Статті в журналах: "Pfic2"

1

Kim, Kang Ho, Jong Min Choi, Feng Li, Armando Arizpe, Clavia Ruth Wooton-Kee, Sayeepriyadarshini Anakk, Sung Yun Jung, Milton J. Finegold, and David D. Moore. "Xenobiotic Nuclear Receptor Signaling Determines Molecular Pathogenesis of Progressive Familial Intrahepatic Cholestasis." Endocrinology 159, no. 6 (April 26, 2018): 2435–46. http://dx.doi.org/10.1210/en.2018-00110.

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Abstract Progressive familial intrahepatic cholestasis (PFIC) is a genetically heterogeneous disorder of bile flow disruption due to abnormal canalicular transport or impaired bile acid (BA) metabolism, causing excess BA accumulation and liver failure. We previously reported an intrahepatic cholestasis mouse model based on loss of function of both farnesoid X receptor (FXR; NR1H4) and a small heterodimer partner (SHP; NR0B2) [double knockout (DKO)], which has strong similarities to human PFIC5. We compared the pathogenesis of DKO livers with that of another intrahepatic cholestasis model,Bsep−/−, which represents human PFIC2. Both models exhibit severe hepatomegaly and hepatic BA accumulation, but DKO showed greater circulating BA and liver injury, andBsep−/− had milder phenotypes. Molecular profiling of BAs uncovered specific enrichment of cholic acid (CA)–derived BAs in DKO livers but chenodeoxycholate-derived BAs inBsep−/− livers. Transcriptomic and proteomic analysis revealed specific activation of CA synthesis and alternative basolateral BA transport in DKO but increased chenodeoxycholic acid synthesis and canalicular transport inBsep−/−. The constitutive androstane receptor (CAR)/pregnane X receptor (PXR)–CYP2B/CYP2C axis is activated in DKO livers but not in other cholestasis models. Loss of this axis inFxr:Shp:Car:Pxr quadruple knockouts blockedCyp2b/Cyp2c gene induction, impaired bilirubin conjugation/elimination, and increased liver injury. Differential CYP2B expression in DKO andBsep−/− was recapitulated in human PFIC5 and PFIC2 livers. In conclusion, loss of FXR/SHP results in distinct molecular pathogenesis and CAR/PXR activation, which promotesCyp2b/Cyp2c gene transcription and bilirubin clearance. CAR/PXR activation was not observed inBsep−/− mice or PFIC2 patients. These findings provide a deeper understanding of the heterogeneity of intrahepatic cholestasis.

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2

Kagawa, Tatehiro, Norihito Watanabe, Kaori Mochizuki, Asano Numari, Yoshie Ikeno, Johbu Itoh, Hirotoshi Tanaka, Irwin M. Arias, and Tetsuya Mine. "Phenotypic differences in PFIC2 and BRIC2 correlate with protein stability of mutant Bsep and impaired taurocholate secretion in MDCK II cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 1 (January 2008): G58—G67. http://dx.doi.org/10.1152/ajpgi.00367.2007.

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Progressive familial cholestasis (PFIC) 2 and benign recurrent intrahepatic cholestasis (BRIC) 2 are caused by mutations in the bile salt export pump (BSEP, ABCB11) gene; however, their prognosis differs. PFIC2 progresses to cirrhosis and requires liver transplantation, whereas BRIC2 is clinically benign. To identify the molecular mechanism(s) responsible for the phenotypic differences, eight PFIC2 and two BRIC2 mutations were introduced in rat Bsep, which was transfected in MDCK II cells. Taurocholate transport activity, protein expression, and subcellular distribution of these mutant proteins were studied in a polarized MDCK II monolayer. The taurocholate transport activity was approximately half of the wild-type (WT) in BRIC2 mutants (A570T and R1050C), was substantially less in two PFIC2 mutants (D482G and E297G), and was almost abolished in six other PFIC2 mutants (K461E, G982R, R1153C, R1268Q, 3767–3768insC, and R1057X). Bsep protein expression levels correlated closely with transport activity, except for R1057X. The half-life of the D482G mutant was shorter than that of the WT (1.35 h vs. 3.49 h in the mature form). BRIC2 mutants and three PFIC mutants (D482G, E297G, and R1057X) were predominantly distributed in the apical membrane. The other PFIC2 mutants remained intracellular. The R1057X mutant protein was stably expressed and trafficked to the apical membrane, suggesting that the COOH-terminal tail is required for transport activity but not for correct targeting. In conclusion, taurocholate transport function was impaired in proportion to rapid degradation of Bsep protein in the mutants, which were aligned in the following order: A570T and R1050C > D482G > E297G > K461E, G982R, R1153C, R1268Q, 3767–3768insC, and R1057X. These results may explain the phenotypic difference between BRIC2 and PFIC2.

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3

Mareux, Elodie, Martine Lapalus, Amel Ben Saad, Renaud Zelli, Mounia Lakli, Yosra Riahi, Marion Almes, et al. "In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators." International Journal of Molecular Sciences 23, no. 18 (September 15, 2022): 10758. http://dx.doi.org/10.3390/ijms231810758.

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ABCB11 is responsible for biliary bile acid secretion at the canalicular membrane of hepatocytes. Variations in the ABCB11 gene cause a spectrum of rare liver diseases. The most severe form is progressive familial intrahepatic cholestasis type 2 (PFIC2). Current medical treatments have limited efficacy. Here, we report the in vitro study of Abcb11 missense variants identified in PFIC2 patients and their functional rescue using cystic fibrosis transmembrane conductance regulator potentiators. Three ABCB11 disease-causing variations identified in PFIC2 patients (i.e., A257V, T463I and G562D) were reproduced in a plasmid encoding an Abcb11-green fluorescent protein. After transfection, the expression and localization of the variants were studied in HepG2 cells. Taurocholate transport activity and the effect of potentiators were studied in Madin–Darby canine kidney (MDCK) clones coexpressing Abcb11 and the sodium taurocholate cotransporting polypeptide (Ntcp/Slc10A1). As predicted using three-dimensional structure analysis, the three variants were expressed at the canalicular membrane but showed a defective function. Ivacaftor, GLP1837, SBC040 and SBC219 potentiators increased the bile acid transport of A257V and T463I and to a lesser extent, of G562D Abcb11 missense variants. In addition, a synergic effect was observed when ivacaftor was combined with SBC040 or SBC219. Such potentiators could represent new pharmacological approaches for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the function of the transporter.

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4

Davit-Spraul, Anne, Monique Fabre, Sophie Branchereau, Christiane Baussan, Emmanuel Gonzales, Bruno Stieger, Olivier Bernard, and Emmanuel Jacquemin. "ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): Phenotypic differences between PFIC1 and PFIC2 and natural history." Hepatology 51, no. 5 (January 28, 2010): 1645–55. http://dx.doi.org/10.1002/hep.23539.

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5

Lam, Ping, Claire L. Pearson, Carol J. Soroka, Shuhua Xu, Albert Mennone, and James L. Boyer. "Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases." American Journal of Physiology-Cell Physiology 293, no. 5 (November 2007): C1709—C1716. http://dx.doi.org/10.1152/ajpcell.00327.2007.

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Human BSEP (ABCB11) mutations are the molecular basis for at least three clinical forms of liver disease, progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), and intrahepatic cholestasis of pregnancy (ICP). To better understand the pathobiology of these disease phenotypes, we hypothesized that different mutations may cause significant differences in protein defects. Therefore we compared the effect of two PFIC2 mutations (D482G, E297G) with two BRIC2 mutations (A570T and R1050C) and one ICP mutation (N591S) with regard to the subcellular localization, maturation, and function of the rat Bsep protein. Bile salt transport was retained in all but the E297G mutant. Mutant proteins were expressed at reduced levels on the plasma membrane of transfected HEK293 cells compared with wild-type (WT) Bsep in the following order: WT > N591S > R1050C ∼ A570T ∼ E297G >> D482G. Total cell protein and surface protein expression were reduced to the same extent, suggesting that trafficking of these mutants to the plasma membrane is not impaired. All Bsep mutants accumulate in perinuclear aggresome-like structures in the presence of the proteasome inhibitor MG-132, suggesting that mutations are associated with protein instability and ubiquitin-dependent degradation. Reduced temperature, sodium butyrate, and sodium 4-phenylbutyrate enhanced the expression of the mature and cell surface D482G protein in HEK293 cells. These results suggest that the clinical phenotypes of PFIC2, BRIC2, and ICP may directly correlate with the amount of mature protein that is expressed at the cell surface and that strategies to stabilize cell surface mutant protein may be therapeutic.

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Evason, Kimberley, Kevin E. Bove, Milton J. Finegold, A. S. Knisely, Sue Rhee, Philip Rosenthal, Alexander G. Miethke, Saul J. Karpen, Linda D. Ferrell, and Grace E. Kim. "Morphologic Findings in Progressive Familial Intrahepatic Cholestasis 2 (PFIC2)." American Journal of Surgical Pathology 35, no. 5 (May 2011): 687–96. http://dx.doi.org/10.1097/pas.0b013e318212ec87.

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7

Goto, Kenji, Kohachiro Sugiyama, Tokio Sugiura, Toshihiro Ando, Fumihiko Mizutani, Koji Terabe, Kyoko Ban, and Hajime Togari. "Bile Salt Export Pump Gene Mutations in Two Japanese Patients With Progressive Familial Intrahepatic Cholestasis." Journal of Pediatric Gastroenterology and Nutrition 36, no. 5 (May 2003): 647–50. http://dx.doi.org/10.1002/j.1536-4801.2003.tb08089.x.

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ABSTRACTBackgroundIn recent years, progressive familial intrahepatic cholestasis has been classified into at least three types by genetic analysis: PFIC1, PFIC2, and MDR3. Liver transplantation is effective for treating patients with this intractable syndrome. Confirming the correct diagnosis is of paramount importance because prognosis after transplantation differs with the genetic type of the disease.MethodsSynthesis of cDNA was accomplished using RNA extracted from liver tissue of two Japanese patients with progressive familial intrahepatic cholestasis. Polymerase chain reaction was performed using 13 primer sets designed for amplification of the bile salt export pump cDNA. Direct sequencing was undertaken, and identified sequences were compared with the sequence for bile salt export pump gene registered with GenBank. In addition, gene sequences for nonprogressive familial intrahepatic cholestasis patients were analyzed.ResultsGenetic analysis of patient 1 revealed that substitutions in bile salt export pump protein sequences, namely R575X and E636G, might be the cause of the disease. In patient 2, V330X and R487H might fulfill the same role. Results of gene analysis in parents and cholestatic controls supported these conclusions.ConclusionsAbsence or presence of bile salt export protein gene mutations was confirmed as representing a useful prognostic marker for clinical course after liver transplantation.

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8

Gooijert, K. E. R., R. Havinga, H. Wolters, R. Wang, V. Ling, S. Tazuma, and H. J. Verkade. "The mechanism of increased biliary lipid secretion in mice with genetic inactivation of bile salt export pump." American Journal of Physiology-Gastrointestinal and Liver Physiology 308, no. 5 (March 1, 2015): G450—G457. http://dx.doi.org/10.1152/ajpgi.00391.2014.

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Human bile salt export pump ( BSEP) mutations underlie progressive familial intrahepatic cholestasis type 2 (PFIC2). In the PFIC2 animal model, Bsep−/−mice, biliary secretion of bile salts (BS) is decreased, but that of phospholipids (PL) and cholesterol (CH) is increased. Under physiological conditions, the biliary secretion of PL and CH is positively related (“coupled”) to that of BS. We aimed to elucidate the mechanism of increased biliary lipid secretion in Bsep−/−mice. The secretion of the BS tauro-β-muricholic acid (TβMCA) is relatively preserved in Bsep−/−mice. We infused Bsep−/−and Bsep+/+(control) mice with TβMCA in stepwise increasing dosages (150–600 nmol/min) and determined biliary bile flow, BS, PL, and CH secretion. mRNA and protein expression of relevant canalicular transporters was analyzed in livers from noninfused Bsep−/−and control mice. TβMCA infusion increased BS secretion in both Bsep−/−and control mice. The secreted PL or CH amount per BS, i.e., the “coupling,” was continuously two- to threefold higher in Bsep−/−mice ( P < 0.05). Hepatic mRNA expression of canalicular lipid transporters Mdr2, Abcg5, and Abcg8 was 45–55% higher in Bsep−/−mice (Abcg5; P < 0.05), as was canalicular Mdr2 and Abcg5 protein expression. Potential other explanations for the increased coupling of the biliary secretion of PL and CH to that of BS in Bsep−/−mice could be excluded. We conclude that the mechanism of increased biliary lipid secretion in Bsep−/−mice is based on increased expression of the responsible canalicular transporter proteins.

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9

Mushiake, S., K. Kawamoto, N. Kobayashi, Y. Etani, Y. Miyoshi, K. Ozono, T. Hasegawa, R. Sumazaki, and A. Matsui. "P0194 A CASE OF PFIC2 WHO UNDERWENT LIVING-RELATED ORTHOTOPIC LIVER TRANSPLANTATION." Journal of Pediatric Gastroenterology and Nutrition 39, Supplement 1 (June 2004): S132. http://dx.doi.org/10.1097/00005176-200406001-00318.

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10

Rumbo, Carolina, Juan P. Santilli, Julio J. Trentadue, and Gabriel E. Gondolesi. "Double Heterozygous Mutation Causing PFIC2 with Synchronic Hepatocellular Carcinomas before Two Years of Age." Transplantation 102 (July 2018): S848. http://dx.doi.org/10.1097/01.tp.0000543914.64104.9e.

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11

Liu, Teng, Ren-Xue Wang, Jun Han, Yi-Ling Qiu, Christoph H. Borchers, Victor Ling, and Jian-She Wang. "Changes in plasma bile acid profiles after partial internal biliary diversion in PFIC2 patients." Annals of Translational Medicine 8, no. 5 (March 2020): 185. http://dx.doi.org/10.21037/atm.2020.01.103.

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12

Lam, Ching-Wan, Ka-Ming Cheung, Man-Shan Tsui, Matthew Shu-Ching Yan, Ching-Yin Lee, and Sui-Fan Tong. "A patient with novel ABCB11 gene mutations with phenotypic transition between BRIC2 and PFIC2." Journal of Hepatology 44, no. 1 (January 2006): 240–42. http://dx.doi.org/10.1016/j.jhep.2005.09.013.

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13

Hayashi, Hisamitsu, Tappei Takada, Hiroshi Suzuki, Hidetaka Akita, and Yuichi Sugiyama. "Two common PFIC2 mutations are associated with the impaired membrane trafficking of BSEP/ABCB11." Hepatology 41, no. 4 (2005): 916–24. http://dx.doi.org/10.1002/hep.20627.

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14

Sheridan, Rachel M., Anita Gupta, Alexander Miethke, Alexander S. Knisely, and Kevin E. Bove. "Multiple Dysplastic Liver Nodules in PFIC2 Underscore Risk for Neoplasia Associated With Functional BSEP Deficiency." American Journal of Surgical Pathology 36, no. 5 (May 2012): 785–86. http://dx.doi.org/10.1097/pas.0b013e3182500c35.

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15

Sohail, Muhammad Imran, Yaprak Dönmez-Cakil, Dániel Szöllősi, Thomas Stockner, and Peter Chiba. "The Bile Salt Export Pump: Molecular Structure, Study Models and Small-Molecule Drugs for the Treatment of Inherited BSEP Deficiencies." International Journal of Molecular Sciences 22, no. 2 (January 14, 2021): 784. http://dx.doi.org/10.3390/ijms22020784.

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The bile salt export pump (BSEP/ABCB11) is responsible for the transport of bile salts from hepatocytes into bile canaliculi. Malfunction of this transporter results in progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2) and intrahepatic cholestasis of pregnancy (ICP). Over the past few years, several small molecular weight compounds have been identified, which hold the potential to treat these genetic diseases (chaperones and potentiators). As the treatment response is mutation-specific, genetic analysis of the patients and their families is required. Furthermore, some of the mutations are refractory to therapy, with the only remaining treatment option being liver transplantation. In this review, we will focus on the molecular structure of ABCB11, reported mutations involved in cholestasis and current treatment options for inherited BSEP deficiencies.

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Ananthanarayanan, Meenakshisundaram, and Yanfeng Li. "PFIC2 and ethnicity-specific bile salt export pump (BSEP, ABCB11) mutations: where do we go from here?" Liver International 30, no. 6 (March 8, 2010): 777–79. http://dx.doi.org/10.1111/j.1478-3231.2010.02227.x.

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17

KAGAWA, T., K. MOCHIZUKI, M. HARRIS, N. WATANABE, T. MINE, S. MATSUZAKI, and I. ARIAS. "475 Bile acid transport activity and intracellular distribution of PFIC2 mutants in MDCKII cells coexpressing NTCP and BSEP." Hepatology 38 (2003): 389. http://dx.doi.org/10.1016/s0270-9139(03)80517-7.

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Bosma, Piter J., Marius Wits, and Ronald P. J. Oude-Elferink. "Gene Therapy for Progressive Familial Intrahepatic Cholestasis: Current Progress and Future Prospects." International Journal of Molecular Sciences 22, no. 1 (December 29, 2020): 273. http://dx.doi.org/10.3390/ijms22010273.

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Progressive Familial Intrahepatic Cholestasis (PFIC) are inherited severe liver disorders presenting early in life, with high serum bile salt and bilirubin levels. Six types have been reported, two of these are caused by deficiency of an ABC transporter; ABCB11 (bile salt export pump) in type 2; ABCB4 (phosphatidylcholine floppase) in type 3. In addition, ABCB11 function is affected in 3 other types of PFIC. A lack of effective treatment makes a liver transplantation necessary in most patients. In view of long-term adverse effects, for instance due to life-long immune suppression needed to prevent organ rejection, gene therapy could be a preferable approach, as supported by proof of concept in animal models for PFIC3. This review discusses the feasibility of gene therapy as an alternative for liver transplantation for all forms of PFIC based on their pathological mechanism. Conclusion: Using presently available gene therapy vectors, major hurdles need to be overcome to make gene therapy for all types of PFIC a reality.

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Hartleb, M., M. Jirsa, M. Zindr, J. Pawlowska, I. Jankowska, and J. Cielecka-Kuszyk. "Slowly Developing Progressive Familial Intrahepatic Cholestasis Type 2 (PFIC2) in an Adolescent with Cholelithiasis, Gilbert's Syndrome and Chronic Calcifying Pancreatitis." Open Gastroenterology Journal 2, no. 1 (June 3, 2008): 38–40. http://dx.doi.org/10.2174/1874259900802010038.

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Gül-Klein, Safak, Robert Öllinger, Moritz Schmelzle, Johann Pratschke, and Wenzel Schöning. "Long-Term Outcome after Liver Transplantation for Progressive Familial Intrahepatic Cholestasis." Medicina 57, no. 8 (August 22, 2021): 854. http://dx.doi.org/10.3390/medicina57080854.

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Background and Objectives: Progressive familial intrahepatic cholestasis (PFIC) is a rare autosomal recessive inherited disease divided into five types (PFIC 1-5). Characteristic for all types is early disease onset, which may result clinically in portal hypertension, fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic manifestations. Liver transplantation (LT) is the only successful treatment approach. Our aim is to present the good long-term outcomes after liver transplantation for PFIC1, focusing on liver function as well as the occurrence of extrahepatic manifestation after liver transplantation. Materials and Methods: A total of seven pediatric patients with PFIC1 underwent liver transplantation between January 1999 and September 2019 at the Department of Surgery, Charité Campus Virchow Klinikum and Charité Campus Mitte of Charité-Universitätsmedizin Berlin. Long-term follow-up data were collected on all patients, specifically considering liver function and extrahepatic manifestations. Results: Seven (3.2%) recipients were found from a cohort of 219 pediatric patients. Two of the seven patients had multilocular HCC in cirrhosis. Disease recurrence or graft loss did not occur in any patient. Two patients (male, siblings) had persistently elevated liver parameters but showed excellent liver function. Patient and graft survival during long-term follow-up was 100%, and no severe extrahepatic manifestations requiring hospitalization or surgery occurred. We noted a low complication rate during long-term follow-up and excellent patient outcome. Conclusions: PFIC1 long-term follow-up after LT shows promising results for this rare disease. In particular, the clinical relevance of extrahepatic manifestations seems acceptable, and graft function seems to be barely affected. Further multicenter studies are needed to analyze the clinically inhomogeneous presentation and to better understand the courses after LT.

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Küçükçongar Yavaş, Aynur, Büşra Çavdarlı, Özlem Ünal Uzun, Ayşen Uncuoğlu, and Mehmet Gündüz. "A novel etiologic factor of highly elevated cholestanol levels: progressive familial intrahepatic cholestasis." Journal of Pediatric Endocrinology and Metabolism 33, no. 5 (May 26, 2020): 665–69. http://dx.doi.org/10.1515/jpem-2019-0314.

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AbstractBackgroundProgressive familial intrahepatic cholestasis type 3 (PFIC3) is an uncommon cholestatic liver disease caused by mutations in the ATP binding cassette subfamily B member 4 (ABCB4) gene. Although PFIC3 is frequently identified in childhood, ABCB4 disease-causing alleles have been described in adults affected by intrahepatic cholestasis of pregnancy, hormone-induced cholestasis, low-phospholipid-associated cholelithiasis syndrome or juvenile cholelithiasis, cholangiocarcinoma and in sporadic forms of primary biliary cirrhosis. Cholestanol is a biomarker which is elevated especially in cerebrotendinous xanthomatosis and rarely in primary biliary cirrhosis (PBC) and Niemann Pick type C.Case presentationHere we report a Turkish patient with compound heterozygous mutations in the ABCB4 gene, who has hepatosplenomegaly, low level of high-density lipoprotein, cholestasis and high level of cholestanol.ConclusionThis is the first PFIC3 case with a high cholestanol level described in the literature. There are very few diseases linked to increased cholestanol levels, two of which are CTX and PBC. From this case, we can conclude that a high cholestanol level might be another indicator of PFIC type 3.

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Atimati, Anthony Oyovwikigho, and Paul Ikhurionan. "A suspected case of Progressive Familial Intra-hepatic Cholestasis in a Six-Year-Old Nigerian Child." Annals of Health Research 5, no. 1 (June 1, 2019): 135–40. http://dx.doi.org/10.30442/ahr.0501-14-44.

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Progressive Familial Intra-hepatic Cholestasis (PFIC) is a group of heterogeneous, autosomal recessive disorders characterized by cholestasis, jaundice and mutilating pruritus, mostly in infancy. The incidence of PFIC ranges from 1:50,000 to 1:100,000. There are three subtypes; Types 1 and 2 typically present in the neonatal period and early infancy while Type 3 can present in early infancy, childhood or adolescence. This report is about a 6-year old Nigerian girl who presented with jaundice and severe pruritus of one-month duration and abdominal pain of a week duration. The symptoms were preceded by ingestion of Atropine meant for ocular examination two days earlier. She was well-nourished, deeply icteric, had generalized healing scratch marks and hepatomegaly. The laboratory findings included conjugated hyperbilirubinaemia, moderately elevated liver transaminases and Gamma-Glutamyltransferase enzymes. She was managed for PFIC3 using oral ursodeoxycholic acid with complete resolution of the disease.

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Centenari, C., M. Fabre, M. Sciveres, E. Jacquemin, and G. Maggiore. "CO18 RELAPSING FEATURES OF BILE SALT EXPORT PUMP (BSEP) DEFICIENCY IN A PATIENT SUCCESSFULLY TRANSPLANTED FOR PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS TYPE 2 (PFIC2)." Digestive and Liver Disease 42 (October 2010): S329. http://dx.doi.org/10.1016/s1590-8658(10)60561-0.

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Maggiore, G., M. Fabre, M. Sciveres, M. J. Redon, B. Stieger, A. Davit-Spraul, and E. Jaquemin. "1128 RELAPSING FEATURES OF BILE SALT EXPORT PUMP (BSEP) DEFICIENCY IN TWO PATIENTS SUCCESSFULLY TRANSPLANTED FOR PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS TYPE 2 (PFIC2)." Journal of Hepatology 52 (April 2010): S435. http://dx.doi.org/10.1016/s0168-8278(10)61129-4.

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Sticova, Eva, Milan Jirsa, and Joanna Pawłowska. "New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications." Canadian Journal of Gastroenterology and Hepatology 2018 (July 26, 2018): 1–12. http://dx.doi.org/10.1155/2018/2313675.

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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). Cases have been reported of initially benign episodic cholestasis that subsequently transitions to a persistent progressive form of the disease. Therefore, BRIC and PFIC seem to represent two extremes of a continuous spectrum of phenotypes that comprise one disease. Thus far, five representatives of PFIC (named PFIC1-5) caused by pathogenic mutations present in both alleles ofATP8B1,ABCB11,ABCB4,TJP2,andNR1H4have been described. In addition to familial intrahepatic cholestasis, partial defects inATP8B1,ABCB11,andABCB4predispose patients to drug-induced cholestasis and intrahepatic cholestasis in pregnancy. This review summarises the current knowledge of the clinical manifestations, genetics, and molecular mechanisms of these diseases and briefly outlines the therapeutic options, both conservative and invasive, with an outlook for future personalised therapeutic strategies.

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Gonzales, E., B. Grosse, M. J. Redon, I. Friteau, A. Davit-Spraul, M. Fabre, and E. Jacquemin. "Allo-immunisation anti-BSEP (Bile Salt Export Pump) post-transplantation hépatique pour cholestase intrahépatique progressive familiale de type 2 (PFIC2) : une complication sous-estimée ?" Archives de Pédiatrie 18, no. 12 (December 2011): 1326. http://dx.doi.org/10.1016/j.arcped.2011.09.015.

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Takahashi, Atsushi, Makoto Hasegawa, Ryo Sumazaki, Makoto Suzuki, Fumiaki Toki, Taketoshi Suehiro, Kazumichi Onigata, et al. "Gradual improvement of liver function after administration of ursodeoxycholic acid in an infant with a novel ABCB11 gene mutation with phenotypic continuum between BRIC2 and PFIC2." European Journal of Gastroenterology & Hepatology 19, no. 11 (November 2007): 942–46. http://dx.doi.org/10.1097/meg.0b013e3282ef4795.

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Wong, Lee-Jun C., David Dimmock, Michael T. Geraghty, Richard Quan, Uta Lichter-Konecki, Jing Wang, Ellen K. Brundage, Fernando Scaglia, and A. Craig Chinault. "Utility of Oligonucleotide Array–Based Comparative Genomic Hybridization for Detection of Target Gene Deletions." Clinical Chemistry 54, no. 7 (July 1, 2008): 1141–48. http://dx.doi.org/10.1373/clinchem.2008.103721.

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Abstract Background: Direct DNA sequencing is the primary clinical technique for identifying mutations in human disease, but sequencing often does not detect intragenic or whole-gene deletions. Oligonucleotide array–based comparative genomic hybridization (CGH) is currently in clinical use to detect major changes in chromosomal copy number. Methods: A custom oligonucleotide-based microarray was constructed to provide high-density coverage of an initial set of 130 nuclear genes involved in the pathogenesis of metabolic and mitochondrial disorders. Standard array CGH procedures were used to test patient DNA samples for regions of copy number change. Sequencing of regions of predicted breakpoints in genomic DNA and PCR analysis were used to confirm oligonucleotide array CGH data. Results: Oligonucleotide array CGH identified intragenic exonic deletions in 2 cases: a heterozygous single-exon deletion of 4.5 kb in the SLC25A13 gene [solute carrier family 25, member 13 (citrin)] in an individual with citrin deficiency and a homozygous 10.5-kb deletion of exons 13–17 in the ABCB11 gene [PFIC2, ATP-binding cassette, sub-family B (MDR/TAP), member 11] in a patient with progressive familial intrahepatic cholestasis. In 2 females with OTC deficiency, we also found 2 large heterozygous deletions of approximately 7.4 Mb and 9 Mb on the short arm of the X chromosome extending from sequences telomeric to the DMD gene [dystrophin (muscular dystrophy, Duchenne and Becker types)] to sequences within or centromeric to the OTC gene (ornithine carbamoyltransferase). Conclusions: These examples illustrate the successful use of custom oligonucleotide arrays to detect either whole-gene deletions or intragenic exonic deletions. This technology may be particularly useful as a complementary diagnostic test in the context of a recessive disease when only one mutant allele is found by sequencing.

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Ayub, Tanzeela, and Michael Pereira. "Personal Tax Planning: What Is at Stake for US Beneficiaries of Canadian Estates." Canadian Tax Journal/Revue fiscale canadienne 70, no. 2 (July 2022): 433–50. http://dx.doi.org/10.32721/ctj.2022.70.2.ptp.

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This article provides an overview of US tax issues that foreign estates with US individual beneficiaries may face. While families may implement planning strategies to effectively manage the transfer of wealth from a domestic perspective, US tax laws can create complex problems and at times adverse consequences for the unwary. The main goal of this article is to identify the general US tax considerations for a foreign estate, including the potential application of the anti-tax-deferral rules governing passive foreign investment companies (PFICs) and controlled foreign corporations (CFCs). A case study is included to illustrate how these rules may apply to US beneficiaries of a Canadian estate if the estate holds shares of a PFIC or a CFC. The article also offers a few guidelines and strategies to reduce potentially adverse US consequences and to mitigate some of the tax risks.

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Martínez-García, Javier, Angie Molina, Gloria González-Aseguinolaza, Nicholas D. Weber, and Cristian Smerdou. "Gene Therapy for Acquired and Genetic Cholestasis." Biomedicines 10, no. 6 (May 26, 2022): 1238. http://dx.doi.org/10.3390/biomedicines10061238.

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Cholestatic diseases can be caused by the dysfunction of transporters involved in hepatobiliary circulation. Although pharmacological treatments constitute the current standard of care for these diseases, none are curative, with liver transplantation being the only long-term solution for severe cholestasis, albeit with many disadvantages. Liver-directed gene therapy has shown promising results in clinical trials for genetic diseases, and it could constitute a potential new therapeutic approach for cholestatic diseases. Many preclinical gene therapy studies have shown positive results in animal models of both acquired and genetic cholestasis. The delivery of genes that reduce apoptosis or fibrosis or improve bile flow has shown therapeutic effects in rodents in which cholestasis was induced by drugs or bile duct ligation. Most studies targeting inherited cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), have focused on supplementing a correct version of a mutated gene to the liver using viral or non-viral vectors in order to achieve expression of the therapeutic protein. These strategies have generated promising results in treating PFIC3 in mouse models of the disease. However, important challenges remain in translating this therapy to the clinic, as well as in developing gene therapy strategies for other types of acquired and genetic cholestasis.

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Alsohaibani, Fahad I., Musthafa C. Peedikayil, Abdulaziz F. Alfadley, Mohamed K. Aboueissa, Faisal A. Abaalkhail, and Saleh A. Alqahtani. "Progressive Familial Intrahepatic Cholestasis: A Descriptive Study in a Tertiary Care Center." International Journal of Hepatology 2023 (July 20, 2023): 1–8. http://dx.doi.org/10.1155/2023/1960152.

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Background. Progressive familial intrahepatic cholestasis (PFIC) is a rare genetic disorder that results from defective mechanisms of bile secretion. We aim to describe different types of PFIC and their clinical features, treatment modalities, and outcomes in Saudi Arabia. Patients and Methods. This is a retrospective study of all patients diagnosed with PFIC at King Faisal Specialist Hospital and Research Center in Riyadh from January 1, 2002, to December 31, 2021. All relevant information was collected from patient charts and transferred into the REDcap® database for statistical analysis. Results. A total of 79 patients were identified with PFIC, and PFIC type 3 was the most common (59.5%), followed by PFIC type 2 (34.2%), PFIC type 1 (5.1%), and PFIC type 4 (1.3%). Males and females were affected in 54.4% and 45.6%, respectively. Mutations in ATP8B1, ABCB11, and ABCB4 genes were observed in PFIC type 1, PFIC type 2, and PFIC type 3, and loss of function in a variant of TJP2 was detected in PFIC type 4, respectively. A total of 51 (64.6%) patients underwent liver transplantation: three patients (3/4) with PFIC type 1 (75%), twenty patients (20/27) with PFIC type 2 (74.1%), twenty-seven patients (27/47) with PFIC type 3 (57.4%), and one patient with PFIC type 4 (100%). The mean duration of disease before transplantation was 53.9 ± 67 months with a median of 30 months. Following liver transplantation, symptomatic control was achieved in 47 patients (92.2%). Recurrence after transplantation occurred in 4 patients (7.8%) within an average of 22.5 months and a median of 17 months. Conclusion. PFIC is considered a rare disorder in Saudi Arabia; however, early recognition of the disease is important for appropriate management and early referral for liver transplantation evaluation. The overall rate of liver transplantation in our cohort was 64.6% with an excellent five-year survival rate.

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Reddy, Saigopala, Nathan Fleishman, Katherine Dempsey, Edwin Ferren, Michal Kamionek, and Vani V. Gopalareddy. "Progressive Familial Intrahepatic Cholestasis-2 Mimicking Non-accidental Injury." ACG Case Reports Journal 11, no. 4 (April 2024): e01312. http://dx.doi.org/10.14309/crj.0000000000001312.

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ABSTRACT Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of disorders characterized by defective secretion of bile acids or transport defects resulting in progressive cholestasis. These disorders usually present during infancy or childhood and are associated with progressive liver disease. PFIC is estimated to affect 1 in 50,000–100,000 births, with PFIC-2 representing half of PFIC cases. PFIC-2 presents with hepatosplenomegaly, jaundice, pruritus, fat-soluble vitamin deficiencies, and growth failure. Laboratory findings include low/normal gamma glutamyl transpeptidase levels and elevated bilirubin, transaminases, and alpha-fetoprotein levels. In this report, we present a case of PFIC-2 presenting with severe coagulopathy, bruising, subcutaneous hematomas, and acute-onset anemia.

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Zampaglione, Lucia, Anne-Laure Rougemont, Laura Rubbia-Brandt, Marc Abramowicz, Michel Guipponi, Enrica Marchionni, McLin Valerie, and Nicolas Goossens. "Variable Intrafamilial Expression of ABCB4 Disease." ACG Case Reports Journal 10, no. 8 (August 2023): e01113. http://dx.doi.org/10.14309/crj.0000000000001113.

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ABSTRACT Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare cholestatic liver disease with autosomal recessive inheritance caused by mutations in the ABCB4 gene. The clinical presentation of PFIC3 varies significantly, displaying incomplete penetrance without clear genotype-phenotype correlations. As such, the suitability of living-related liver donation for children with advanced disease has been questioned. We report here the long-term follow-up of a patient with PFIC3 resulting in decompensated cirrhosis at 11 years who successfully underwent living donor liver transplantation from his father, who carried the same ABCB4 homozygous mutation.

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Hüpper, Maria Noelle, Judith Pichler, Wolf-Dietrich Huber, Andreas Heilos, Rebecca Schaup, Martin Metzelder, and Sophie Langer. "Surgical versus Medical Management of Progressive Familial Intrahepatic Cholestasis—Case Compilation and Review of the Literature." Children 10, no. 6 (May 26, 2023): 949. http://dx.doi.org/10.3390/children10060949.

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(1) Background: Progressive familial intrahepatic cholestasis (PFIC) is a rare cause of liver failure. Surgical biliary diversion (SBD) and ileal bile salt inhibitors (IBAT) can delay or prevent liver transplantation (LTX). A comparison of the two methodologies in the literature is lacking. The combination has not been investigated. (2) Methods: We performed a literature survey on medical and surgical treatments for PFIC and reviewed the charts of our patients with PFIC of a tertiary hospital. The end points of our analysis were a decrease in serum bile acid (sBA) levels, reduction of pruritus and delay or avoidance of (LTX). (3) Results: We included 17 case series on SBD with more than 5 patients and a total of 536 patients. External or internal SBD, either conventional or minimally invasive, can reduce pruritus and sBA, but not all PFIC types are suitable for SBD. Six publications described the use of two types of IBAT in PFIC with a total of 118 patients. Treatment response was dependent on genetic type and subtype. Patients with PFIC 2 (nt-BSEP) showed the best response to treatment. Four out of eleven PFIC patients underwent SBD at our centre, with two currently receiving IBAT. (4) Conclusions: Limited data on IBAT in selected patients with PFIC show safety and effectiveness, although surgical methods should still be considered as a successful bridging procedure. Further studies to evaluate a possible combination of IBAT and SBD in PFIC are warranted and treatment decision should be discussed in an interdisciplinary board.

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Jansen, Peter LM, and Michael Müller. "Genetic Cholestasis: Lessons from the Molecular Physiology of Bile Formation." Canadian Journal of Gastroenterology 14, no. 3 (2000): 233–38. http://dx.doi.org/10.1155/2000/514172.

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Progressive familial intrahepatic cholestasis (PFIC) is a group of severe genetic cholestatic liver diseases of early life. PFIC types 1 and 2 are characterized by cholestasis and a low to normal serum gamma-glutamyltransferase (GGT) activity, whereas in PFIC type 3, the serum GGT activity is elevated. PFIC types 1 and 2 occur due to mutations in loci at chromosome 18 and chromosome 2, respectively. The pathophysiology of PFIC type 1 is not well understood. PFIC types 2 and 3 are caused by transport defects in the liver affecting the hepatobiliary secretion of bile acids and phospholipids, respectively. Benign recurrent intrahepatic cholestasis (BRIC) is linked to a mutation in the same familial intrahepatic cholestasis 1 locus at chromosome 18. Defects of bile acid synthesis may be difficult to differentiate from these transport defects.Intrahepatic cholestasis of pregnancy (ICP) appears to be related to these cholestatic diseases. For example, heterozygosity in families with PFIC type 3 is associated with ICP, but ICP has also been reported in families with BRIC.In Dubin-Johnson syndrome there is no cholestasis; only the hepatobiliary transport of conjugated bilirubin is affected. This, therefore, is a mild disease, and patients have a normal lifespan.

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Qi, Yue, Chun Li Zheng, and Yong Huan Yang. "Aerobic Degradation of Nitrobenzene by Immobilization of Streptomyces albidoflavus in Polyurethane Foam." Advanced Materials Research 610-613 (December 2012): 1845–52. http://dx.doi.org/10.4028/www.scientific.net/amr.610-613.1845.

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Streptomyces albidoflavus Z2 was immobilized in polyurethane foam and its ability to degrade nitrobenzene was investigated. Batch experiments showed that polyurethane-foam-immobilized cells (PFIC) possessed a higher degradation capacity. Compared to freely suspended cells (FSC), PFIC degraded nitrobenzene more efficiently under alkali and acid conditions, as well as higher temperature. Kinetic of nitrobenzene degradation by PFIC was well described by Andrews inhibition equation, which demonstrated that PFIC tolerated higher concentration of nitrobenzene than FSC and degraded nitrobenzene at a quicker speed. Moreover, in the presence of NaCl (≤7%, w/v), phenol (≤250 mg L-1) and aniline (100 mg L-1), respectively, PFIC exhibited better tolerance toward salinity and toxic chemicals than FSC. Therefore immobilization could be a promising method for treating nitrobenzene industrial wastewater.

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Hang, Chenyue, Yijie Jin, Yi Luo, Mingxuan Feng, Tao Zhou, Jianjun Zhu, Jianjun Zhang, Yuan Liu, and Qiang Xia. "Long-Term Results of Pediatric Liver Transplantation for Progressive Familial Intrahepatic Cholestasis." Journal of Clinical Medicine 11, no. 16 (August 11, 2022): 4684. http://dx.doi.org/10.3390/jcm11164684.

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We analyzed the long-term survival rate and development of progressive familial intrahepatic cholestasis (PFIC) patients after liver transplantation (LT). From October 2007 to May 2019, 41 patients were diagnosed as PFIC (type I-III) and received LT in Ren Ji Hospital due to end-stage liver diseases. The median age at LT was 2.93 years, with 75.6% of patients receiving living donor liver transplantation (LDLT). The 5- and 10-year patient survival rates after LT were 92.7% and 92.7%, respectively, and no difference was found among the three subtypes of PFIC. Two PFIC type II patients received re-transplantation due to vascular complications. Liver function and bile acid metabolism returned to normal levels in all living recipients. Catch-up growth was recorded as the height and weight Z scores increased from −2.53 and −1.54 to −0.55 and −0.27 with a median follow-up time of 5.55 years. Improved psychomotor ability and age-appropriate study ability was also observed. A total of 72.4% of school-aged recipients exhibited average academic performance. Diarrhea was reported in all PFIC type I recipients but resolved after resin absorptive treatment. However, allograft steatosis occurred in one PFIC type I patient and exhibited a “remission–relapse circle” under the treatment of cholestyramine. In conclusion, LT is an effective treatment for end-stage PFIC patients with encouraging long-term survival rate and development. However, allograft steatosis should be closely monitored in PFIC type I patients even if diarrhea has been well treated.

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Kavallar, Anna M., Franka Messner, Stefan Scheidl, Rupert Oberhuber, Stefan Schneeberger, Denise Aldrian, Valeria Berchtold, et al. "Internal Ileal Diversion as Treatment for Progressive Familial Intrahepatic Cholestasis Type 1-Associated Graft Inflammation and Steatosis after Liver Transplantation." Children 9, no. 12 (December 14, 2022): 1964. http://dx.doi.org/10.3390/children9121964.

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Background: Progressive Familial Intrahepatic cholestasis type I (PFIC1) is a rare congenital hepatopathy causing cholestasis with progressive liver disease. Surgical interruption of the enterohepatic circulation, e.g., surgical biliary diversion (SBD) can slow down development of liver cirrhosis. Eventually, end stage liver disease necessitates liver transplantation (LT). PFIC1 patients might develop diarrhea, graft steatosis and inflammation after LT. SBD after LT was shown to be effective in the alleviation of liver steatosis and graft injury. Case report: Three PFIC1 patients received LT at the ages of two, two and a half and five years. Shortly after LT diarrhea and graft steatosis was recognized, SBD to the terminal ileum was opted to prevent risk for ascending cholangitis. After SBD, inflammation and steatosis was found to be reduced to resolved, as seen by liver biochemistry and ultrasounds. Diarrhea was reported unchanged. Conclusion: We present three PFIC1 cases for whom SBD to the terminal ileum successfully helped to resolve graft inflammation and steatosis.

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Mirza, Nida, Smita Malhotra, and Anupam Sibal. "A Novel Compound Heterozygous Mutation in ABCB4 Gene Leading to Cholelithiasis, Progressive Familial Intrahepatic Cholestasis (Type 3), and Cirrhosis in a Child." Journal of Child Science 10, no. 01 (January 2020): e134-e136. http://dx.doi.org/10.1055/s-0040-1717106.

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AbstractProgressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive disorders of childhood which presents with intermittent or progressive episodes of cholestasis, with jaundice and pruritus as most common presenting symptoms. PFIC type 3 occurs due to mutations in the ABCB4 gene, mutation in this gene has wide spectrum of features which include intrahepatic stones, cholelithiasis, PFIC type 3, and intrahepatic cholestasis of pregnancy. Here, we are reporting a peculiar case of young male adolescent with novel variant compound heterozygote missense mutation in ABCB4 gene who had gall stone as initial symptom, followed by symptoms of PFIC and eventually decompensated chronic liver disease.

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Gómez-Mellado, Valentina E., Jung-Chin Chang, Kam S. Ho-Mok, Carmen Bernardino Morcillo, Remco H. J. Kersten, Ronald P. J. Oude Elferink, Arthur J. Verhoeven, and Coen C. Paulusma. "ATP8B1 Deficiency Results in Elevated Mitochondrial Phosphatidylethanolamine Levels and Increased Mitochondrial Oxidative Phosphorylation in Human Hepatoma Cells." International Journal of Molecular Sciences 23, no. 20 (October 15, 2022): 12344. http://dx.doi.org/10.3390/ijms232012344.

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ATP8B1 is a phospholipid flippase that is deficient in patients with progressive familial intrahepatic cholestasis type 1 (PFIC1). PFIC1 patients suffer from severe liver disease but also present with dyslipidemia, including low plasma cholesterol, of yet unknown etiology. Here we show that ATP8B1 knockdown in HepG2 cells leads to a strong increase in the mitochondrial oxidative phosphorylation (OXPHOS) without a change in glycolysis. The enhanced OXPHOS coincides with elevated low-density lipoprotein receptor protein and increased mitochondrial fragmentation and phosphatidylethanolamine levels. Furthermore, expression of phosphatidylethanolamine N-methyltransferase, an enzyme that catalyzes the conversion of mitochondrial-derived phosphatidylethanolamine to phosphatidylcholine, was reduced in ATP8B1 knockdown cells. We conclude that ATP8B1 deficiency results in elevated mitochondrial PE levels that stimulate mitochondrial OXPHOS. The increased OXPHOS leads to elevated LDLR levels, which provides a possible explanation for the reduced plasma cholesterol levels in PFIC1 disease.

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Dimopoulou, Anastasia, Dimitra Dimopoulou, Nikolaos Zavras, Eleni Kontaki, George Vaos, and Smaragdi Fessatou. "Ileal bypass for pruritus relief in a 3-year-old boy with advanced progressive familial intrahepatic cholestasis: how effective is it?" Folia Medica 65, no. 1 (February 28, 2023): 183–85. http://dx.doi.org/10.3897/folmed.65.e73628.

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Анотація:

Progressive familial intrahepatic cholestasis (PFIC) is a group of liver disorders that manifest in early childhood with cholestasis and pruritus resulting progressively in liver failure. We present a case of a 3-year-old boy with advanced PFIC from refractory pruritus. In order to offer an effective treatment of pruritus, our patient underwent ileal bypass and after a 2-month period free of symptoms, unexpectedly relapsed after a Rota viral infection. Finally, the child underwent orthotopic liver transplantation. Patients with advanced PFIC do not seem to benefit from nontransplant invasive interventions regarding the relief of pruritus.

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Abi Radi Abou Jaoudeh, Rasha, Brendan McCleary, and Kadakkal Radhakrishnan. "Low Gamma-Glutamyl Transferase Cholestasis in a Patient With X-Linked Myotubular Myopathy and Crohn's Disease." ACG Case Reports Journal 11, no. 1 (January 2024): e01240. http://dx.doi.org/10.14309/crj.0000000000001240.

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ABSTRACT X-linked myotubular myopathy (XLMTM) is a neuromuscular disorder manifesting at birth with hypotonia and respiratory distress. We describe the XLMTM case presenting at birth who developed normal gamma-glutamyl transferase cholestasis at 1 year of age. He was also diagnosed with Crohn's disease 4 years later. His cholestasis could be attributed to progressive familial intrahepatic cholestasis (PFIC) or primary sclerosing cholangitis in the setting of Crohn's disease. However, genetic testing ruled-out PFIC, and his radiographic and liver biopsy findings were not suggestive of primary sclerosing cholangitis. We believe that this cholestasis is related to XLMTM leading to a PFIC-like state.

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Tibesar, Eric, Christine Karwowski, Paula Hertel, Ann Scheimann, and Wikrom Karnsakul. "Two Cases of Progressive Familial Intrahepatic Cholestasis Type 2 Presenting with Severe Coagulopathy without Jaundice." Case Reports in Pediatrics 2014 (2014): 1–4. http://dx.doi.org/10.1155/2014/185923.

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Анотація:

Progressive familial intrahepatic cholestasis (PFIC) type 2 results from a mutation in the bile salt exporter pump, impeding bile acid transport. Patients usually present with jaundice, pruritus, growth failure, and fat soluble vitamin deficiencies. We present two patients diagnosed with PFIC type 2 due to severe coagulopathy and bleeding without jaundice.

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Saleem, Komal, Qingbo Cui, Tahir Zaib, Siqi Zhu, Qian Qin, Yusi Wang, Jinxi Dam, et al. "Evaluation of a Novel Missense Mutation in ABCB4 Gene Causing Progressive Familial Intrahepatic Cholestasis Type 3." Disease Markers 2020 (June 16, 2020): 1–10. http://dx.doi.org/10.1155/2020/6292818.

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Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a hepatic disorder occurring predominantly in childhood and is difficult to diagnose. PFIC3, being a rare autosomal recessive disease, is caused by genetic mutations in both alleles of ABCB4, resulting in the disruption of the bile secretory pathway. The identification of pathogenic effects resulting from different mutations in ABCB4 is the key to revealing the internal cause of disease. These mutations cause truncation, instability, misfolding, and impaired trafficking of the MDR3 protein. Here, we reported a girl, with a history of intrahepatic cholestasis and progressive liver cirrhosis, with an elevated gamma-glutamyltransferase level. Genetic screening via whole exome sequencing found a novel homozygous missense mutation ABCB4:c.1195G>C:p.V399L, and the patient was diagnosed with PFIC3. Various computational tools predicted the variant to be deleterious and evolutionary conserved. For functional characterization studies, plasmids, encoding ABCB4 wild-type and selected established mutant constructs, were expressed in human embryonic kidney (HEK-293T) and hepatocellular carcinoma (HepG2) cells. In vitro expression analysis observed a reduced expression of mutant protein compared to wild-type protein. We found that ABCB4 wild type was localized at the apical canalicular membrane, while mutant p.V399L showed intracellular retention. Intracellular mistrafficking proteins usually undergo proteasomal or lysosomal degradation. We found that after treatment with proteasomal inhibitor MG132 and lysosomal inhibitor bafilomycin A1, MDR3 expression of V399L was significantly increased. A decrease in MDR3 expression of mutant V399L protein may be a result of proteasomal or lysosomal degradation. Pharmacological modulator cyclosporin A and intracellular low temperature (30°C) treatment significantly rescued both the folding defect and the active maturation of the mutant protein. Our study identified a novel pathogenic mutation which expanded the mutational spectrum of the ABCB4 gene and may contribute to understanding the molecular basis of PFIC3. Therefore, genetic screening plays a conclusive role in the diagnosis of rare heterogenic disorders like PFIC3.

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Сергиенко, Е. Н., О. Н. Романова, А. А. Ключарева, А. В. Сукало, С. К. Клецкий, А. М. Кашкан, Л. И. Кастюкевич, and Е. П. Михаленко. "Clinical Case of the Byler’s Syndrome in a Child." Педиатрия. Восточная Европа, no. 4 (January 24, 2021): 578–88. http://dx.doi.org/10.34883/pi.2020.8.4.009.

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Прогрессирующий семейный внутрипеченочный холестаз (ПСВХ) – это редкая форма наследственной патологии печени, которая обусловлена дефектами секреции желчи, непрерывно прогрессирует и способствует формированию фиброза и цирроза печени. Частота данной патологии составляет 1 на 50 000–100 000 новорожденных. Начинается заболевание, как правило, в младенчестве, но прогрессирование процесса может быть и в подростковом возрасте. Выделяют три типа ПСВХ: при ПСВХ 1-го и 2-го типа нарушается секреция солей желчных кислот, а при ПСВХ 3-го типа изменена экскреция фосфолипидов. Диагностика основана на клинических проявлениях, результатах холангиографии, УЗИ, гистологии печени и специфических тестах. Терапия урсодезоксихолевой кислотой должна быть начата во всех случаях для предотвращения прогрессирования повреждения печени. Тем не менее, большинство пациентов с ПСВХ в конечном итоге являются кандидатами на трансплантацию печени. Таким образом, ранняя диагностика ПСВХ позволяет своевременно определять тактику ведения пациентов с целью предотвращения необратимого исхода заболевания. Progressive familial intrahepatic cholestasis (PFIC) is a rare form of hereditary diseases of the liver, which (due to defects in bile secretion) constantly progresses and promotes the formation of liver fibrosis and cirrhosis. Its incidence is estimated as 1 to 50.000–100.000 newborns. The onset of the disease is generally in infancy, but the diagnosis may be delayed until adolescence. Three types of PFIC are distinguished: in PFIC types I, II, the secretion of bile salts deteriorates, whereas in PFIC type III, the excretion of phospholipids is altered. Diagnosis is based on clinical manifestations,cholangiography, liver ultrasonography, and histology, as well as on specific tests. Ursodeoxycholic acid therapy should be initiated in all patients to prevent the progression of liver damage. However, the majority of PFIC patients are ultimately candidates for liver transplantation. Thus, early diagnosis of PFIC allows timely determination of patient management tactics in order to prevent an irreversible outcome of the disease.

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Utagawa, Claudia Yamada, Ana Clara Gonçalves Oliveira, Isabela Ribeiro Pereira, and Thamires Pereira Noronha. "Colestase intra-hepática familiar progressiva: relato de dois casos." Revista da Faculdade de Ciências Médicas de Sorocaba 19, no. 3 (November 13, 2017): 160. http://dx.doi.org/10.23925/1984-4840.2017v19i3a13.

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A colestase intra-hepática familiar progressiva (PFIC) é um grupo heterogêneo de doenças raras, de herança autossômica recessiva, que se apresenta com colestase hepatocelular devido a um defeito na secreção biliar, geralmente manifestada na infância. Suas características clínicas comuns são: icterícia na primeira infância, hepatosesplenomegalia, prurido intratável grave e retardo de crescimento. Não se conhece bem a epidemiologia dessas doenças, mas estima-se que a incidência seja de 1:50 mil a 1:100 mil nascimentos. A PFIC acomete igualmente ambos os sexos e tem sido relatada em diversas regiões geográficas. Descrevemos dois casos de irmãos, filhos de pais consanguíneos com a PFIC tipo 1. O presente relato busca ampliar o conhecimento médico dessas manifestações genéticas raras e auxiliar no diagnóstico precoce dos pacientes com a enfermidade.

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Panasiti, Ilenia, Silvana Briuglia, Stefano Costa, and Lucia Caminiti. "Comorbidity between progressive familial intrahepatic cholestasis and atopic dermatitis in a 19-month-old child." BMJ Case Reports 12, no. 10 (October 2019): e230152. http://dx.doi.org/10.1136/bcr-2019-230152.

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Atopic dermatitis (AD) is the most common chronic skin disease in children, with an increasing prevalence in the past three decades. Adequate treatment is prescribed for individual patient based on symptoms and disease severity. However, further underlying diagnosis should be researched when therapeutic strategies for symptoms fail and skin lesions and pruritus persist. We reported herein the case of a 19-month-old infant with a history of AD unresponsive to treatment due to the type 2 progressive familial intrahepatic cholestasis (PFIC). A new homozygous mutation of the ABCB11 gene was found. The severe pruritus, the early onset jaundice, poor growth and raised transaminase levels with normal gamma glutamyl transpeptidase have led to the suspicion of PFIC. The presence of severe AD and intrahepatic chronic cholestasis, both pruritus associated, could delay a proper diagnosis. To our knowledge, for the first time, a case of comorbidity between type 2 PFIC and AD-like disease had been described.

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48

Sokol, Ronald J. "Molecular Chaperones as Therapy for PFIC." Journal of Pediatric Gastroenterology and Nutrition 62, no. 3 (March 2016): 360–62. http://dx.doi.org/10.1097/mpg.0000000000001109.

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Thompson, R. J. "P0019 PP SURGICAL MANAGEMENT OF PFIC." Journal of Pediatric Gastroenterology and Nutrition 39, Supplement 1 (June 2004): S63. http://dx.doi.org/10.1097/00005176-200406001-00143.

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50

Volynets, Galina V. "FAMILIAL INTRAHEPATIC CHOLESTASIS IN CHILDREN: PROBLEMS AND PROSPECTS." Russian Pediatric Journal 22, no. 6 (December 15, 2019): 388–94. http://dx.doi.org/10.18821/1560-9561-2019-22-6-388-394.

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The review presents various aspects of the clinic and diagnosis of familial intrahepatic cholestasis (FIC) in children, including such forms of liver pathology as progressive FIC (PFIC) types 1-5; PFIC associated with mutations in the MYO5B gene; non-progressive forms of intrahepatic cholestasis (benign recurrent IC, gestational IC, drug-induced cholestasis, hypophospholipid-associated cholelithiasis and liver cancer accompanied by cholestasis). The main methods for the diagnosis and treatment of cholestatic diseases in children are described. The feasibility of using full-exomic sequencing for the accurate diagnosis of HPV in children is shown.

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