Abstract
Background
Progressive 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 presentation
Here 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.
Conclusion
This 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.
Author contributions: Aynur Küçükçongar Yavaş wrote the paper, Aynur Küçükçongar Yavaş, Özlem Ünal Uzun and Mehmet Gündüz collected the data of the case, Ayşen Uncuoğlu evaluated the case and organized the molecular test for PFIC type3, and Büşranur Çavdarlı analyzed the genetic test. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Jacquemin E, De Vree JM, Cresteil D, Sokal EM, Sturm E, et al. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 2001;120:1448–58.10.1053/gast.2001.23984Search in Google Scholar
2. Chen HL, Chang PS, Hsu HC, Lee JH, Ni YH, et al. Progressive familial intrahepatic cholestasis with high gamma-glutamyltranspeptidase levels in Taiwanese infants: role of MDR3 gene defect? Pediatr Res 2001;50:50–5.10.1203/00006450-200107000-00011Search in Google Scholar
3. Ziol M, Barbu V, Rosmorduc O, Frassati-Biaggi A, Barget N, et al. ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults. Gastroenterology 2008;135:131–41.10.1053/j.gastro.2008.03.044Search in Google Scholar
4. Nikkilä K, Miettinen TA. Serum cholesterol precursors, cholestanol, and plant sterols in primary biliary cirrhosis. Scand J Gastroenterol 1988;23:967–72.10.3109/00365528809090155Search in Google Scholar
5. Nemes K, Aberg F, Gylling H, Isoniemi H. Cholesterol metabolism in cholestatic liver disease and liver transplantation: from molecular mechanism to clinical implications. World J Hepatol 2016;8:924–32.10.4254/wjh.v8.i22.924Search in Google Scholar
6. Gylling H, Vuoristo M, Farkkila M, Miettinen TA. The metabolism of cholestanol in primary biliary cirrhosis. J Hepatol 1996;24:444–51.10.1016/S0168-8278(96)80165-6Search in Google Scholar
7. Salen G, Steiner RD. Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX). J Inherit Metab Dis 2017;40:771–81.10.1007/s10545-017-0093-8Search in Google Scholar PubMed
8. Delaunay JL, Durand-Schneider AM, Dossier C, Falguières T, Gautherot J, et al. A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3. Hepatology 2016;63:1620–31.10.1002/hep.28300Search in Google Scholar PubMed
9. Richards S, Aziz N, Bale S, Bick D, Das S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–24.10.1038/gim.2015.30Search in Google Scholar PubMed PubMed Central
10. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016;536:285–91.10.1038/nature19057Search in Google Scholar PubMed PubMed Central
11. Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 2016;99:877–88.10.1016/j.ajhg.2016.08.016Search in Google Scholar PubMed PubMed Central
12. Song Y, XU C, Shao S, Liu J, Xing W, et al. Thyroid- stimulating hormone regulates hepatic bile acid homeostasis via SREBP-2/HNF-4 alfa /CYP7A1 axis. J Hepatol 2015;62:1171–9.10.1016/j.jhep.2014.12.006Search in Google Scholar PubMed
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