1.Current status of research on infantile cholestatic liver disease in China: a visualization analysis.
Qiong LIAO ; Chao-Min WAN ; Yu ZHU ; Xiao-Yan YANG ; Min SHU
Chinese Journal of Contemporary Pediatrics 2017;19(5):529-533
OBJECTIVETo investigate the current status of research on infantile cholestatic liver disease in China and future research trends.
METHODSA co-word analysis was performed in October 2016. Document retrieval and screening were performed in the Chinese databases CNKI and Wanfang Data using "cholestasis" and "infant" as key words. Excel 2010 was used to establish a co-occurrence matrix of high-frequency key words, and Ucinet 6.0 and Netdraw were used to develop a visualized network of these high-frequency key words.
RESULTSA total of 383 articles were included. The co-occurrence analysis showed that "infant" and "cholestasis" were the core of research in this field, and "infantile hepatitis syndrome", "neonate", "intrahepatic", "biliary atresia", "heredity and metabolism", "hepatitis", "cytomegalovirus", "jaundice", and "conjugated bilirubin" were main research topics. Most of the other articles focused on "parenteral nutrition", "hepatobiliary imaging", "gene mutation", and "liver biopsy". There were relatively few articles on surgical diagnostic techniques and treatment for this disease.
CONCLUSIONSThe research on infantile cholestatic liver disease in China focuses on etiology and differential diagnosis, and genetic diagnosis has become a hot topic in recent years. The research on treatment should be enhanced, and new diagnostic techniques are the research interest in future.
Cholestasis, Intrahepatic ; diagnosis ; etiology ; genetics ; therapy ; Humans ; Infant
2.Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency in Korean Infants.
Jae Sung KO ; Jung Han SONG ; Sung Sup PARK ; Jeong Kee SEO
Journal of Korean Medical Science 2007;22(6):952-956
Citrin is a liver-type mitochondrial aspartate-glutamate carrier encoded by the SLC25A13 gene, and its deficiency causes adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Here, the authors investigated clinical findings in Korean infants with NICCD and performed mutation analysis on the SLC25A13 gene. Of 47 patients with neonatal cholestasis, three infants had multiple aminoacidemia (involving citrulline, methionine, and arginine) and galactosemia, and thus were diagnosed as having NICCD. Two of these three showed failure to thrive. The laboratory findings showed hypoproteinemia and hyperammonemia, and liver biopsies revealed micro-macrovesicular fatty liver and cholestasis. The three patients each harbored compound heterozygous 1,638-1,660 dup/ S225X mutation, compound heterozygous 851del4/S225X mutation, and heterozygous 1,638-1,660 dup mutation, respectively. With nutritional manipulation, liver functions were normalized and catch-up growth was achieved. NICCD should be considered in the differential diagnosis of cholestatic jaundice in Korean infants.
Amino Acids/blood
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Calcium-Binding Proteins/*deficiency
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Cholestasis, Intrahepatic/*etiology/genetics
;
Citrullinemia/genetics
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Humans
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Infant
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Membrane Transport Proteins/genetics
;
Mitochondrial Proteins/genetics
;
Mutation
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Organic Anion Transporters/*deficiency
3.Progresses and perspectives in the study on citrin deficiency.
Yao-bang LU ; Fei PENG ; Meng-xian LI ; Keiko KOBAYASHI ; Takeyori SAHEKI
Chinese Journal of Medical Genetics 2006;23(6):655-658
Citrin deficiency causes autosomal recessive disorders including adult-onset type II citrullinemia (CTLN2) and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). The responsive gene of citrin deficiency, SLC25A13, locates on chromosome 7q21.3 and encodes citrin as a liver-type mitochondrial aspartate/glutamate carrier (AGC). The mutations on SLC25A13 will result in deficiency of citrin and CTLN2 or NICCD. Citrin deficiency was found at first in Japan. However, recently, some of cases were identified in China, Korea, Vietnam, Israel, Czech, United States and England, and racial differences of the SLC25A13 mutations were found, suggesting the patients with citrin deficiency maybe exist worldwide. In this article, authors reviewed the progresses in the study on citrin deficiency up to now and put forward authors' considerations for further research on it.
Animals
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Calcium-Binding Proteins
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deficiency
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genetics
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Cholestasis, Intrahepatic
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genetics
;
surgery
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Chromosomes, Human, Pair 7
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Citrullinemia
;
etiology
;
genetics
;
surgery
;
Humans
;
Liver Transplantation
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Membrane Transport Proteins
;
genetics
;
Mitochondrial Membrane Transport Proteins
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Mitochondrial Proteins
;
genetics
;
Organic Anion Transporters
;
deficiency
;
genetics
;
Point Mutation
4.Failure to thrive and dyslipidemia caused by citrin deficiency: a novel clinical phenotype.
Yuan-Zong SONG ; Li GUO ; Yan-Ling YANG ; Lian-Shu HAN ; Keiko KOBAYASHI ; Takeyori SAHEKI
Chinese Journal of Contemporary Pediatrics 2009;11(5):328-332
Two clinical phenotypes for citrin deficiency (CD) have been reported. One is adult-onset citrullinemia type II (CTLN2) and another is neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). A child with CD and who had failure to thrive (FTT) and dyslipidemia as main clinical manifestations is reported here. Both the weight-and length-for-age at 18 months dropped below the 3rd percentile in the corresponding WHO anthropometry percentile charts, while blood biochemical analysis revealed dramatically increased triglyceride and total cholesterol, together with reduced HDL-cholesterol. Inquiries revealed his aversion to rice and fondness for fish since the age of one year, a peculiar habit which could not be corrected. Since the age of two years, the peculiar diet became more obvious, and slightly increased citrulline and threonine levels were detected on blood amino acid analysis. At the age of two years and five months he was suspected to have CD. Since then, he has been fed in accordance with his own food preferences, and FTT improved gradually, with weight-for-age, in particular, recovering beyond the 3rd percentile at three years of age, and dyslipidemia was also ameliorated gradually. SLC25A13 gene analysis revealed a homozygote of 851del4, and CD was thus confirmed. Diet survey at four years and seven months revealed a fondness for high-protein and low-carbohydrate foods, such as seafood, meat, eggs and milk. This child presented with FTT and dyslipidemia as main clinical manifestations and this was a novel CD phenotype different from NICCD and CTLN2.
Body Weight
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Calcium-Binding Proteins
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deficiency
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Cholestasis, Intrahepatic
;
etiology
;
Citrulline
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blood
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Dyslipidemias
;
etiology
;
Failure to Thrive
;
etiology
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Humans
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Infant
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Lipids
;
blood
;
Male
;
Mitochondrial Membrane Transport Proteins
;
genetics
;
Mutation
;
Organic Anion Transporters
;
deficiency
;
Phenotype
5.Neonatal intrahepatic cholestasis caused by citrin deficiency: a histopathologic study of 10 cases.
Guang-yu JIANG ; Zhao-ming CHENG ; Kai-shan LIU
Chinese Journal of Pathology 2012;41(7):452-455
OBJECTIVETo investigate the diagnostic value of histopathological changes in the liver of patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD).
METHODSLiver specimens from 10 cases of NICCD were evaluated by hematoxylin-eosin stain, histochemistry and immunohistochemistry (EnVision method). SLC25A13 mutation analysis was performed to correlate with histopathology.
RESULTSMost specimens showed varying degrees of fat deposition in hepatocytes, necrotic inflammation, cholestasis and fibrosis (so-called tetralogy). The combination of the above four histological changes was highly characteristic for NICCD. With the progression of the disease, hepatic fibrosis deteriorated and ultimately led to cirrhosis.
CONCLUSIONSNICCD should be suspected in the presence of cholestasis during infancy. A liver biopsy must be performed to rule out other liver diseases. The tetralogy of the hepatic histopathological changes has a highly diagnostic value for NICCD, which is also practical for accurately assessing the degree of inflammation and fibrosis, and similarly the progression of hepatic cirrhosis.
Biopsy ; Calcium-Binding Proteins ; deficiency ; genetics ; metabolism ; Cholestasis, Intrahepatic ; etiology ; genetics ; pathology ; Disease Progression ; Female ; Hepatocytes ; pathology ; Humans ; Infant ; Liver ; pathology ; Liver Cirrhosis ; pathology ; Male ; Mitochondrial Membrane Transport Proteins ; genetics ; Mutation ; Organic Anion Transporters ; deficiency ; genetics ; metabolism
6.Identification and diagnosis of three novel mutations in SLC25A13 gene of neonatal intrahepatic cholestasis caused by citrin deficiency.
Yuan-zong SONG ; Jian-sheng SHENG ; Miharu USHIKAI ; Wuh-liang HWU ; Chun-hua ZHANG ; Keiko KOBAYASHI
Chinese Journal of Pediatrics 2008;46(6):411-415
OBJECTIVENeonatal intrahepatic cholestasis caused by citrin deficiency (NICCD, OMIM #605814) is a novel autosomal recessive disease caused by mutations in the gene SLC25A13 that encodes for citrin, a liver-type aspartate/glutamate carrier located in the mitochondrial inner membrane. SLC25A13 was cloned in 1999 by Kobayashi et al at Kagoshima University in Japan, and until now, most of the NICCD patients reported in the world were Japanese. Most of the Chinese NICCD patients diagnosed by genetic analysis had the same SLC25A13 mutations as Japanese, however, in some cases, known mutations were not detected. This research aimed to identify novel SLC25A13 mutations in Chinese NICCD patients and to explore the experimental conditions for their genetic diagnosis.
METHODSGenomic DNA was extracted from blood samples of 3 NICCD patients from Taiwan (P757), Guangdong (P1194) and Hebei province (P1443) of China, respectively, and all the 18 exons and their flanking sequences of SLC25A13 gene were sequenced. Furthermore, the identified novel mutations were diagnosed by amplification with PCR, digestion with corresponding restriction endonuclease, and agarose gel electrophoresis.
RESULTSThree novel mutations identified in SLC25A13 gene of the 3 NICCD patients were an abnormal splicing IVS7-2A > G (P757), a missense A541D (c.1622C > A, P1194) and a nonsense R319X (c.955C > T, P1443). The PCR-restriction fragment length polymorphism (RFLP) procedures for their genetic diagnosis were also established, with specific fragments on electrophoresis after digestion of the PCR products with three different restriction endonucleases Msp I, Hpy188I and Taq I, respectively.
CONCLUSIONSSo far as we know, the three novel mutations in SLC25A13 gene of Chinese NICCD patients were first identified, suggesting that SLC25A13 mutation distributed in Chinese population is somewhat different from that in Japanese. Moreover, the PCR-RFLP diagnostic procedures established in this research provide valuable tools not only for the genetic diagnosis of NICCD but also for further molecular epidemiologic investigations in Chinese population.
Asian Continental Ancestry Group ; genetics ; Base Sequence ; Calcium-Binding Proteins ; deficiency ; Child, Preschool ; Cholestasis, Intrahepatic ; diagnosis ; etiology ; genetics ; Female ; Humans ; Infant ; Male ; Mitochondrial Membrane Transport Proteins ; genetics ; Molecular Sequence Data ; Mutation ; Organic Anion Transporters ; deficiency
7.SLC25A13 gene mutation analysis in a pedigree of neonatal intrahepatic cholestasis caused by citrin deficiency.
Yuan-Zong SONG ; Miharu USHIKAI ; Jian-sheng SHENG ; Mikio IIJIMA ; Keiko KOBAYASHI
Chinese Journal of Pediatrics 2007;45(6):408-412
OBJECTIVENeonatal intrahepatic cholestasis caused by citrin deficiency (NICCD, MIM#605814) is an inherited metabolic disease resulting from mutations of the gene SLC25A13, which encodes citrin, a liver-type mitochondrial aspartate-glutamate carrier. Mutation analysis is necessary for definitive diagnosis of NICCD patients. So far (March, 2007), 36 kinds of mutation, including 7 nonsense, 10 missense, 11 abnormal splicing, 4 insertion and 4 deletion, have been identified by Kobayashi's group, who cloned the gene in Kagoshima, Japan. To date, most of the NICCD patients reported in the world are Japanese. This study aimed to explore the gene diagnosis procedure of two known SLC25A13 mutations in a pedigree with an NICCD patient from China.
METHODSDNA was extracted from dried blood spots collected with filter papers from the proband and other 9 members in a NICCD pedigree from China, and then PCR amplification and agarose gel electrophoresis were performed, revealing two mutations preliminarily, which were further proved by Genescan, a procedure established in our laboratory already. Furthermore, the positions and characteristics of the mutations were finally confirmed by DNA sequencing.
RESULTSThe proband is a compound heterozygote of two mutations, 851-854del in exon 9 and 1638-1660dup in exon 16 of SLC25A13 gene. His mother and brother carry the former mutation, which predicts a frameshift and introduction of a stop codon at position 286, while his father, one aunt and her son carry the latter, resulting in a frameshift at codon 554, and introducing a stop codon at position 570.
CONCLUSIONA deletion mutation 851-854del in exon 9 and an insertion mutation 1638-1660dup in exon 16 of SLC25A13 gene were identified in the pedigree, providing reliable evidences for both diagnostic confirmation of the patient and the genetic counseling from other members in the pedigree.
Calcium-Binding Proteins ; deficiency ; genetics ; metabolism ; China ; Cholestasis ; etiology ; genetics ; Cholestasis, Intrahepatic ; genetics ; metabolism ; Citrullinemia ; complications ; genetics ; DNA Mutational Analysis ; Genetic Testing ; Hepatocytes ; Humans ; Infant ; Japan ; Liver Diseases ; genetics ; Male ; Membrane Transport Proteins ; Mitochondrial Membrane Transport Proteins ; genetics ; Mutation ; Organic Anion Transporters ; deficiency ; genetics ; Pedigree ; Urea Cycle Disorders, Inborn ; genetics
8.Analysis of clinical features and SLC25A13 gene mutations in a family affected with neonatal intrahepatic cholestasis.
Ling WANG ; Xinran CHENG ; Li YAN ; Yan WEI ; Fang TANG ; Xin DONG ; Yanjiao YUAN ; Yanmei XIE
Chinese Journal of Medical Genetics 2016;33(5):670-673
OBJECTIVETo analyze the clinical features and potential mutations of the SLC25A13 gene in a boy affected with neonatal intrahepatic cholestasis.
METHODSClinical data and peripheral venous blood sample of the child, and peripheral venous blood samples of both parents, were collected. All coding exons of the SLC25A13 gene were amplified with PCR and subjected to direct DNA sequencing.
RESULTSThe boy was found to be a compound heterozygote carrying c.851_854delGTAT and IVS16ins3kb mutations of the SLC25A13 gene, which were respectively inherited from his mother and father.
CONCLUSIONBased on its clinical and genetic features, the patient was diagnosed with neonatal intrahepatic cholestasis caused by citrin deficiency.
Base Sequence ; Cholestasis, Intrahepatic ; etiology ; genetics ; Citrullinemia ; complications ; DNA Mutational Analysis ; Family Health ; Female ; Heterozygote ; Humans ; Infant ; Infant, Newborn ; Male ; Mitochondrial Membrane Transport Proteins ; genetics ; Mutagenesis, Insertional ; Mutation ; Sequence Deletion
9.A case of neonatal intrahepatic cholestasis caused by citrin deficiency complicated with congenital biliary atresia.
Fan TONG ; Jian-bin YANG ; Xiao-lei HUANG ; Xue-lian ZHOU ; Ru-lai YANG
Chinese Journal of Pediatrics 2013;51(11):863-865
Biliary Atresia
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diagnosis
;
etiology
;
therapy
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Bilirubin
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blood
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Biomarkers
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blood
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Calcium-Binding Proteins
;
deficiency
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Cholangiopancreatography, Magnetic Resonance
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Cholestasis, Intrahepatic
;
diagnosis
;
etiology
;
therapy
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Citrullinemia
;
diagnosis
;
etiology
;
therapy
;
DNA Mutational Analysis
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Humans
;
Infant
;
Jaundice
;
diagnosis
;
etiology
;
therapy
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Liver Function Tests
;
Male
;
Mitochondrial Membrane Transport Proteins
;
genetics
;
Mutation
;
Organic Anion Transporters
;
deficiency
10.Clinical and histological features of fibrosing cholestatic hepatitis.
Youfu ZHU ; Kangxian LUO ; Lixin YU
Chinese Journal of Hepatology 2002;10(6):434-436
OBJECTIVETo investigate the clinical and histological characteristics of fibrosing cholestatic hepatitis (FCH) and the therapeutic effect of lamivudine.
METHODSBy retrospective analysis, 17 cases developed severe jaundice in 794 renal-transplanted recipients, and of them, FCH was clinically suggested in 11 and confirmed by liver biopsy in 6 cases.
RESULTSThe prevalence of chronic HBV infection in renal transplantation patients was 9.3%, of whom the FCH occurred in 22.9%. In 6 liver-biopsied cases, the onset was within 1.5-22 months. Two cases remitted who had early received lamivudine and 4 cases who were treated with the drug before transplantation did not develop the disease. All patients received large amounts of multiple immuno-suppressors after transplantation. About one fifth of HBV-infected cases gradually developed cholestatic hepatitis and some of them rapidly proceeded to hepatic failure. All had very high serum level of HBV DNA. The histology revealed unique lesion combination. The hepatocytes had widespread ballooning change and some ground-glass appearance. There were liver cytolysis and focal cell loss, bile stasis, periportal fibrosis, while only mild lymphocytic infiltration.
CONCLUSIONSFibrosing cholestatic hepatitis may happen following renal transplantation. Lamivudine has marked therapeutic effect for FCH.
Adult ; Anti-HIV Agents ; therapeutic use ; Cholestasis, Intrahepatic ; drug therapy ; etiology ; pathology ; DNA, Viral ; blood ; genetics ; Female ; Fibrosis ; Hepatitis B ; blood ; complications ; Hepatitis B virus ; genetics ; Hepatocytes ; drug effects ; pathology ; Humans ; Kidney Transplantation ; adverse effects ; Lamivudine ; therapeutic use ; Male ; Middle Aged ; Retrospective Studies