Intrahepatic Cholestasis Caused by Citrin Deficiency

Citrullinemia is the earliest identifiable biochemical abnormality in 13 neonates with intrahepatic cholestasis due to a citrin deficiency (NICCD) and it has 14 been included in newborn screening panels using tandem mass spectrometry. 15 However, only one neonate was positive among 600,000 infants born in Sapporo 16 city and Hokkaido, Japan between 2006 and 2017. We investigated 12 neonates with 17 NICCD who were initially considered normal in newborn mass screening (NBS) by 18 tandem mass spectrometry, but were later diagnosed with NICCD by DNA tests. 19 Using their initial NBS data, we examined citrulline concentrations and ratios of 20 citrulline to total amino acids. Although their citrulline values exceeded the mean 21 of the normal neonates and 80 % of them surpassed +3SD, all were below the cutoff 22 of 40 nmol/mL. The ratios of citrulline to total amino acids significantly elevated in 23 patients with NICCD compared to the control. By evaluating two indicators 24 simultaneously, we could select about 80% of patients with missed NICCD. 25 Introducing an estimated index comprising citrulline values and citrulline to total 26 amino acid ratios could assure NICCD detection by NBS. 27