Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Clinical Research Article
  • Published:

The prognosis of citrin deficiency differs between early-identified newborn and later-onset symptomatic infants

Pediatric Research volume 94, pages 1151–1157 (2023)Cite this article

Abstract

Background

The prognosis for patients with citrin deficiency is not always benign. This study examined the differences between patients identified early by newborn screening and patients identified later with cholestasis/hepatitis.

Materials and methods

This retrospective study included 42 patients with genetically confirmed SLC25A13 mutations who were born between May 1996 and August 2019. Fifteen patients were identified during newborn screening (NBS group) and 27 patients were identified through the onset of cholestasis/hepatitis in infancy (clinical group).

Results

Overall, 90% of the patients presented with cholestasis, among whom 86% (31/36) recovered at a median age of 174 days. Compared with patients in the clinical group, patients in the NBS group were significantly younger at diagnosis and at cholestasis-free achievement; they also had significantly lower levels of peak direct bilirubin and liver enzymes. At the median follow-up age of 11.8 years, 21% of the patients had dyslipidemia, whereas 36% of the patients had failure to thrive. The overall mortality rate was 2.4%. Variant c.851_854del was the most frequent, constituting 44% of the mutant alleles.

Conclusion

Patients identified early by NBS had a better prognosis, demonstrating the importance of a timely diagnosis of NICCD and the need for careful follow-up.

Impact

  • Some cases of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) are not benign.

  • Compared with patients identified later based on the presence of cholestasis/hepatitis, patients identified early by newborn screening have less severe cholestasis and are cholestasis-free at a significantly younger age.

  • A timely diagnosis is needed, along with follow-up examinations that assess metabolic profile and body weight, to improve the long-term prognosis of NICCD patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Patient flow for cholestasis analysis.
Fig. 2: Probability of a cholestasis-free status in patients identified by newborn screening (NBS group) and by cholestasis workup (clinical group).

Similar content being viewed by others

Data availability

The data analyzed during the current study are not publicly available due to individual privacy concerns but are available from the corresponding author on reasonable request.

References

  1. Saheki, T. & Song Y. Z. Citrin deficiency. GeneReviews (eds Adam M. P. et al.) 31–40 (University of Washington, Seattle, WA, 1993–2023).

  2. Saheki, T. & Kobayashi, K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J. Hum. Genet 47, 333–341 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Saheki, T. et al. Pathogenesis and pathophysiology of citrin (a mitochondrial aspartate glutamate carrier) deficiency. J. Metab. Brain Dis. 17, 335–346 (2002).

    Article  CAS  Google Scholar 

  4. Komatsu, M. et al. Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease. J. Hepatol. 49, 810–820 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Tamamori, A. et al. Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency. J. Pediatr. Res. 56, 608–614 (2004).

    Article  CAS  Google Scholar 

  6. Ohura, T. et al. Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). J. Inherit. Metab. Dis. 30, 139–144 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Tamamori, A. et al. Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation. Eur. J. Pediatr. 161, 609–613 (2002).

    Article  PubMed  Google Scholar 

  8. Shigeta, T. et al. Liver transplantation for an infant with neonatal intrahepatic cholestasis caused by citrin deficiency using heterozygote living donor. Pediatr. Transplant. 14, E86–E88 (2010).

    Article  PubMed  Google Scholar 

  9. Yeh, J.-N. et al. Hepatic steatosis and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in Taiwanese infants. J. Pediatr. 148, 642–646 (2006).

    Article  PubMed  Google Scholar 

  10. Chen, H.-W. et al. Chubby face and the biochemical parameters for the early diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency. J. Pediatr. Gastroenterol. Nutr. 47, 187–192 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Hayasaka, K. & Numakura, C. Adult-onset type II citrullinemia: current insights and therapy. Appl Clin. Genet 11, 163 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen, S.-T. et al. Diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency using high-resolution melting analysis and a clinical scoring system. J. Pediatr. 161, 626–631. e622 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Lee, N.-C. et al. Time course of acylcarnitine elevation in neonatal intrahepatic cholestasis caused by citrin deficiency. J. Inherit. Metab. Dis. 29, 551–555 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Wang, L.-Y. et al. Newborn screening for citrin deficiency and carnitine uptake defect using second-tier molecular tests. BMC Med Genet 14, 1–6 (2013).

    Article  Google Scholar 

  15. Song, Y.-Z. et al. Neonatal intrahepatic cholestasis caused by citrin deficiency: clinical and laboratory investigation of 13 subjects in mainland of China. Dig. Liver Dis. 41, 683–689 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Song, Y.-Z. et al. Genotypic and phenotypic features of citrin deficiency: five-year experience in a Chinese pediatric center. J. Int. J. Mol. Med. 28, 33–40 (2011).

    PubMed  Google Scholar 

  17. Zhang, T. et al. Dynamic changes of metabolic characteristics in neonatal intrahepatic cholestasis caused by citrin deficiency. Front. Mol. Biosci. 9, 939837 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen, H.-A. et al. Improved diagnosis of citrin deficiency by newborn screening using a molecular second-tier test. J. Mol. Genet. Metab. 136, 330–336 (2022).

    Article  CAS  Google Scholar 

  19. Shen, Q.-L. et al. Assessment of liver fibrosis by Fibroscan as compared to liver biopsy in biliary atresia. World J. Gastroenterology 21, 6931 (2015).

    Article  Google Scholar 

  20. Rajakannu, M., Coilly, A., Adam, R., Samuel, D. & Vibert, E. Prospective validation of transient elastography for staging liver fibrosis in patients undergoing hepatectomy and liver transplantation. J. Hepatol. 68, 199–200 (2018).

    Article  Google Scholar 

  21. Serra-Burriel, M. et al. Transient elastography for screening of liver fibrosis: cost-effectiveness analysis from six prospective cohorts in Europe and Asia. J. Hepatol. 71, 1141–1151 (2019).

    Article  PubMed  Google Scholar 

  22. Abuduxikuer, K., Chen, R., Wang, Z.-L. & Wang, J.-S. Risk factors associated with mortality in neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and clinical implications. BMC Pediatr. 19, 1–8 (2019).

    Article  Google Scholar 

  23. Okano, Y., Ohura, T., Sakamoto, O. & Inui, A. Current treatment for citrin deficiency during NICCD and adaptation/compensation stages: strategy to prevent CTLN2. Mol. Genet. Metab. 127, 175–183 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Dimmock, D. et al. Citrin deficiency: a novel cause of failure to thrive that responds to a high-protein, low-carbohydrate diet. J. Pediatr. 119, e773–e777 (2007).

    Article  Google Scholar 

  25. Kido, J. et al. Clinical manifestation and long‐term outcome of citrin deficiency: report from a nationwide study in Japan. J. Inherit. Metab. Dis. 45, 431–444 (2022).

    Article  CAS  PubMed  Google Scholar 

  26. Numakura, C. et al. Growth impairment in individuals with citrin deficiency. J. Inherit. Metab. Dis. 42, 501–508 (2019).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank parents, physicians, co-workers participating in newborn screening, and the Health Promotion Administration, Ministry of Health and Welfare for supporting and overseeing the newborn screening program.

Author information

Authors and Affiliations

  1. Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan

    Cheng-Yu Chen, Mei-Hwei Chang, Huey-Ling Chen, Yin-Hsiu Chien & Jia-Feng Wu

  2. Department of Pediatrics, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan

    Cheng-Yu Chen

  3. Department of Medical Genetics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan

    Yin-Hsiu Chien

Authors
  1. Cheng-Yu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mei-Hwei Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huey-Ling Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yin-Hsiu Chien
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jia-Feng Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.-Y.C., the first author of the study, is responsible for data management, manuscript writing, and revising. M.-H.C., H.-L.C., and Y.-H.C. are responsible for patient recruitment and critical review of the manuscript. J.-F.W. and Y.-H.C. are the equal contributing corresponding authors responsible for the study design, patient recruitment, and critical writing of the manuscript. All authors have approved the final version.

Corresponding authors

Correspondence to Yin-Hsiu Chien or Jia-Feng Wu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, CY., Chang, MH., Chen, HL. et al. The prognosis of citrin deficiency differs between early-identified newborn and later-onset symptomatic infants. Pediatr Res 94, 1151–1157 (2023). https://doi.org/10.1038/s41390-023-02585-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41390-023-02585-3

Search

Advanced search

Quick links