Gepato-gastroenterologik tadqiqotlar jurnali 2022, №4

Subject of the article



Gudkov R.A.;Dmitriev A.V.;Fedina N.V.; Petrova V.I.


University named after academician I.P. Pavlov Ryazan, Russian Federation


The article discusses various causes of direct hyperbilirubinemia in young children. Earlier in issue 3 for 2021 in this journal, we published an article on familial progressive intrahepatic cholestasis, as one of the causes of cholestatic jaundice. In this article, we present others, including more frequent (such as biliary atresia) and rarer and rarer pathologies. The proposed review may be useful in the differential diagnosis of direct hyperbilirubinemia syndrome in children of early age.

Key words

direct hyperbilirubinemia, cholestatic jaundice, young children.


. Kelly D.A. Managing liver failure. //Postgrad Med J 2002 Nov; 78(925):660-7. 2. Arora N.K. et al. Hepatic technetium-99m-membrofenin iminodiacetate scans and serum gamma-glutamil transpeptidase levels interpreted in series to differenciate between extrahepatic biliary atresia and neonatal hepatitis. //Acta Paediatr 2001 Sep; 90(9):975-81. 3. Gottesman L.E., Del Vecchio M.T., Aronoff S.C. Etiologies of conjugated hyperbilirubinemia in infancy: a systematic review of 1692 subjects. BMC Pediatrics. 2015;15:192. doi: 10.1186/s12887-015-0506-5. 4. Grochowski CM, Loomes KM, Spinner NB. Jagged1 (JAG1): structure, expression, and disease associations. Gene. 2016;576:381–4. 5. Gottesman L. E., Del Vecchio M. T. and Aronoff S. C. Etiologies of conjugated hyperbilirubinemia in infancy: a systematic review of 1692 subjects. BMC Pediatrics. 2015Nov 20. №15. p. 192. doi: 10.1186/s12887-015-0506-5. 6. Goryainova A.N., Belenovich E.V., Khudyakova A.A., Bronnikova Yu.A., Churilova L.V. Bile thickening syndrome in newborns and young children: risk factors, therapy, prognosis. Analysis of a clinical case. Medical advice. 2020;(18):134–141 (Russ). doi: 10.21518/2079-701X-2020-18-134-141. 7. Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. 1975;86:63–71. 8. Federal Clinical Guidelines for the Diagnosis and Treatment of Alagille Syndrome. M., 2015. 25 p. Available at: Update date 04/25/22 (Russ). 9. Jansen PL, Sturm E. Genetic cholestasis, causes and consequences for hepatobiliary transport. Liver Int. 2003;23:315-22. 10. Santos JL, Choquette M, Bezerra JA. Cholestatic liver disease in children. Curr Gastroenterol Rep. 2010;12:30-9. 11. Loomes KM, Emerick KM. Pediatric cholestatic liver disease. In: Wyllie R, Hyams JS, Kay M ed. Pediatric gastrointestinal and liver disease. 5th edition. Elsevier (Philadelphia, PA) 2016:851-869. 12. Kelly DA ed. Diseases of the liver and biliary system in children. 4th edition. Wiley Blackwell (Oxford, UK) 2017:99-126. 13. Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases Huey-Ling Chen, Shang-Hsin Wu, Shu-Hao Hsu, Bang-Yu Liou, Hui-Ling Chen and Mei-Hwei Chang. Journal of Biomedical Science 2018 25 :75 14. Expanding etiology of progressive familial intrahepatic cholestasis. Henkel SA, Squires JH, Ayers M, Ganoza A, Mckiernan P, Squires JE. World J Hepatol. 2019 May 27;11(5):450-463. doi: 10.4254/wjh.v11.i5.450. 15. Sambrotta M, Strautnieks S, Papouli E, Rushton P, Clark BE, Parry DA, et al. Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet. 2014;46(4):326-8. doi: 10.1038/ng.2918. 16. Gomez-Ospina N, Potter CJ, Xiao R, Manickam K, Kim MS, Kim KH, et al. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat Commun. 2016;7:10713. doi: 10.1038/ncomms10713. 17. Progressive familial intrahepatic cholestasis: diagnosis, management, and treatment Mithat Gunaydin and Asudan Tugce Bozkurter Cil Hepat Med. 2018; 10: 95–104. 18. Qiu YL, Gong JY, Feng JY, Wang RX, Han J, Liu T, et al. Defects in myosin VB are associated with a spectrum of previously undiagnosed low y-glutamyltransferase cholestasis. Hepatology. 2017;65(5):1655-1669. doi: 10.1002/hep.29020. 19. Gonzales E, Taylor SA, Davit-Spraul A, Thébaut A, Thomassin N, Guettier C. et al. MYO5B mutations cause cholestasis with normal serum gamma-glutamyl transferase activity in children without microvillous inclusion disease. Hepatology. 2017;65(1):164-73. doi: 10.1002/hep.28779. 20. Сlayton P.T., leonard J.V., lawson А.M., Setchell K. et al. Familial giant cell hepatitis associated with synthesis of 3-beta, 7-alpha-dihy-droxy- and 3-beta, 7-alpha, 12-alpha-trihydroxy-5-cholenoic acids. J. clin. invest. 1987; 79: 1031–8. 21. Namazova-Baranova L.S., Polyakova S.I. Violations of the synthesis of primary bile acids. Russian pediatric journal. 2015; 18(6): 35–40 (Russ) 22. Maslennikov D.N. Violation of the synthesis of primary bile acids: [Electronic resource] // GENOCARD Genetic Encyclopedia. 2021. (Russ) - URL: (Date of access: 04/17/2022). 23. Yerushalmi B. Niemann-pick disease type C in neonatal cholestasis at a North American Center/ Yerushalmi B., Sokol RJ., Narkewicz MR., et al. J Pediatr Gastroenterol Nutr. 2002. №35. P.44-50. 24. Bombieri C, Claustres M, De Boeck K, Derichs N, Dodge J, Girodon E. at al. Recommendations for the classification of diseases as CFTR-related disorders. J Cyst Fibros. 2011; 10(2): 86–102. 25. Castro P.T., Matos A.P.P., Werner H. et al. Prenatal Diagnosis of Caroli Disease Associated With Autosomal Recessive Polycystic Kidney Disease by 3-D Ultrasound and Magnetic Resonance Imaging. J Obstet Gynaecol Can. 2017;39(12):1176–9. 26. Hao X., Liu S., Dong Q. et al. Whole exome sequencing identifies recessive PKHD1 mutations in a Chinese twin family with Caroli disease. PLoS One. 2014;9(4):92661. 27. Yang X.Y., Zhu L.P., Liu X.Q., Zhang C.Y., Yao Y., Wu Y. Genetic diagnosis of Caroli syndrome with autosomal recessive polycystic kidney disease: a case report and literature review. Beijing Da Xue Xue Bao Yi Xue Ban. 2018;50(2):335–339 28. Rock N., McLin V. Liver involvement in children with ciliopathies. Clin Res Hepatol Gastroenterol. 2014;38(4):407–14. 29. Lasagni A., Cadamuro M., Morana G. at al. Fibrocystic liver disease: novel concepts and translational perspectives. Transl Gastroenterol Hepatol. 2021 Apr 5;6:26. 30. Kelly D.A. Managing liver failure. //Postgrad Med J 2002 Nov; 78(925):660-7. 31. Ipatova M.G., Itkis Yu.S., Bychkov I.O., Grishina A.N., Tumanova E.L., Zakharova E.Yu. Mitochondrial DNA depletion syndrome in a newborn child. Pediatrics. Journal named after G.N. Speransky. 2018; 97(1): 71-77. (Russ) 32. Suomalainen A. Fibroblast growth factor 21: a novel biomarker for human muscle-manifesting mitochondrial disorders. Expert Opin Med Diagn. 2013 Jul;7(4):313-7 33. Fujita Y, Ito M, Kojima T et al. GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases. Mitochondrion. 2014; 20:34-42. 34. Kalko SG, Paco S, Jou C et al. Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies. BMC Genomics 2014; 15:91. 35. Yatsuga S, Fujita Y, Ishii A, Fukumoto Y, Arahata H, Kakuma T, Kojima T, Ito M, Tanaka M, Saiki R, Koga Y. Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders. Ann Neurol. 2015 Nov;78(5):814-23. 36. Montero R, Yubero D, Villarroya J. GDF-15 Is Elevated in Children with Mitochondrial Diseases and Is Induced by Mitochondrial Dysfunction. PLoS One. 2016 Feb 11;11(2): e0148709. 37. Davis RL, Liang C, Sue CM. A comparison of current serum biomarkers as diagnostic indicators of mitochondrial diseases. Neurology. 2016 May 24;86(21):2010-5 38. Analysis of GFM1 gene mutations in a family with combined oxidative phosphorylation deficiency 1 [Article in Chinese] Yaping Shen, Kai Yan, Minyue Dong, Rulai Yang, Xinwen Huang Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020 Oct 25;49(5):574-580. doi: 10.3785/j.issn.1008-9292.2020.10.04. 39. Nakamura M. et al. The characteristics of food intake in patients with type II citrullinemia // J. Nutr. Sci. Vitaminol. (Tokyo). 2011. Vol. 57, № 3. P. 239–245. 40. Kelly D.A. Managing liver failure. //Postgrad Med J 2002 Nov; 78(925):660-7. Saheki T. et al. Pathogenesis and pathophysiology of citrin (a mitochondrial aspartate glutamate carrier) deficiency.//Metab Brain Dis. 2002 Dec; 17(4):335-46. 41. Tamamori A et al. Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation. Eur J Pediatr. //2002 Nov; 161(11): 609-13. 42. Tazawa Y et al. Infantile cholestatic jaundice associated with adult-onset type II citrullinemia. //J Pediatr. 2001 May;138(5):735-40). 43. Vandborg P. K., Hansen B. M., Greisen G., Jepsen M. and Ebbesen F. Follow-up of Neonates With Total Serum Bilirubin Levels ≥25 mg/dL: A Danish Population-Based Study // Pediatrics. – 2012 Jul. –№ 130(1). – p. 61-6. doi: 10.1542/peds.2011-2760. Epub 2012 Jun 25. 44. Tang L., Chen L., Wang H., Dai L., Pan S. Case report: An adult-onset type II citrin deficiency patient in the emergency department // Exp Ther Med. 2016 Jul. № 12(1). – p. 410-414. 45. DCDC2 Mutations Cause Neonatal Sclerosing Cholangitis. M.Girard, A. Bizet, A. Lachaux, E. Gonzales, E. Filhol, S. Collardeau-Frachon et al. Hum Mutat. 2016 Oct;37(10):1025-9. doi: 10.1002/humu.23031. Epub 2016 Aug 24. DOI: 10.1002/humu.23031 46. Taylor SA, Kelly S, Alonso EM, Whitington PF. The effects of gestational Alloimmune liver disease on fetal and infant morbidity and mortality. J Pediatr. 2018;196:123–8. 47. Zhou, Y., Zhang, J. Arthrogryposis–renal dysfunction–cholestasis (ARC) syndrome: from molecular genetics to clinical features. Ital J Pediatr 40, 77 (2014). 48. Von Linstow M.-L. and Rosenfeldt V. Neonatal Hepatitis as First Manifestation of Hyperimmunoglobulinemia D Syndrome // Case Reports in Pediatrics Volume 2014, Article ID 936890, 4 p.