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Concept: Progressive familial intrahepatic cholestasis

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Alagille syndrome (AS) is a multisystemic disease autosomal dominant, with variable expression. The major clinical manifestations are: chronic cholestasis, congenital heart disease, posterior embryotoxon in the eye, characteristic facial phenotype, and butterfy vertebrae. AS is caused by mutations in JAGGED1 (more than 90%) and in NOTCH2. Differential diagnosis include: infections, genetic-metabolic diseases, biliary atresia, idiopathic cholestasis. Cholestasis, pruritus and xanthomas have been successfully treated with choleretic agents (ursodeoxycholic acid) and other medications (cholestyramine, rifampin, naltrexone). In certain cases, partial external biliary diversion has also proved successful. Liver transplantation is indicated in children with cirrhosis and liver failure.

Concepts: Medicine, Cancer, Medical terms, Liver, Gastroenterology, Hepatology, Progressive familial intrahepatic cholestasis, Alagille syndrome

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As conceptions have changed regarding the suitability of oral contraceptives for women with a history of intrahepatic cholestasis of pregnancy (ICP), we studied whether the contraindications formerly in force had affected family planning decisions and mode of contraception among women with such a history.

Concepts: Birth control, Sexual intercourse, Family planning, Combined oral contraceptive pill, Abortion, Cholestasis, Progressive familial intrahepatic cholestasis, Intrahepatic cholestasis of pregnancy

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We performed a meta-analysis to evaluate the effects of ursodeoxycholic acid (UDCA) on pruritus, liver test results, and outcomes of babies born to women with intrahepatic cholestasis of pregnancy (ICP).

Concepts: Childbirth, Fetus, Obstetrics, Hepatology, Cholestasis, Progressive familial intrahepatic cholestasis, Intrahepatic cholestasis of pregnancy, Ursodiol

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Objective The total bile acid (TBA) concentration criterion for diagnosing intrahepatic cholestasis of pregnancy varies in the published literature. The purpose of this study was to establish pregnancy-specific reference ranges for the TBA concentration among Latina women.Study Design Self-identified Latina women (n = 211) over 18 years of age with a singleton pregnancy were recruited and had random serum samples drawn during the second and third trimesters. The total and fractionated bile acid concentrations were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and reference ranges were calculated. Laboratory-provided general reference ranges from a general population of adult men and nonpregnant women were used for comparison.Results The TBA reference range for our Latina pregnant population (<8.5 µmol/L) was markedly lower than the laboratory-provided reference range (4.5 to 19.2 µmol/L).Conclusion These data suggest that the upper TBA concentration reference range in our Latina pregnant population is 8.5 µmol/L, based on LC-MS/MS measurements.

Concepts: Pregnancy, Obstetrics, Hepatology, Bile acid, Cholestasis, Liquid chromatography-mass spectrometry, Progressive familial intrahepatic cholestasis, Intrahepatic cholestasis of pregnancy

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Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from α1-antitrypsin deficiency and Alagille syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy.

Concepts: Gene, Liver, Glycogen, Bile, Gallbladder, Hepatocyte, Progressive familial intrahepatic cholestasis, Alagille syndrome

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Bile salt export pump (BSEP) plays an important role in hepatic secretion of bile acids and its deficiency results in severe cholestasis and liver failure. Mutation of the ABCB11 gene encoding BSEP induces BSEP deficiency and progressive familial intrahepatic cholestasis type 2 (PFIC2). Because liver transplantation remains standard treatment for PFIC2, the development of a novel therapeutic option is desired. However, a well reproducible model, which is essential for the new drug development for PFIC2, has not been established. Therefore, we attempted to establish a PFIC2 model by using iPSC technology. Human iPSCs were generated from patients with BSEP-deficiency (BD-iPSC), and were differentiated into hepatocyte-like cells (HLCs). In the BD-iPSC derived HLCs (BD-HLCs), BSEP was not expressed on the cell surface and the biliary excretion capacity was significantly impaired. We also identified a novel mutation in the 5'-untranslated region of the ABCB11 gene that led to aberrant RNA splicing in BD-HLCs. Furthermore, to evaluate the drug efficacy, BD-HLCs were treated with 4-phenylbutyrate (4PBA). The membrane BSEP expression level and the biliary excretion capacity in BD-HLCs were rescued by 4PBA treatment. In summary, we succeeded in establishing a PFIC2 model, which may be useful for its pathophysiological analysis and drug development.

Concepts: Cholesterol, DNA, Gene expression, Liver, Hepatology, Bile, Bile acid, Progressive familial intrahepatic cholestasis

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Partial internal biliary diversion (PIBD) is an alternative approach for the treatment of devastating pruritus in patients with progressive familial intrahepatic cholestasis (PFIC). In these patients quality of life can be improved and progression of liver disease can be delayed while waiting for liver transplantation. The aim of our study was to evaluate six patients with PFIC who have undergone PIBD in long-term follow-up.

Concepts: Life, Liver, Liver function tests, Hepatology, Cholestasis, Liver disease, Progressive familial intrahepatic cholestasis, Intrahepatic cholestasis of pregnancy

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Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations. Most cases are associated with mutations in JAGGED1 (JAG1), which encodes a Notch ligand, although it is not clear how these contribute to disease development. We aimed to develop a mouse model of Alagille syndrome to elucidate these mechanisms.

Concepts: Genetic disorder, Mutation, Point mutation, Missense mutation, Progressive familial intrahepatic cholestasis, Alagille syndrome, JAG1, NOTCH2

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Bile salt export pump BSEP (ABCB11) is a liver-specific adenosine triphosphate-cassette binding transporter that mediates canalicular bile salt excretion from hepatocytes. Human mutations in ABCB11 cause progressive familial intrahepatic cholestasis type II (PFIC2). Although over 150 ABCB11 variants have been reported, our understanding of their biological consequences is limited by the lack of experimental model that recapitulates the patient phenotypes. We applied CRISPR/Cas9-based genome editing technology to knockout abcb11b, the ortholog of human ABCB11, in zebrafish and found that these mutants died prematurely. Histological and ultrastructural analyses showed that abcb11b mutant zebrafish exhibited hepatocyte injury similar to that seen in patients with PFIC2. Hepatocytes of the mutant zebrafish failed to excrete the fluorescently tagged bile acid that is a substrate of human BSEP. Multi-drug resistance protein 1 (MDR1), which is thought to play a compensatory role in Abcb11 knockout mice, was mislocalized to the hepatocyte cytoplasm in abcb11b mutant zebrafish and in a patient lacking BSEP protein due to nonsense mutations in ABCB11. We discovered that BSEP deficiency induced autophagy in both human and zebrafish hepatocytes. Treatment with rapamycin restored bile acid excretion, attenuated hepatocyte damage, and extended lifespan of abcb11b mutant zebrafish, correlating with the recovery of canalicular Mdr1 localization.

Concepts: Gene, Mutation, Hepatology, Bile, Bile acid, Cholestasis, Excretion, Progressive familial intrahepatic cholestasis

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Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in many polyvinylchloride medical devices and is washed out easily. Thereby critically ill infants can become exposed to DEHP concentrations significantly exceeding the recommended threshold. We suspect DEHP to play an important role in the development of intestinal failure associated liver disease. The aim of this study was therefore, to determine the direct influence of DEHP on different liver cell types.

Concepts: Liver function tests, Hepatology, In vitro, Phthalate, Progressive familial intrahepatic cholestasis, Plasticizer, Polyvinyl chloride, Bis(2-ethylhexyl) phthalate