European Journal of Pediatrics

, Volume 178, Issue 4, pp 515–523 | Cite as

Metabolic liver diseases presenting with neonatal cholestasis: at the crossroad between old and new paradigms

  • Helena Moreira-Silva
  • Inês Maio
  • Anabela Bandeira
  • Esmeralda Gomes-Martins
  • Ermelinda Santos-SilvaEmail author
Original Article


Metabolic liver diseases (MLD) are an important group of disorders presenting with neonatal cholestasis (NC). The spectrum of liver involvement is wide and the presumptive diagnosis is traditionally based on clinical and laboratory findings. Recently, next-generation sequencing (NGS) panels have emerged as an appealing tool to diagnose neonatal/infantile cholestatic disorders. The aim of this study was to identify clinical phenotypes of liver injury and contribute to find a diagnostic methodology that integrates new molecular diagnostic tools. We retrospectively analyzed the clinical and biochemical features of 16 patients with MLD and NC. Patients were categorized into three groups: A—NC with liver failure (N = 8): tyrosinemia type I (n = 2), classic galactosemia (n = 5), mitochondrial DNA depletion syndrome (n = 1); B—NC evolving with chronic liver disease (N = 5): argininemia (n = 2); mitochondrial cytopathy (n = 1); congenital disorders of glycosylation type Ia (n = 1); Zellweger syndrome (n = 1); and C—transient NC (N = 3): Niemann-Pick type C (n = 2), citrullinemia type II (n = 1).

Conclusion: MLD presenting with NC can be categorized into three main clinical phenotypes of liver injury. We highlight transient NC as a clue for MLD that must be pursued. New molecular diagnostic tools can play a key role, but application criteria must be established to make them cost-effective.

What is Known:

Metabolic liver diseases are an important group of disorders presenting with neonatal cholestasis.

The diagnostic approach is challenging and traditionally based on clinical and laboratory findings. Next-generation sequencing is a recent and rapidly developing tool in pediatric hepatology.

What is New:

We provide a liver-targeted characterization of metabolic liver diseases presenting with neonatal cholestasis, categorizing them into three clinical phenotypes that may narrow the diagnostic possibilities.

A clinical decision-making algorithm is proposed, in which the NGS technology is integrated.


Neonatal cholestasis Transient neonatal cholestasis Liver failure Metabolic liver diseases Next-generation sequencing panels 



Conjugated bilirubin


Congenital disorder of glycosylation




Hepatic encephalopathy


Inborn errors of metabolism


International normalized ratio


Liver failure


Metabolic liver diseases


Newborn screening


Neonatal cholestasis


Next-generation sequencing


Niemann-Pick type C


Orthotopic liver transplant


Progressive familiar intrahepatic cholestasis


Authors’ Contributions

Helena Moreira Silva: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript.

Inês Maio: acquisition of data, analysis and interpretation of data.

Anabela Bandeira and Esmeralda Martins: patient diagnosis and follow-up, analysis and interpretation of data; critical revision of the manuscript.

Ermelinda Santos Silva: patient diagnosis and follow-up, study concept and design; study supervision; critical revision of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by our institutional scientific and ethics committee [Study N/REF.ª 2016. 081 (069-DEFI/066-CES)].

Clinical trial registration

Not applicable.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Balistreri WF (1985) Neonatal cholestasis. J Pediatr 106(2):171–184CrossRefPubMedGoogle Scholar
  2. 2.
    Behjati S, Tarpey PS (2013) What is next generation sequencing? Arch Dis Child Educ Pract Ed 98(6):236–238CrossRefPubMedGoogle Scholar
  3. 3.
    Bodamer OA, Hoffmann GF, Lindner M (2007) Expanded newborn screening in Europe 2007. J Inherit Metab Dis 30:439–444CrossRefPubMedGoogle Scholar
  4. 4.
    Bosch AM (2006) Classical galactosemia revisited. J Inherit Metab Dis 29:516–525CrossRefPubMedGoogle Scholar
  5. 5.
    Braga AC, Vilarinho L, Ferreira E, Rocha H (1997) Hyperargininemia presenting as persistent neonatal jaundice and hepatic cirrhosis. J Pediatr Gastroenterol Nutr 24(2):218–221CrossRefPubMedGoogle Scholar
  6. 6.
    Burton BK, Balwani M, Feillet F et al (2015) A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency. N Engl J Med 373(11):1010–1020CrossRefPubMedGoogle Scholar
  7. 7.
    Champion V, Carbajal R, Lozar J, Girard I, Mitanchez D (2012) Risk factors for developing transient neonatal cholestasis. J Pediatr Gastroenterol Nutr 55(5):592–598CrossRefPubMedGoogle Scholar
  8. 8.
    Clayton PT (2011) Disorders of bile acid synthesis. J Inherit Metab Dis 34(3):593–604CrossRefPubMedGoogle Scholar
  9. 9.
    Coene KLM, Kluijtmans LAJ, van der Heeft E, Engelke UFH, de Boer S, Hoegen B, Kwast HJT, van de Vorst M, Huigen MCDG, Keularts IMLW, Schreuder MF, van Karnebeek CDM, Wortmann SB, de Vries MC, Janssen MCH, Gilissen C, Engel J, Wevers RA (2018) Next-generation metabolic screening: targeted and untargeted metabolomics for the diagnosis of inborn errors of metabolism in individual patients. J Inherit Metab Dis 41(3):337–353CrossRefPubMedGoogle Scholar
  10. 10.
    Damen G, de Klerk H, Huijmans J, den Hollander J, Sinaasappel M (2004) Gastrointestinal and other clinical manifestations in 17 children with congenital disorders of glycosylation type Ia, Ib, and Ic. J Pediatr Gastroenterol Nutr 38(3):282–287CrossRefPubMedGoogle Scholar
  11. 11.
    Fawaz R, Baumann U, Ekong U, Fischler B, Hadzic N, Mack CL, McLin VA, Molleston JP, Neimark E, Ng VL, Karpen SJ (2017) Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 64:154–168CrossRefPubMedGoogle Scholar
  12. 12.
    Fellman V, Kotarsky H (2011) Mitochondrial hepatopathies in the newborn period. Semin Fetal Neonatal Med 16(4):222–228CrossRefPubMedGoogle Scholar
  13. 13.
    Ghosh A, Schlecht H, Heptinstall LE (2017) Diagnosing childhood-onset inborn errors of metabolism by next-generation sequencing. Arch Dis Child 102(11):1019–1029CrossRefPubMedGoogle Scholar
  14. 14.
    Gomes Martins E, Santos Silva E, Vilarinho S, Saudubray JM, Vilarinho L (2010) Neonatal cholestasis: an uncommon presentation of hyperargininemia. J Inherit Metab Dis 33(Suppl 3):S503–S506CrossRefPubMedGoogle Scholar
  15. 15.
    Herbst SM, Schirmer S, Posovszky C, Jochum F, Rödl T, Schroeder JA, Barth TF, Hehr U, Melter M, Vermehren J (2015) Taking the next step forward - diagnosing inherited infantile cholestatic disorders with next generation sequencing. Mol Cell Probes 29(5):291–298CrossRefPubMedGoogle Scholar
  16. 16.
    Kuhlenbäumer G, Hullmann J, Appenzeller S (2011) Novel genomic techniques open new avenues in the analysis of monogenic disorders. Hum Mutat 32:144–151CrossRefPubMedGoogle Scholar
  17. 17.
    Mancuso M, Ferraris S, Pancrudo J, Feigenbaum A, Raiman J, Christodoulou J, Thorburn DR, DiMauro S (2005) New DGK gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome. Arch Neurol 62:745–747CrossRefPubMedGoogle Scholar
  18. 18.
    Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A, Anbinder Y, Berkowitz D, Hartman C, Barak M, Eriksson S, Cohen N (2001) The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nature Genet 29:337–341CrossRefPubMedGoogle Scholar
  19. 19.
    Marques-da-Silva D, dos Reis Ferreira V, Monticelli M, Janeiro P, Videira PA, Witters P, Jaeken J, Cassiman D (2017) Liver involvement in congenital disorders of glycosylation (CDG): a systematic review of the literature. J Inherit Metab Dis 40:195–207CrossRefPubMedGoogle Scholar
  20. 20.
    Matthijs G, Schollen E, Pardon E, Veiga-Da-Cunha M, Jaeken J, Cassiman JJ, Van Schaftingen E (1997) Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). Nature Genet 16:88–92CrossRefPubMedGoogle Scholar
  21. 21.
    Mayorandan S, Meyer U, Gokcay G, Segarra NG, de Baulny HO, van Spronsen F, Zeman J, de Laet C, Spiekerkoetter U, Thimm E, Maiorana A, Dionisi-Vici C, Moeslinger D, Brunner-Krainz M, Lotz-Havla AS, Cocho de Juan JA, Couce Pico ML, Santer R, Scholl-Bürgi S, Mandel H, Bliksrud YT, Freisinger P, Aldamiz-Echevarria LJ, Hochuli M, Gautschi M, Endig J, Jordan J, McKiernan P, Ernst S, Morlot S, Vogel A, Sander J, Das AM (2014) Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice. Orphanet J Rare Dis 9(1):107CrossRefPubMedGoogle Scholar
  22. 22.
    McKiernan PJ (2002) Neonatal cholestasis. SeminNeonatol 7(2):153–165Google Scholar
  23. 23.
    Mengel E, Klünemann HH, Lourenço CM, Hendriksz CJ, Sedel F, Walterfang M, Kolb SA (2013) Niemann-Pick disease type C symptomatology: an expert-based clinical description. Orphanet J Rare Dis 8:166CrossRefPubMedGoogle Scholar
  24. 24.
    Moyer V, Freese DK, Whitington PF, Olson AD, Brewer F, Colletti RB, Heyman MB (2004) Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 39(2):115–128CrossRefPubMedGoogle Scholar
  25. 25.
    Nicastro E, D’Antiga L (2018) Next generation sequencing in pediatric hepatology and liver transplantation. Liver Transpl 24(2):282–293CrossRefPubMedGoogle Scholar
  26. 26.
    Santos Silva E, Moreira Silva H, Azevedo Lijnzaat L, Melo C, Costa E, Martins E, Lopes AI (2017) Clinical practices among healthcare professionals concerning neonatal jaundice and pale stools. Eur J Pediatr 176(3):361–369CrossRefPubMedGoogle Scholar
  27. 27.
    Santos Silva E, Klaudel-Dreszler M, Bakuła A, Oliva T, Sousa T, Fernandes PC, Tylki-Szymańska A, Kamenets E, Martins E, Socha P (2018) Early onset lysosomal acid lipase deficiency presenting as secondary hemophagocytic lymphohistiocytosis: two infants treated with sebelipase alfa. Clin Res Hepatol Gastrenterol 42(5):e77–e82CrossRefGoogle Scholar
  28. 28.
    Schukfeh N, Metzelder ML, Petersen C, Reismann M, Pfister ED, Ure BM, Kuebler JF (2012) Normalization of serum bile acids after partial external biliary diversion indicates an excellent long-term outcome in children with progressive familial intrahepatic cholestasis. J Pediatr Surg 47(3):501–505CrossRefPubMedGoogle Scholar
  29. 29.
    Silva ES, Cardoso ML, Vilarinho L, Medina M, Barbot C, Martins E (2013) Liver transplantation prevents progressive neurological impairment in argininemia. JIMD Rep 11:25–30CrossRefPubMedGoogle Scholar
  30. 30.
    Squires RH, Shneider BL, Bucuvalas J, Alonso E, Sokol RJ, Narkewicz MR, Dhawan A, Rosenthal P, Rodriguez-Baez N, Murray KF, Horslen S, Martin MG, Lopez MJ, Soriano H, McGuire BM, Jonas MM, Yazigi N, Shepherd RW, Schwarz K, Lobritto S, Thomas DW, Lavine JE, Karpen S, Ng V, Kelly D, Simonds N, Hynan LS (2006) Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr 148(5):652–658CrossRefPubMedGoogle Scholar
  31. 31.
    Togawa T, Sugiura T, Ito K, Endo T, Aoyama K, Ohashi K, Negishi Y, Kudo T, Ito R, Kikuchi A, Arai-Ichinoi N, Kure S, Saitoh S (2016) Molecular genetic dissection and neonatal/infantile intrahepatic cholestasis using targeted next-generation sequencing. J Pediatr 171:171–7.e1–4CrossRefPubMedGoogle Scholar
  32. 32.
    Vilarinho L, Rocha H, Sousa C, Marcão A, Fonseca H, Bogas M, Osório RV (2010) Four years of expanded newborn screening in Portugal with tandem mass spectrometry. J Inherit Metab Dis 33(Suppl 3):S133–S138CrossRefPubMedGoogle Scholar
  33. 33.
    Yerushalmi B, Sokol RJ, Narkewicz MR, Smith D, Ashmead JW, Wenger DA (2002) Niemann-Pick disease type C in neonatal cholestasis at a North American center. J Pediatr Gastroenterol Nutr 35(1):44–50CrossRefPubMedGoogle Scholar
  34. 34.
    Yubero D, Brandi N, Ormazabal A, Garcia-Cazorla À, Pérez-Dueñas B, Campistol J, Ribes A, Palau F, Artuch R, Armstrong J (2016) Targeted next generation sequencing in patients with inborn errors of metabolism. PLoS One 11(5):e0156359CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Pediatric Gastroenterology Unit, Centro Materno Infantil do Norte – CMINCentro Hospitalar Universitário do PortoPortoPortugal
  2. 2.Pediatric Metabolic Unit, Centro Materno Infantil do Norte – CMINCentro Hospitalar Universitário do PortoPortoPortugal
  3. 3.Instituto de Ciências Biomédicas Abel SalazarPortoPortugal

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