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Concept: Progressive familial intrahepatic cholestasis


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


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


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


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


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


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


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


Hepatic osteodystrophy caused by vitamin D and calcium malabsorption is thought to develop in children with cholestatic liver disease leading to secondary hyperparathyroidism and rickets or osteomalacia. The aim of this study was to evaluate the dental and bone mineral densities and the serum level of vitamin D in cholestatic infants and children and to correlate this process with clinical and laboratory parameters.

Concepts: Progressive familial intrahepatic cholestasis, Water, Primary sclerosing cholangitis, Osteomalacia, Jaundice, Liver function tests, Osteoporosis, Vitamin D


Alagille syndrome (ALGS) is an inherited multisystem disorder typically manifesting as cholestasis, and potentially leading to end-stage liver disease and death.

Concepts: Natural history, Nature, Disease, Liver function tests, Alagille syndrome, Liver, Hepatology, Progressive familial intrahepatic cholestasis


The bile salt export pump (BSEP) plays an important role in biliary secretion. Mutations in ABCB11, the gene encoding BSEP, induce progressive familial intrahepatic cholestasis type 2 (PFIC2), which presents with severe jaundice and liver dysfunction. A less severe phenotype, called benign recurrent intrahepatic cholestasis type 2, is also known. About 200 missense mutations in ABCB11 have been reported. However, the phenotype-genotype correlation has not been clarified. Furthermore, the frequencies of ABCB11 mutations differ between Asian and European populations. We report a patient with PFIC2 carrying a homozygous ABCB11 mutation c.386G>A (p.C129Y) that is most frequently reported in Japan. The pathogenicity of BSEPC129Yhas not been investigated. In this study, we performed the molecular analysis of this ABCB11 mutation using cells expressing BSEPC129Y. We found that trafficking of BSEPC129Yto the plasma membrane was impaired and that the expression of BSEPC129Yon the cell surface was significantly lower than that in the control. The amount of bile acids transported via BSEPC129Ywas also significantly lower than that via BSEPWT. The transport activity of BSEPC129Ymay be conserved because the amount of membrane BSEPC129Ycorresponded to the uptake of taurocholate into membrane vesicles. In conclusion, we demonstrated that c.386G>A (p.C129Y) in ABCB11 was a causative mutation correlating with the phenotype of patients with PFIC2, impairment of biliary excretion from hepatocytes, and the absence of canalicular BSEP expression in liver histological assessments. Mutational analysis in ABCB11 could facilitate the elucidation of the molecular mechanisms underlying the development of intrahepatic cholestasis.

Concepts: Point mutation, Cholestasis, Liver, Bile acid, Hepatology, Mutation, Progressive familial intrahepatic cholestasis, Bile