Patient 2, the elder brother of patient 1, was born at 40 weeks of gestation, weighing 2950 g. At 11.7 years of age, hepatic dysfunction and dyslipidemia were detected during health screening at school (Table 2). His height and weight were both in the 10th percentile, with BMI in the 25th percentile (Fig. 1). Hyperammonemia (127 μmol/L) was detected, but plasma amino acid levels were unremarkable. Liver biopsy revealed microvesicular fatty change and NAFLD. At 14.9 years of age, mild citrullinemia (74 μmol/L) was observed (Table 2). At 15.9 years of age, because of persistent citrullinemia thought to be CTLN1, he was commenced on a low-protein diet (1 g · kg−1 · day−1) and a high-carbohydrate diet constituting 57% of total daily energy, along with ammonia-lowering therapy of sodium benzoate and sodium phenylbutyrate and arginine. At age 18, he suddenly developed stupor and disorientation due to aggravating hyperammonemia (376 μmol/L). He was brought to our hospital for further evaluation. He showed peculiar dietary habits as well as stunted growth (Fig. 1). Chronic hepatic dysfunction with coagulopathy, citrullinemia, and hyperargininemia were noted (Table 2). Abdominal ultrasound showed mild hepatosplenomegaly and a bright liver appearance. He also carries the same mutations in SLC25A13 as patient 1. With the diagnosis of CTLN2, we recommended low-carbohydrate, protein-rich foods with ammonia-lowering medications and arginine. One month later, this dietetic advice aggravated his hyperammonemia, which was relieved by reduction of dietary protein (Table 2).
Citrin, a liver-type mitochondrial aspartate-glutamate carrier, is encoded by the SLC25A13 gene. It plays an important role in urea synthesis from ammonia and translocating cytosolic nicotinamide adenine dinucleotide reducing equivalent (NADH) into mitochondria. Citrin deficiency causes both neonatal intrahepatic cholestasis by citrin deficiency (NICCD; Online Mendelian Inheritance in Man no. 605814) and CTLN2, and some patients with NICCD develop CTLN2 in their later lives (4–7). Although being a rare disease, CTLN2 is now recognized as a panethnic disorder, not restricted to eastern Asian ancestries (9).
Although hyperammonemic encephalopathy in young adulthood is the typical presentation, most patients with CTLN2 remain in the dormant stage for an unknown period before the episode (4,5,10). Our report shows that the 2 siblings presented with NAFLD in the dormant stage of CTLN2. Moreover, patient 1 did not show hyperammonemia, whereas patient 2 already had liver cirrhosis with hyperammonemic encephalopathy at diagnosis, indicating the importance of early diagnosis. For the early diagnosis, the following findings should be borne in mind. The patients with CTLN2 show peculiar dietary habits, preference for protein- or lipid-rich foods but dislike of carbohydrate-rich foods; however, there is evidence of stunted growth. More detailed laboratory workup for CTLN2 can reveal intermittent hyperammonemia, elevation of several plasma amino acids, including citrulline, methionine, and threonine, but normal argininemia (4,5,7,10–12). Genetic counseling is also an integral part of the early diagnosis. Being inherited in an autosomal-recessive manner, careful evaluation for CTLN2 including genetic testing is mandatory for the siblings even when they have no manifestations because they could be in the dormant stage.
NAFLD in CTLN2 is associated with high lipid intake, increased hepatic cholesterol synthesis, and decreased fatty acid oxidation (5,7,10). In addition, a high-carbohydrate diet can increase the cytosolic NADH/NAD+ ratio, which cannot be restored efficiently in citrin deficiency, causing hyperammonemia. It can also interfere with lipid metabolism to aggravate dyslipidemia (4,5,7,11). Therefore, the peculiar dietary habits in patients with CTLN2 should be considered as a compensatory mechanism to avoid hyperammonemia (11). The long-term complications of dyslipidemia in CTLN2 are not yet known, but it needs to be evaluated whether dyslipidemia in CTLN2 is a risk factor for cardiovascular disease, as in obesity (2).
Considering its pathophysiology, the management for NAFLD by CTLN2 should be different from the metabolic syndrome or urea cycle disorders including CTLN1. Carbohydrate-rich foods should be restricted, but lipid- or protein-rich foods should not be avoided. However, for patients with cirrhosis, protein-rich foods can aggravate hyperammonemia, as noticed in patient 2. In addition, a lipid-rich diet may aggravate dyslipidemia (5,7,10). Therefore, dietary therapy should be individualized, with careful monitoring of blood ammonia, hepatic functions, and lipid profiles. According to a recent report by Saheki et al (11), patients with CTLN2 show higher protein and lipid intake but much lower carbohydrate intake comprising 120%, 140%, and 50% of age- and sex-matched normal controls, respectively, which can be used as a reference for dietetic advice.
In addition to dietary modification, nitrogen-scavenging medications including sodium benzoate and sodium phenylbutyrate as well as arginine to facilitate the urea cycle have been recommended (5,12). Recently, sodium pyruvate is tried in patients in the dormant stage by relieving high cytosolic NADH/NAD+ ratio as well as playing a role as a direct source of energy production, whose long-term efficacy needs to be determined (12). In conclusion, although being rare, CTLN2 should always be included in the differential diagnosis of childhood NAFLD, especially when associated with stunted growth. Early detection and individualized managements are mandatory for the patient prognosis.
1. Patton HM, Sirlin C, Behling C, et al
. Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research. J Pediatr Gastroenterol Nutr 2006; 43:413–427.
2. Ebbeling CB, Pawlak DB, Ludwig DS. Childhood obesity: public-health crisis, common sense cure. Lancet 2002; 360:473–482.
3. Weiss R, Dziura J, Burgert TS, et al
. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004; 350:2362–2374.
4. Saheki T, Kobayashi K, Iijima M, et al
. Pathogenesis and pathophysiology of citrin (a mitochondrial aspartate glutamate carrier) deficiency. Metab Brain Dis 2002; 17:335–346.
5. Saheki T, Kobayashi K, Iijima M, et al
. Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle. Mol Genet Metab 2004; 81(Suppl 1):S20–S26.
6. Kobayashi K, Sinasac DS, Iijima M, et al
. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet 1999; 22:159–163.
7. 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.
8. Ko JM, Kim GH, Kim JH, et al
. Six cases of citrin deficiency in Korea. Int J Mol Med 2007; 20:809–815.
9. Dimmock D, Maranda B, Dionisi-Vici C, et al
. Citrin deficiency, a perplexing global disorder. Mol Genet Metab 2009; 96:44–49.
10. Nagasaka H, Okano Y, Tsukahara H, et al
. Sustaining hypercitrullinemia, hypercholesterolemia and augmented oxidative stress in Japanese children with aspartate/glutamate carrier isoform 2-citrin-deficiency even during the silent period. Mol Genet Metab 2009; 97:21–26.
11. Saheki T, Kobayashi K, Terashi M, et al
. Reduced carbohydrate intake in citrin-deficient subjects. J Inherit Metab Dis 2008; 31:386–394.
© 2010 Lippincott Williams & Wilkins, Inc.
12. Mutoh K, Kurokawa K, Kobayashi K, et al. Treatment of a citrin-deficient patient at the early stage of adult-onset type II citrullinaemia with arginine and sodium pyruvate. J Inherit Metab Dis
October 29, 2008 [Epub ahead of print].