Share this article on:

Citrin Deficiency: Learn More, and Don't Forget to Add It to the List of Neonatal Cholestasis and the NASH Trash Bin

Vajro, Pietro; Veropalumbo, Claudio

Journal of Pediatric Gastroenterology and Nutrition: June 2010 - Volume 50 - Issue 6 - p 578–579
doi: 10.1097/MPG.0b013e3181dee0e3

Department of Pediatrics, University of Naples “Federico II”, Naples, Italy.

Received 16 March, 2010

Accepted 17 March, 2010

Address correspondence and reprint requests to Pietro Vajro, Department of Pediatrics, University of Naples “Federico II”, Via S. Pansini, 5–80131 Naples, Italy (e-mail:

The authors report no conflicts of interest.

Citrin is the liver-type mitochondrial aspartate glutamate carrier. Its deficiency, also known as type II citrullinemia, is an autosomal recessive genetic disorder causing metabolic derangements in aerobic glycolysis and gluconeogenesis. Urea cycle mechanisms, uridine diphosphate-galactose epimerase activity, acylcarnitine metabolism, and fatty acid synthesis and utilization are also affected mainly due to a defective aspartate export from the mitochondria to the cytosol and impairment of the malate-aspartate shuttle. Patients with this defect may harbor different mutations on gene SLC25A13 located on chromosome 7q21.3. Mutations have a carrier rate of 1:65 in Japan and China, whereas they are much less frequent in the Western world, and are responsible for 2 phenotypes of the disease. The first is a usually self-limiting neonatal (intrahepatic) cholestatic and steatotic condition (neonatal intrahepatic cholestasis caused by citrin deficiency [NICCD], OMIM #605814). The second is an adult-onset disease, mainly characterized by fatty liver and late recurrent hyperammonemic neurological disturbance (citrullinemia2, OMIM #603471) (1). Failure to thrive may be an additional presentation (2). In this issue of JPGN, Lee et al (3) present 2 cases that examine some basic aspects of this often still poorly recognized disorder.

NICCD is associated with growth retardation/failure to thrive, severe intrahepatic cholestatic jaundice and fatty liver, hypoproteinemia, hypoglycemia, galactosemia, and multiple aminoacidemia including citrulline, methionine, threonine, and tyrosine and increased serum concentration of pancreatic secretory trypsin inhibitor (4). Possible misdiagnosis of galactosemia and tyrosinemia may arise. The occurrence of a chubby face, objectively measurable by the “Chubby index,” has recently been described in JPGN (5) as a useful clinical marker. Similar to the biochemical findings, this phenotypic feature tends to disappear mostly within the first year of life. Probably because most citrin deficiency cases have been reported in east Asian children, the current North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition recommendations for the evaluation of infants with cholestatic jaundice did not include NICCD testing (6). A more recent expert opinion (7) based on case reports from other ethnic groups (1) advises us to consider this condition when evaluating an infant with cholestasis, whichever her or his ethnicity. Although NICCD is usually reported as a self-limiting condition, the occurrence of a progressive liver failure needing liver transplantation has also been described (8). Prompt detection and specific lactose-free treatment of this etiology may contribute to the avoidance of a complicated course.

Adult-type citrullinemia (CTLN)2 may present an associated liver-specific, secondary decrease in urea cycle enzyme argininosuccinate synthetase. Typical natural history is usually characterized by fatty liver (9) and hyperammonemic encephalopathy in a nonobese east Asian person aged from the second decade of life onward, sometimes having experienced NICCD 1 or more decades before. An increasing number of individuals (bearing mutations different from the common Asian ones) have, however, subsequently been identified in Israel, the United States, the United Kingdom, and the Czech Republic. In some cases, hyperlipidemia, pancreatitis, and hepatoma have also been described (1). Starting at age 2 years, most CTLN2 subjects exhibit a particular fondness for protein- or lipid-rich foods and a dislike of carbohydrate-rich foods. This carbohydrate dislike is contrary to the protein aversion seen in other urea cycle disorders (10). Early identification plays a key role in management because when encephalopathy appears, prognosis is already poor and liver transplantation may become necessary as the ultimate therapeutic approach. Lee et al (3) describe a pediatric presentation of “adult”-type CTLN2 in 2 Korean teenage dyslipidemic siblings, with ultrasonographic and biopsy-proven nonalcoholic fatty liver disease (NAFLD). It has been suggested that hepatic steatosis could depend on an increase in the cytosolic NADH/NAD+ ratio following carbohydrate metabolism, which activates the citrate-malate shuttle in compensation for the hepatic aspartate glutamate carrier insufficiency. This will result in the overproduction of fatty acids in the hepatocytes (11). Further histological progression of the liver disease may be explained by the finding that citrin downregulation induces apoptosis of hepatocytes through the mitochondrial death pathway. One of the patients of Dr Lee had increased ammonia levels and some neurological disturbance. Through careful workup of fatty liver disease, they made the diagnosis of early-onset adult-type CTLN2 and recommended low-carbohydrate, protein-rich foods and arginine in both patients, and ammonia-lowering medication in the second one. After appropriate dietary adjustments, both patients did well. It has been emphasized that the carbohydrate aversion in citrin deficiency is unique and in contrast to protein dislike seen in other urea cycle enzyme deficiencies or in lysinuric protein intolerance (10). As a consequence, fondness for proteins and lipids should not be discouraged, although it may appear illogical in view of existing hyperammonemia and hepatic steatosis, respectively.

Why an editorial on citrin deficiency? The article by Lee and colleagues gives the opportunity to pay attention to the unusual pediatric presentation of another genetic/metabolic disorder causing fatty liver, adding to the now increasingly overflowing NAFLD “trash bin” (9,12). Because of the possible occurrence of citrin deficiency in Western countries, adult-type CTLN2 should always be taken into account, particularly when observing a not-overweight subject with fatty liver and particular dietetic habits. This may be true also in the young (3,13), and in the absence of hyperammonemia and overt encephalopathy (3). Correct diagnosis and specific dietary treatment is crucial to ensure a good prognosis in such patients. Especially outside Asia, novel diagnostic strategies including Western blot analysis of citrin in lymphocytes or cultured fibroblasts will be useful to diagnose citrin deficiency even in individuals without known genetic mutations. We believe that reading this report will help pediatric gastroenterologists, hepatologists, and nutritionists to think of panethnic citrin deficiency when evaluating patients with NAFLD and/or cholestasis and/or failure to thrive with enigmatic clinical and laboratory pictures. Recent observations suggest that metabolic abnormalities do already exist during the silent period, thus making it possible to confirm the clinical suspicion during all stages of the disease.

Back to Top | Article Outline


1. Kobayashi K, Saheki T. Citrin deficiency. In: Pagon RA, Bird TC, Dolan CR, et al, eds. Gene Reviews—NCBI Bookshelf. Seattle, WA: University of Washington; 1993–2009
2. Dimmock D, Kobayashi K, Iijima M, et al. Citrin deficiency: a novel cause of failure to thrive that responds to a high-protein, low-carbohydrate diet. Pediatrics 2007; 119:e773–e777.
3. Lee BH, Jin HY, Kim GH, Choi JH, Yoo HW. Nonalcholic fatty liver disease in two siblings with adult-onset type II citrullinemia. J Pediatr Gastroenterol Nutr 2010;50:682–5.
4. Ohura T, Kobayashi K, Tazawa Y, et al. Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). J Inherit Metab Dis 2007; 30:139–144.
5. Chen HW, Chen HL, Ni YH, et al. Chubby face and the biochemical parameters for the early diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency. J Pediatr Gastroenterol Nutr 2008; 47:187–192.
6. Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2004; 39:115–128.
7. Roberts EA. The jaundiced baby. In: Kelly D, editor. Diseases of the Liver and Biliary System in Children. 3rd ed. Oxford, UK: Wiley-Blackwell; 2008. pp. 57–105.
8. Shigeta T, Kasahara M, Kimura T, et al. Liver transplantation for an infant with neonatal intrahepatic cholestasis caused by citrin deficiency using heterozygote living donor. Pediatr Transplant. 2009 April 3. [Epub ahead of print]
9. Komatsu M, Yazaki M, Tanaka N, et al. Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease. J Hepatol 2008; 49:810–820.
10. Saheki T, Kobayashi K, Terashi M, et al. Reduced carbohydrate intake in citrin-deficient subjects. J Inherit Metab Dis 2008; 31:386–394.
11. 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 2002; 47:333–341.
12. Cassiman D, Jaeken J. NASH may be trash. Gut 2008; 57:141–144.
13. Tomomasa T, Kobayashi K, Kaneko H, et al. Possible clinical and histologic manifestations of adult-onset type II citrullinemia in early infancy. J Pediatr 2001; 138:741–743.
© 2010 Lippincott Williams & Wilkins, Inc.