Elsevier

Journal of Hepatology

Volume 49, Issue 5, November 2008, Pages 810-820
Journal of Hepatology

Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease

https://doi.org/10.1016/j.jhep.2008.05.016Get rights and content

Background/Aims

Citrin deficiency caused by SLC25A13 gene mutations develops into adult-onset type II citrullinemia (CTLN2) and may be accompanied with hepatic steatosis and steatohepatitis. As its clinical features remain unclear, we aimed to explore the characteristics of fatty liver disease associated with citrin deficiency.

Methods

The prevalence of hepatic steatosis in 19 CTLN2 patients was examined, and clinical features were compared with those of non-alcoholic fatty liver disease (NAFLD) patients without known SLC25A13 gene mutations.

Results

Seventeen (89%) CTLN2 patients had steatosis, and 4 (21%) had been diagnosed as having NAFLD before appearance of neuropsychological symptoms. One patient had steatohepatitis. Citrin deficiency-associated fatty livers showed a considerably lower prevalence of accompanying obesity and metabolic syndrome, higher prevalence of history of pancreatitis, and higher serum levels of pancreatic secretory trypsin inhibitor (PSTI) than fatty livers without the mutations. Receiver operating characteristic curve analyses revealed that a body mass index < 20 kg/m2 and serum PSTI > 29 ng/mL were associated with citrin deficiency.

Conclusions

Patients presenting with non-alcoholic fatty liver unrelated to obesity and metabolic syndrome might have citrin deficiency, and serum PSTI may be a useful indicator for distinguishing this from conventional NAFLD.

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.

Section snippets

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.

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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.

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