*Department of Pediatrics, Korea
†Medical Genetics Clinic and Laboratory, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Received 13 September, 2009
Accepted 28 January, 2010
Address correspondence and reprint requests to Han-Wook Yoo, Department of Pediatrics, Medical Genetics Clinic and Laboratory, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap-dong, Songpa-gu, Seoul 138-736, Korea (e-mail: email@example.com).
This study was supported in part by grant A080588 from the Korean Ministry of Health, Welfare, and Family Affairs.
The authors report no conflicts of interest.
Nonalcoholic fatty liver disease (NAFLD) is characterized by elevated hepatic enzymes, radiological feature of fatty change, and steatosis with inflammation and fibrosis in liver biopsy (1). Excluding infectious diseases, autoimmune diseases, drugs, α1-antirypsin deficiency, and Wilson disease, NAFLD in the preadolescent and adolescent periods is suggested to be mainly associated with obesity due to rapidly growing prevalence (1–3).
Diverse inherited metabolic disorders including citrin deficiency can exhibit hepatic manifestations, mostly in the neonate or infant periods; however, citrin deficiency can also present in the late adolescent to adult period. The typical presentation of citrullinemia type II (CTLN2) is hyperammonemic encephalopathy accompanying hepatic dysfunction and NAFLD, which is called adult-onset CTLN2 (Online Mendelian Inheritance in Man no. 603471) (4–7). In contrast to a urea cycle disorder or citrullinemia type I (CTLN1), citrullinemia is not prominent and the plasma arginine level is usually normal in CTLN2. The patients have peculiar dietary habits, preference for protein- or lipid-rich foods, such as eggs, meat, fish, and beans, but dislike of carbohydrate-rich foods like rice, bread, and sweets; however, they show stunted growth patterns. Once a patient experiences hyperammonemic encephalopathy, the prognosis is believed to be poor due to repeated hyperammonemic episodes and accompanying liver cirrhosis, and liver transplantation is the only curative management (4,5,7). Therefore, early identification and adequate management are important for the patient prognosis.
Here, we report 2 teenage siblings with CTLN2 manifesting as NAFLD before they experienced hyperammonemic encephalopathy, indicating that NAFLD is an important early sign of CTLN2.
Patient 1, the son of nonconsanguineous parents, was born at 40 weeks of gestation, weighing 2900 g. His growth and development had been unremarkable until 10.6 years of age, when multiple xanthomatous skin lesions were detected on the trunk. His height, weight, and body mass index (BMI) were each in the 25th percentile (Fig. 1). His liver was not enlarged. Hepatic dysfunction and dyslipidemia were detected, but the blood ammonia level was normal (10 μmol/L) (Table 1). To control his dyslipidemia, he was advised to avoid fat-rich foods and weight gain, with no improvement. The extensive evaluations for infectious diseases and Wilson disease were normal. Plasma amino acid analysis at 11.8 years of age showed mild citrullinemia (127 μmol/L) but normal ammonia, arginine, glutamine, and alanine levels (Table 1). At 14 years of age, liver biopsy was performed due to persistent hepatic dysfunction and dyslipidemia, and the histological examination showed mixed macro- and microvesicular fatty change with periportal fibrosis, suggesting NAFLD. At 14.8 years of age, he visited our hospital. He showed peculiar dietary habits, being fond of protein-rich foods, eggs, fish, and meat, but not sweet foods. His height, body weight, and BMI were lower than the third percentile, indicating stunted growth (Fig. 1). Citrullinemia and hepatic dysfunction persisted (Table 1). Genetic analysis of SLC25A13 revealed that he carries the compound heterozygous mutations c. 1177+1G>A and ins3kbIVS16, both of which are the common mutations of SLC25A13 in Korea (8). Following a diagnosis of CTLN2, we recommended a low-carbohydrate diet with arginine supplementation.
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.
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