent to LTX and pool composition that is at least as hydrophilic as produced by LTX.Journal of Pediatric Gastroenterology and Nutrition 11/2014; DOI:10.1097/MPG.0000000000000630 · 2.87 Impact Factor