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Open Access
CC BY 4.0 · Neuropediatrics
DOI: 10.1055/a-2773-6076
Original Article

Hepatocellular Carcinoma: A Critical Complication in Patients Treated with Pyridoxal Phosphate

Autor*innen

  • Marion M. Brands 

    1   Department of Pediatrics, Division of Metabolic Diseases, Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands

  • Chloé de Puyraimond

    2   Department of Pediatrics, Reference Center for Inborn Errors of Metabolism, Necker Hospital, APHP, Université Paris-Cité, G2m Network, MetabERN, Paris, France

  • Sidney M. Gospe Jr

    3   Departments of Neurology and Pediatrics, University of Washington, Seattle, Washington, United States
    4   Department of Pediatrics, Duke University, Durham, North Carolina, United States

  • Manuel M. Schiff

    2   Department of Pediatrics, Reference Center for Inborn Errors of Metabolism, Necker Hospital, APHP, Université Paris-Cité, G2m Network, MetabERN, Paris, France
    5   INSERM UMR _S1163, Institut Imagine, Université Paris-Cité, Paris, France

  • Bregje Jaeger

    6   Department of Child Neurology, Emma's Children's Hospital, Amsterdam UMC, Amsterdam, The Netherlands

  • Bart G. Koot

    7   Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Netherlands

  • Martine F. Raphael

    8   Department of Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands

  • Charlotte M. Lubout

    9   Department of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

  • Bertrand Soto

    10   Department of Pediatrics, CH Auxerre, Auxerre, France

  • Julian Delanne

    11   Department of Genetics, CHU Dijon Bourgogne, Dijon, France

  • Apolline Imbard

    12   Department of Biochemistry, Hôpital Necker-Enfants Malades, APHP, Paris, France
    13   Département Médicaments et Technologies pour La Santé (DMTS), Paris-Saclay University, CEA, Gif-sur-Yvette, France

  • John Zempel

    14   Departments of Neurology and Pediatrics, Washington University, St. Louis, Missouri, United States

  • Kathelijne C. Kraal

    15   Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

  • René Scheenstra

    16   Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

  • Peter T. Clayton

    17   Inborn Errors of Metabolism, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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Abstract

Background

Pyridoxal-5′-phosphate (PLP) is in most patients the effective treatment for pyridox(am)ine-5′-phosphate oxidase (PNPO) deficiency, a rare autosomal recessive cause of neonatal-onset developmental and epileptic encephalopathy. Although generally considered safe, long-term high-dose PLP exposure may have hepatotoxic effects, particularly in the absence of pharmaceutical-grade formulations.

Methods

We report a series of four pediatric patients with vitamin B6–dependent epilepsy who received long-term PLP therapy. Two had genetically confirmed PNPO deficiency, and two were later diagnosed with ALDH7A1 deficiency. All received high-dose oral PLP, with frequent changes in formulation due to availability issues.

Results

Three of the four patients developed hepatocellular carcinoma after several years of PLP treatment; one developed fully reversible severe hepatotoxicity. The shared exposure to prolonged high-dose PLP across all affected patients, despite differing metabolic conditions, suggests a possible role for PLP toxicity independent of the underlying metabolic disorder. Known toxic mechanisms include mitochondrial dysfunction, Schiff base–mediated protein modification, and accumulation of reactive PLP degradation products. In two patients, the total PLP dose was successfully reduced by over 30% through increasing administration frequency, without loss of seizure control.

Conclusion

These findings raise significant concerns about the long-term hepatic safety of oral PLP in patients with vitamin B6–dependent epilepsies. As intravenous PLP is unfeasable for lifelong therapy, there is an urgent need for standardized, high-quality PLP preparations and exploration of alternative delivery routes such as intranasal administration. Regular hepatic monitoring should be implemented in all patients receiving chronic PLP therapy.

Keywords

B6 epilepsy - liver toxicity - risk for malignancy - Epilepsy - Neurometabolics

Contributors' Statement

M.M.B.: conceptualization, data curation, formal analysis, investigation, methodology, project administration, writing - original draft. C.D.P.C: writing - original draft, writing - review & editing. S.M.G.: writing - original draft, writing - review & editing. M.S.: writing - review & editing. B.J.: writing - review & editing. B.K.: writing - review & editing. M.R.: writing - review & editing. C.L.: writing - review & editing. B.S.: writing - review & editing. J.D.: Writing - review & editing. A.I.: writing - review & editing. J.Z.: writing - review & editing. K.K.: writing - review & editing. R.S.: writing - review & editing. P.C.: Conceptualization, investigation, supervision, writing - review & editing.




Publikationsverlauf

Eingereicht: 02. Oktober 2025

Angenommen: 15. Dezember 2025

Accepted Manuscript online:
22. Dezember 2025

Artikel online veröffentlicht:
06. Januar 2026

© 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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