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Neonatal cholestasis: development of a diagnostic decision algorithm from multivariate predictive models

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Abstract

Despite the recent advances involving molecular studies, the neonatal cholestasis (NC) diagnosis still relays on the expertise of medical teams. Our aim was to develop models of etiological diagnosis and unfavourable prognosis which may support a rationale diagnostic approach. We retrospectively analysed 154 patients born between January 1985 and October 2019. The cohort was divided into two main groups: (A) transient cholestasis and (B) other diagnosis (with subgroups) and also in two groups of outcomes: (I) unfavourable and (II) favourable. Multivariate logistic regression analysis identified the lower gestational age as the only variable independently associated with an increased risk of transient cholestasis and signs and/or symptoms of sepsis with infectious or metabolic diseases. Gamma-glutamyl transferase serum levels > 300 IU/L had a positive predictive value for both diagnosis of biliary atresia and for alpha-1-antitrypsin deficiency (A1ATD) and for unfavourable prognosis. A model of diagnosis for A1ATD (n = 34) showed an area under the ROC curve = 0.843 [confidence interval (CI): 0.773–0.912].

Conclusion: This study identified some predictors of diagnosis and prognosis which helped to build a diagnostic decision algorithm. The unusually large subgroup of patients with A1ATD in this cohort emphasizes its predictive diagnostic model.

What Is Known

• The etiological diagnosis of neonatal cholestasis (NC) requires a step-by-step guided approach, and diagnostic models have been developed only for biliary atresia.

• Current algorithms neither address the epidemiology changes nor the application of the new molecular diagnostic tools.

What Is New

• This study provides diagnostic predictive models for patients with A1ATD, metabolic/infectious diseases, and transient cholestasis, and two models of unfavourable prognosis for NC.

• A diagnostic decision algorithm is proposed based on this study, authors expertise and the literature.

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Data Availability

The data analysed in this study is subject to the following licenses/restrictions: The data are recorded in the patients’ clinical files and in the hospital databases. In order to have access, it is necessary to ask for authorization from the Ethics Committee and the Board of Directors of the hospital. This authorization was requested and obtained to carry out this study. Requests to access these datasets should be directed to Ethics Committee, secretariado.etica@chporto.min- saude.pt, and Departement of Education, Training and Research (DEFI), secretariado.cg.defi@chporto.min-saude.pt.

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Acknowledgements

Many thanks to Dr Margarida Medina (emeritus paediatrician of Hospital Geral de Santo António, and Hospital de Crianças Maria Pia, Porto, Portugal) for providing and caring for many study patients.

Funding

This work was supported by a PhD scholarship from the Department of Education, Training, and Research of the Centro Hospitalar Universitário do Porto, and by Applied Molecular Biosciences Unit (UCIBIO), which is financed by national funds from FCT/MCTES (UID/MULTI/04378/2019).

Author information

Authors and Affiliations

  1. Gastroenterology Unit, Paediatrics Division, Child and Adolescent Department, Centro Materno-Infantil do Norte, Centro Hospitalar Universitário do Porto, Largo da Maternidade, n° 45, 4050-651, Porto, Portugal

    Ermelinda Santos Silva & Helena Moreira Silva

  2. Integrated Master in Medicine, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313, Porto, Portugal

    Ermelinda Santos Silva

  3. UCIBIO, REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313, Porto, Portugal

    Ermelinda Santos Silva, Cristina Catarino & Alice Santos-Silva

  4. MEDCIDS (Departamento de Medicina da Comunidade, Informação e Decisão em Saúde) and CINTESIS (Centro de Investigação em Tecnologias e em Serviços de Saúde), Faculdade de Medicina da Universidade do Porto, Rua Dr Plácido da Costa, s/n, 4200-450, Porto, Portugal

    Cláudia Camila Dias

  5. Paediatric Gastroenterology Unit, Paediatrics Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Av. Prof. Egas Moniz, 1600-190, Lisboa, Portugal

    Ana-Isabel Lopes

  6. Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal

    Ana-Isabel Lopes

Authors
  1. Ermelinda Santos Silva
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  2. Helena Moreira Silva
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  3. Cristina Catarino
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  4. Cláudia Camila Dias
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  5. Alice Santos-Silva
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  6. Ana-Isabel Lopes
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Contributions

ESS diagnosed and followed patients, designed the study, collected and analysed data, and elaborated the draft of the manuscript.

HMS collected and analysed data, contributed to the design of the study, and critically reviewed the manuscript.

CC analysed data and critically reviewed the manuscript.

CCD built and helped to interpret the predictive models of diagnosis and prognosis, revised all statistical analysis, and critically reviewed the manuscript.

ASS and AIL contributed to the conception of the study and the interpretation of data and critically reviewed the manuscript.

All authors approved the final version of the manuscript, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Ermelinda Santos Silva.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was in accordance with the ethical standards of the participating healthcare institution committee (Studies N/REF.ª 2016. 081 (069-DEFI/066-CES) and N/REF.ª 2016. 084 (072-DEFI/069-CES)), and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent to participate

Informed consent was obtained from all individuals included in the study.

Consent for publication

Informed consent was obtained from all individuals included in the study.

Code availability

Software Statistical Package for the Social Sciences v. 24.0.

Additional information

Communicated by Peter de Winter

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Supplementary Information

Online Resource 1

Clinical and biochemical variables tested in the predictive models (PDF 35 kb)

Online Resource 2

Detailed description of underlying entities. Legend: CDG, congenital disorders of glycosylation; PFIC, progressive familial intra-hepatic cholestasis; A1ATD, alpha-1-antitrypsin deficiency; UTI, urinary tract infection. (PDF 52 kb)

Online Resource 3

Participants flow diagram (PDF 240 kb)

Online Resource 4

Participants characteristics (I): transient cholestasis versus all other diagnosis. (PDF 76 kb)

Online Resource 5

Overall survival: transient cholestasis versus other diagnosis. (PDF 63 kb)

Online Resource 6

Participants characteristics (II): comparison between some subgroups of “other diagnosis”. (PDF 95 kb)

Online Resource 7

Participants characteristics (III): unfavourable versus favourable outcome. (PDF 73 kb)

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Santos Silva, E., Moreira Silva, H., Catarino, C. et al. Neonatal cholestasis: development of a diagnostic decision algorithm from multivariate predictive models. Eur J Pediatr 180, 1477–1486 (2021). https://doi.org/10.1007/s00431-020-03886-z

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  • DOI: https://doi.org/10.1007/s00431-020-03886-z

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