Metabolic liver diseases presenting with neonatal cholestasis: at the crossroad between old and new paradigms
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).
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.
KeywordsNeonatal cholestasis Transient neonatal cholestasis Liver failure Metabolic liver diseases Next-generation sequencing panels
Congenital disorder of glycosylation
Inborn errors of metabolism
International normalized ratio
Metabolic liver diseases
Niemann-Pick type C
Orthotopic liver transplant
Progressive familiar intrahepatic cholestasis
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.
The study was approved by our institutional scientific and ethics committee [Study N/REF.ª 2016. 081 (069-DEFI/066-CES)].
Clinical trial registration
Informed consent was obtained from all individual participants included in the study.
- 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
- 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
- 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.McKiernan PJ (2002) Neonatal cholestasis. SeminNeonatol 7(2):153–165Google Scholar
- 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
- 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.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
- 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.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