Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease☆
Introduction
Citrin is a liver-type mitochondrial aspartate–glutamate carrier (AGC) known to exchange mitochondrial aspartate for cytosolic glutamate and a proton [1], [2], [3]. This function is important in translocating cytosolic nicotinamide adenine dinucleotide (NADH) reducing equivalents into the mitochondria as a part of the malate-aspartate shuttle, and NADH produced by malate is oxidized to generate adenosine triphosphate (ATP) in the oxidative phosphorylation pathway. Moreover, liver-specific AGC also plays an important role in supplying aspartate to argininosuccinate synthetase (ASS) in the cytosol to generate argininosuccinate in the urea cycle. Thus, a deficiency of liver-specific AGC, namely citrin, results in dysfunction of the urea cycle and hyperammonemia [2], [3].
Citrin deficiency is an autosomal recessive disorder caused by a mutation of the SLC25A13 gene encoding citrin, which is located on chromosome 7q21.3 [2], [3], [4]. Some of the mutations identified in Japanese patients are frequently found in the East Asian population, and the prevalence of these mutations has been estimated to be 1/65 in China, 1/112 in Korea, and 1/69 in Japan [3], [5], [6]. Furthermore, several cases with SLC25A13 gene mutations have been reported in Israel, USA, and elsewhere [7], [8], [9], indicating a world-wide incidence of citrin deficiency.
The SLC25A13 gene mutation leads to neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and adult-onset type II citrullinemia (CTLN2) [2], [3]. Citrin deficiency is sometimes asymptomatic in adults probably by metabolic adaptation, but CTLN2 is characterized by the sudden onset of various neuropsychological symptoms including disorientation, abnormal behavior, convulsions, and coma due to hyperammonemia, which may result in rapidly progressive and irreversible brain edema and death. Generally speaking, the prognosis of patients with CTLN2 is not favorable after the onset of encephalopathy, and liver transplantation is required for severe CTLN2 which is refractory to various ammonia-lowering and neuroprotective therapies. Furthermore, certain types of conventional treatments for brain edema, such as intravenous administration of hyperosmotic and high sugar solutions, have been reported to aggravate encephalopathy [2], [10], [11], and the mechanism of toxicity of carbohydrate overload for citrin deficiency has been recently clarified using mouse models [12]. Thus, early diagnosis of citrin deficiency and CTLN2 and appropriate treatment might improve prognosis.
Citrin deficiency has been demonstrated to present with hepatic steatosis and steatohepatitis. Previously, we reported the case of a patient with non-alcoholic fatty liver disease (NAFLD) who was later shown to carry SLC25A13 gene mutation [13]. The patient had elevation of serum aminotransferase levels and fatty liver of unknown causes, and was first diagnosed as having NAFLD by liver biopsy at the age of 23. Ten years afterwards, serious encephalopathy suddenly appeared after accidental consumption of alcohol. The patient was then diagnosed as having CTLN2, but did not respond to any conservative treatments and required urgent liver transplantation [13], [14]. Moreover, Takagi et al. have also reported three CTLN2 patients with liver histologies of steatohepatitis [15]. These findings suggest the possibility that citrin deficiency may be present in adults who are diagnosed as having NAFLD or non-alcoholic steatohepatitis (NASH), and elucidating the characteristics of fatty liver related to citrin deficiency may be helpful in the early distinction of this disease from conventional NAFLD. However, the clinical features of this phenomenon have not been fully investigated.
In the present study, we evaluated the clinical characteristics of citrin deficiency-associated fatty liver through analysis of CTLN2 patients presenting with fatty liver, and sought to find key indicators to detect citrin deficiency in NAFLD patients.
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Patients
Nineteen CTLN2 patients (11 men and 8 women, mean age 37 ± 10 yrs), who had been admitted to Shinshu University Hospital between 1979 and 2007, were examined in this study. All patients had experienced neuropsychological symptoms due to hyperammonemia. CTLN2 was suspected from the presence of neurological abnormalities and elevated plasma ammonia and citrulline levels, and diagnosis was confirmed by the presence of SLC25A13 gene mutations. In these patients, the presence of fatty liver was
Prevalence of fatty liver in CTLN2 patients at time of admission
Clinical features of the 19 CTLN2 patients are summarized in Table 1. Their median age was 40 years. Only one patient (No. 11) had a past history of prolonged neonatal jaundice, a symptom suggestive of NICCD [26]. Thirteen (68%) patients tended to consume with frequency protein-rich foods such as beans, eggs, or cheese, but the others did not have any peculiar dietary preferences. All patients demonstrated hypercitrullinemia and had SLC25A13 gene mutations (9 homozygotes), and all patients
Discussion
The present study demonstrates that citrin deficiency can superficially mimic NAFLD before the onset of neurological abnormalities. However, fatty liver patients with SLC25A13 mutations lacked the complications of obesity, metabolic syndrome, and diabetes. Furthermore, BMI and serum PSTI appeared to be clues in distinguishing citrin deficiency from conventional NAFLD. As far as we know, this is the first study to review the clinical features of citrin deficiency-associated fatty liver disease
Acknowledgements
The authors would like to thank Mr. Trevor Ralph for his editorial assistance. This study was supported in part by Grants-in-Aid for Scientific Research (B: No. 16390100 and 19390096) and for the Asia–Africa Scientific Platform Program from the Japan Society for the Promotion of Science.
References (42)
- et al.
Metabolic derangements in deficiency of citrin, a liver-type mitochondrial aspartate–glutamate carrier
Hepatol Res
(2005) - et al.
Screening of nine SLC25A13 mutations: their frequency in patients with citrin deficiency and high carrier rates in Asian populations
Mol Genet Metab
(2003) - et al.
Infantile citrullinemia caused by citrin deficiency with increased dibasic amino acids
Mol Genet Metab
(2002) - et al.
Citrin/mitochondrial glycerol 3-phosphate double-knockout mice recapitulate features of human citrin deficiency
J Biol Chem
(2007) - et al.
A lean man with nonalcoholic fatty liver disease
Clin Gastroenterol Hepatol
(2007) - et al.
Adult onset type II citrullinemia as a cause of non-alcoholic steatohepatitis
J Hepatol
(2006) - et al.
The utility of radiological imaging in nonalcoholic fatty liver disease
Gastroenterology
(2002) - et al.
Variant clinical courses of 2 patients with neonatal intrahepatic cholestasis who have a novel mutation of SLC25A13
Metabolism
(2005) - et al.
Impaired ketogenesis in patients with adult-type citrullinemia
Gastroenterology
(1994) - et al.
Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor α (PPARα)
J Biol Chem
(1998)
Effectiveness of carbohydrate-restricted diet and arginine granules therapy for adult-onset type II citrullinemia: a case report of siblings showing homozygous SLC25A13 mutation with and without the disease
Hepatol Res
Homozygous SLC25A13 mutation in a Taiwanese patient with adult-onset citrullinemia complicated with steatosis and hepatocellular carcinoma
J Formos Med Assoc
Novel diagnostic approach to citrin deficiency: analysis of citrin protein in lymphocytes
Mol Genet Metab
Pyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice
J Hepatol
Citrin and aralar1 are Ca2+-stimulated aspartate/glutamate transporters in mitochondria
EMBO J
Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis
J Hum Genet
The gene mutated in adult-onset type II citrullinemia encodes a putative mitochondrial carrier protein
Nat Genet
Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency
J Hum Genet
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in a European patient
J Inherit Metab Dis
Citrin deficiency: a novel cause of failure to thrive that responds to a high-protein, low-carbohydrate diet
Pediatrics
Risk of worsened encephalopathy after intravenous glycerol therapy in patients with adult-onset type II citrullinemia (CTLN2)
Intern Med
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The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript.