Hepatocellular Carcinoma in a Case of Adult-onset Type II Citrullinemia

Hagiwara, Naoki; Sekijima, Yoshiki; Takei, Yo‐ichi; Ikeda, Shu‐ichi; Kawasaki, Seiji; Kobayashi, Keiko; Saheki, Takeyori

doi:10.2169/internalmedicine.42.978

Cited by 34 publications

(24 citation statements)

References 15 publications

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“…Since all liver samples analyzed were obtained shortly after the onset of neurological abnormalities and the initiation of ammonia-reducing therapy, the possibility that the development of hepatic fibrosis can be attributed to inadequate therapeutic interventions (e.g., strict protein restriction, long-term intravenous hyperalimentation) seems very low. More importantly, citrin deficiency can induce HCC [2,27,[38][39][40], meaning clinicians should also consider citrin deficiency as one of the etiologies of cryptogenic cirrhosis or HCC.…”

Section: Discussionmentioning

confidence: 99%

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

Komatsu

Yazaki

Tanaka

et al. 2008

Journal of Hepatology

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NAS, NAFLD activity score; ROC, receiver-operating characteristic; AUC, area under the ROC curve; γGT, γ-glutamyltransferase; HCC, hepatocellular carcinoma.2 Abstract 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 nonalcoholic 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/m 2 and serum PSTI > 29 ng/mL were associated with citrin deficiency. Conclusion: Patients presenting with nonalcoholic 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.

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Section: Discussionmentioning

confidence: 99%

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

Komatsu

Yazaki

Tanaka

et al. 2008

Journal of Hepatology

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“…Although our microarray analyses were performed primarily to uncover genes that might be involved in the major symptoms of citrin deficiency, they also have the potential to identify pathways involved in additional conditions associated with human citrin deficiency, such as an increased incidence of hepatocellular carcinoma, pancreatitis, steatohepatitis, and hyperlipidemia in CTLN2 patients (1,2,8,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). From our present results, we found profound changes in gene expression related to pathways involved in drug metabolism, fat metabolism, oxidative stress, and cell growth in the liver of double knock-out mice.…”

Section: Discussionmentioning

confidence: 99%

“…The elevated pancreatic secretory trypsin inhibitor in CTLN2 patients results from its up-regulated transcriptional expression in the liver (20). Finally, CTLN2 patients also have an increased incidence of hepatocellular carcinoma, pancreatitis, and hyperlipidemia (1,2,8,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”

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confidence: 99%

Citrin/Mitochondrial Glycerol-3-phosphate Dehydrogenase Double Knock-out Mice Recapitulate Features of Human Citrin Deficiency

Saheki

Iijima

et al. 2007

Journal of Biological Chemistry

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Citrin is the liver-type mitochondrial aspartate-glutamate carrier that participates in urea, protein, and nucleotide biosynthetic pathways by supplying aspartate from mitochondria to the cytosol.Citrin also plays a role in transporting cytosolic NADH reducing equivalents into mitochondria as a component of the malate-aspartate shuttle. In humans, loss-of-function mutations in the SLC25A13 gene encoding citrin cause both adult-onset type II citrullinemia and neonatal intrahepatic cholestasis, collectively referred to as human citrin deficiency. Citrin knock-out mice fail to display features of human citrin deficiency. Based on the hypothesis that an enhanced glycerol phosphate shuttle activity may be compensating for the loss of citrin function in the mouse, we have generated mice with a combined disruption of the genes for citrin and mitochondrial glycerol 3-phosphate dehydrogenase. The resulting double knock-out mice demonstrated citrullinemia, hyperammonemia that was further elevated by oral sucrose administration, hypoglycemia, and a fatty liver, all features of human citrin deficiency. An increased hepatic lactate/pyruvate ratio in the double knock-out mice compared with controls was also further elevated by the oral sucrose administration, suggesting that an altered cytosolic NADH/NAD ؉ ratio is closely associated with the hyperammonemia observed. Microarray analyses identified over 100 genes that were differentially expressed in the double knock-out mice compared with wild-type controls, revealing genes potentially involved in compensatory or downstream effects of the combined mutations. Together, our data indicate that the more severe phenotype present in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice represents a more accurate model of human citrin deficiency than citrin knock-out mice.

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“…The patient was a 40-year-old Japanese woman whose detailed clinical course was reported elsewhere (21). Briefly, at age 39 in October 2000, she developed disturbance of consciousness accompanied by abnormal behavior.…”

Section: Patientmentioning

confidence: 99%

Risk of Worsened Encephalopathy after Intravenous Glycerol Therapy in Patients with Adult-onset Type II Citrullinemia (CTLN2)

et al. 2005

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Objective We report a risk of worsening of encephalopathy by glycerol infusion when this osmotic agent is used for the treatment of brain edema in patients with adult-onset type II citrullinemia (CTLN2) caused by citrin deficiency.Patients and Methods We performed a retrospective investigation of 3 patients with CTLN2 treated for brain edema at our institute: a 31-year-old male patient and a 40-year-old female patient received treatment for encephalopathy-related brain edema with 10% glycerol infusion and 20% D-mannitol, and a 40-year-old male patient received only 20% D-mannitol infusion. In addition, we also performed a retrospective study in 11 CTLN2 patients reported previously (8 patients treated with 10% glycerol, 2 treated with 10% glycerol and 20% mannitol, and 1 treated with 20% mannitol).Results The 12 patients treated with 10% glycerol, including 2 of our patients, died due to rapidly deteriorating encephalopathy and brain edema. On the other hand, the 2 patients who received only 20% D-mannitol, including one of our patients, recovered with the disappearance of brain edema.Conclusion In CTLN2 patients, glycerol infusion seems to be associated with exacerbation of encephalopathy itself and only mannitol should be used for the treatment of brain edema in patients with this disorder. (Internal Medicine 44: 188-195, 2005)

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Hepatocellular Carcinoma in a Case of Adult-onset Type II Citrullinemia

Cited by 34 publications

References 15 publications

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

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

Citrin/Mitochondrial Glycerol-3-phosphate Dehydrogenase Double Knock-out Mice Recapitulate Features of Human Citrin Deficiency

Risk of Worsened Encephalopathy after Intravenous Glycerol Therapy in Patients with Adult-onset Type II Citrullinemia (CTLN2)

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