Beyond citrulline: The diagnostic accuracy of amino acid ratios in neonatal intrahepatic cholestasis caused by citrin deficiency.

Biallelic SLC25A13 variants deprive the liver of citrin, the mitochondrial aspartate-glutamate carrier, altering plasma amino acid profiles.

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), due to biallelic SLC25A13 variants, requires specific dietary management that differs fundamentally from that of idiopathic neonatal hepatitis (INH), hence the value of rapid non-invasive diagnostic tools. This single-centre retrospective study compared 29 patients with genetically confirmed NICCD, evaluated between 2011 and 2026, with a total INH clinical cohort (n = 39) and a genetically negative INH subgroup (n = 18), using two-tiered ROC analysis. The citrulline/alanine and citrulline/tryptophan ratios achieved an AUC above 0.95, sensitivity above 85% and both specificity and positive predictive value of 100% across both comparisons, with performance comparable to citrulline alone; the threonine/alanine ratio outperformed the established threonine/serine ratio. Genotype-phenotype analysis showed that the c.852_855del variant was associated with abnormal newborn screening (p = 0.016), whereas the IVS16ins3kb variant consistently yielded normal results (p = 0.011).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The practical value is having ratios computable from an amino acid chromatography already performed, with no additional test, in a cholestatic newborn. The most important finding may lie elsewhere: the IVS16ins3kb variant escapes biochemical newborn screening, which immediately limits the reach of any purely metabolic strategy and argues for SLC25A13 genotyping in unexplained cholestasis. Small numbers and a single centre, with thresholds to be revalidated locally before any integration into an algorithm.

Analysis by Dr Thibaut Benquey