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

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Abstract

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.

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Abbreviations

cB:

Conjugated bilirubin

CDG:

Congenital disorder of glycosylation

GGT:

Gamma-glutamyltransferase

HE:

Hepatic encephalopathy

IEM:

Inborn errors of metabolism

INR:

International normalized ratio

LF:

Liver failure

MLD:

Metabolic liver diseases

NBS:

Newborn screening

NC:

Neonatal cholestasis

NGS:

Next-generation sequencing

NP-C:

Niemann-Pick type C

OLT:

Orthotopic liver transplant

PFIC:

Progressive familiar intrahepatic cholestasis

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Authors and Affiliations

  1. Pediatric Gastroenterology Unit, Centro Materno Infantil do Norte – CMIN, Centro Hospitalar Universitário do Porto, Largo da Maternidade de Júlio Dinis, 4050-651, Porto, Portugal

    Helena Moreira-Silva, Inês Maio & Ermelinda Santos-Silva

  2. Pediatric Metabolic Unit, Centro Materno Infantil do Norte – CMIN, Centro Hospitalar Universitário do Porto, Porto, Portugal

    Anabela Bandeira & Esmeralda Gomes-Martins

  3. Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal

    Esmeralda Gomes-Martins & Ermelinda Santos-Silva

Authors
  1. Helena Moreira-Silva
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  2. Inês Maio
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  3. Anabela Bandeira
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  4. Esmeralda Gomes-Martins
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  5. Ermelinda Santos-Silva
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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.

Corresponding author

Correspondence to Ermelinda Santos-Silva.

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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.

Additional information

Communicated by Peter de Winter

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Moreira-Silva, H., Maio, I., Bandeira, A. et al. Metabolic liver diseases presenting with neonatal cholestasis: at the crossroad between old and new paradigms. Eur J Pediatr 178, 515–523 (2019). https://doi.org/10.1007/s00431-019-03328-5

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  • DOI: https://doi.org/10.1007/s00431-019-03328-5

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