Neonatal intrahepatic cholestasis due to citrin deficiency

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a rare inherited metabolic disorder caused by mutations in the SLC25A13 gene, which encodes citrin, a mitochondrial aspartate-glutamate carrier predominantly expressed in the liver. Citrin plays a critical role in the urea cycle and in the malate-aspartate shuttle, which is essential for transferring reducing equivalents across the mitochondrial membrane. NICCD is also known as neonatal-onset type II citrullinemia or citrin deficiency — neonatal form. It primarily affects the liver and metabolic systems, presenting in the neonatal period with intrahepatic cholestasis characterized by prolonged jaundice, hepatomegaly, elevated liver enzymes, hypoproteinemia, decreased coagulation factors, and variable degrees of liver dysfunction. Laboratory findings typically include elevated citrulline, threonine, methionine, tyrosine, and galactose levels, as well as increased alpha-fetoprotein. Most affected infants present within the first few months of life with jaundice, failure to thrive, and fatty liver. The cholestasis and liver dysfunction in NICCD are generally transient and tend to resolve spontaneously by around one year of age with appropriate nutritional management. However, citrin deficiency is a lifelong condition, and some individuals may later develop failure to thrive and dyslipidemia in childhood (known as FTTDCD — failure to thrive and dyslipidemia caused by citrin deficiency), or adult-onset type II citrullinemia (CTLN2), which can cause recurrent hyperammonemia and neuropsychiatric symptoms. Treatment of NICCD focuses on dietary management, including the use of lactose-free and medium-chain triglyceride (MCT)-enriched formulas, which bypass the metabolic block. Supplementation with fat-soluble vitamins may also be necessary. Avoidance of excessive carbohydrate intake is important throughout life, as high-carbohydrate diets can exacerbate metabolic derangements in citrin-deficient individuals. In severe cases of later-onset complications, liver transplantation may be considered. NICCD is most commonly reported in East Asian populations, particularly in Japan, China, and Korea.

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