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

ATP Binding Cassette Transporter, Sub-Family B ; genetics ; Cholestasis, Intrahepatic ; classification ; genetics ; Humans

Progressive familial intrahepatic cholestasis type I (PFIC1) is an autosomal recessive disorder caused by biallelic mutations of ATP8B1 gene, with progressive cholestasis as the main clinical manifestation. This paper reports the clinical and genetic features of a PFIC1 patient definitely diagnosed by ATP8B1 genetic analysis. The patient, a boy aged 14 months, was referred to the hospital with the complaint of jaundiced skin and sclera over 10 months. The patient had been managed in different hospitals, but the therapeutic effects were unsatisfactory due to undetermined etiology. On physical examination, hepatosplenomegaly was discovered in addition to jaundice of the skin and sclera. The liver was palpable 4 cm below the right subcostal margin and 2 cm below the xiphoid while the spleen 2 cm below the left subcostal margin. The liver function test revealed elevated levels of serum total bile acids, bilirubin, and transaminases; however, the γ-glutamyl transferase level was normal. The diagnosis was genetic cholestasis of undetermined origin. At the age of 1 year and 8 months, a Roux-en-Y cholecystocolonic bypass operation was performed, and thereafter the jaundice disappeared. At 5 years and 1 month, via whole genome sequencing analysis and Sanger sequencing confirmation, the boy was found to be a homozygote of mutation c.2081T>A(p.I694N) of ATP8B1 gene, and thus PFIC1 was definitely diagnosed. The boy was followed up until he was 6 years, and jaundice did not recur, but the long-term outcome remains to be observed.
Adenosine Triphosphatases ; genetics ; Cholestasis, Intrahepatic ; genetics ; DNA Mutational Analysis ; Humans ; Infant ; Male ; Mutation ; Sequence Analysis, DNA

Adenosine Triphosphatases ; genetics ; Adolescent ; Adult ; Cholestasis, Intrahepatic ; diagnosis ; genetics ; Chronic Disease ; Female ; Humans ; Male ; Young Adult

OBJECTIVETo explore whether SLC25A13 gene mutation exists and what is its mutation spectrum in mainland Chinese infants with intrahepatic cholestasis and abnormal blood amino acids.

METHODSBlood amino acids were analyzed by mass chromatographic analysis in infants referred to Fudan University Children's Hospital from June 2003 to June 2007 for investigations of intrahepatic cholestasis of unknown origin. SLC25A13 gene mutations were studied in 14 children whose serum levels of citrulline and/or methionine were at least two times above the upper normal range. In patients in whom only one mutation was detected, all other exons and their neighboring sequences were then analyzed.

RESULTSEight patients with SLC25A13 gene mutations, including 2 with compound heterozygous mutation 851del4/1638ins23, one with homozygous mutation 851del4/851del4, one with compound heterozygous mutation 851del4/R184X, one with homozygous mutation IVS6+1G more than A/IVS6+1G more than A, and 3 with heterozygous mutation 851del4 were found.

CONCLUSIONSSLC25A13 gene mutations exist in Chinese infants with intrahepatic cholestasis and abnormal blood amino acids. Their mutation spectrum is different from that in Japan. 851del4 is the most common mutation in our study. IVS6+1G more than A is a mutation that has not been reported before.

Amino Acids ; blood ; Cholestasis, Intrahepatic ; blood ; genetics ; DNA Mutational Analysis ; Humans ; Infant ; Infant, Newborn ; Mitochondrial Membrane Transport Proteins ; genetics ; Mutation

OBJECTIVENeonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) which resulted from mutation in SLC25A13 gene can present transient intrahepatic cholestasis, low birth weight, growth retardation, hypoproteinemia and so on. This study aimed to identify the mutation type of NICCD patients by DNA sequencing.

METHODSTwenty children diagnosed as NICCD were consented to enroll in this study. PCR assays were performed to amplify the eighteen exons and its flanking sequences of SLC25A13 gene, which were defined as the upstream and downstream 50 bp from starting and ending site of the exons. Then the PCR products were purified and followed by automated DNA sequencing. The IVS16ins3kb mutation was detected by nested PCR and RT-PCR.

RESULTSSeven genetic variations of SLC25A13, termed as 851del4, 1638ins23, IVS16ins3kb, IVS6+5G>A, c.775C>T (p.Q259X), c.1505C>T (p.P502L) and c.1311C>T (p.C437C), were identified in the subjects, of which c.775C>T (p.Q259X), c.1505C>T (p.P502L) and c.1311C>T (p.C437C) were reported for the first time in NICCD patients. And a compound mutation of［1638ins23+IVS16ins3kb］was also identified. In 20 patients with NICCD, 6 patients were 851del4 homozygotes, 7 patients were compound heterozygotes, and 7 patients were heterozygotes of single mutation. 851del4 was the major mutation type (64%), followed by 1638ins23 (15%), IVS16ins3kb (12%) and IVS6+5G>A (6%).

CONCLUSIONS851del4 is the major mutation type in Chinese patients with NICCD.

Cholestasis, Intrahepatic ; genetics ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Mitochondrial Membrane Transport Proteins ; deficiency ; genetics ; Mutation ; Sequence Analysis, DNA

OBJECTIVE: To explore the clinical characteristics and genetic findings of patients with infantile intrahepatic cholestasis. METHODS: The clinical data were collected in children who were admitted to the Department of Gastroenterology in Children's Hospital, Capital Institute of Pediatrics from June 2017 to June 2019 and were suspected of inherited metabolic diseases. Next generation sequencing based on target gene panel was used for gene analysis in these children. Sanger sequencing technology was used to verify the genes of the members in this family. RESULTS: Forty patients were enrolled. Pathogenic gene variants were identified in 13 patients (32%), including CONCLUSIONS The etiology of infantile intrahepatic cholestasis is complex. Next generation sequencing is helpful in the diagnosis of infantile intrahepatic cholestasis.
Alagille Syndrome/genetics* ; Child ; Cholestasis, Intrahepatic/genetics* ; Citrullinemia ; Genetic Testing ; High-Throughput Nucleotide Sequencing ; Humans ; Mitochondrial Membrane Transport Proteins ; Mutation

OBJECTIVETo explore the relationship between human leukocyte antigen-DQA1 (HLA-DQA1) allele gene polymorphism and intrahepatic cholestasis of pregnancy (ICP).

METHODSForty-five patients with ICP, eighteen ICP families, forty-five normal pregnant women and eighteen normal control families were tested for HLA-DQA1 allele gene polymorphism by polymerase chain reaction with sequence-specific primer (PCR-SSP) method.

RESULTSThe frequency of HLA-DQA1*0301 in normal pregnant women was markedly higher than that in the ICP group (P>0.05). No significant differences were observed between the frequencies of other detected HLA-DQA1 alleles in both groups. The analysis of feto-maternal or couples sharing of the HLA-DQA1 alleles showed that no significant differences were observed between the two groups.

CONCLUSIONThe above findings suggest that there is no significant association between the genetic polymorphisms in HLA-DQA1 and ICP in Chengdu district; HLA-DQA1*0301 may be a protective gene against ICP. It may prevent the development of ICP.

Adult ; Alleles ; Cholestasis, Intrahepatic ; genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; genetics ; HLA-DQ Antigens ; genetics ; Humans ; Polymerase Chain Reaction ; Polymorphism, Genetic ; genetics ; Pregnancy ; Pregnancy Complications ; genetics

OBJECTIVETo investigate the relation ship of estrogen receptor 2 gene (ESR2) polymorphism associated with intrahepatic cholestasis of pregnancy (ICP) in Chengdu of China.

METHODSBy polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, the Rsa I polymorphism in exon 5 and the Alu I polymorphism in exon 8 of ESR2 were detected in 100 pregnant women with ICP (ICP group) and 100 normal pregnant women (control group) in Chengdu.

RESULTS(1) The frequency of the allele A of Alu I polymorphism in exon 8 was significantly higher in ICP group than in control group (P=0.031, OR=1.975), so did the frequency of the Aa+AA genotypes (P=0.028, OR=2.144). (2) The genotype distributions (rr, Rr and RR) and allele frequencies (r and R) of Rsa I polymorphism in exon 5 were not significantly different between the two groups (P>0.05).

CONCLUSIONThe Alu I polymorphism in exon 8 of ESR2 may be associated with the susceptibility of ICP in Chengdu. The Aa+AA genotype significantly elevated the risk suffering from the ICP. The Rsa I polymorphism in exon 5 of ESR2 is not associated with the risk getting the ICP in Chengdu.

Cholestasis, Intrahepatic ; genetics ; Estrogen Receptor beta ; genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; genetics ; Genotype ; Humans ; Polymorphism, Genetic ; genetics ; Polymorphism, Restriction Fragment Length ; Pregnancy ; Pregnancy Complications ; genetics

OBJECTIVE: To explore the characteristics of SLC25A13 gene variants in 16 infants with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). METHODS: The infants were subjected to high-throughput DNA sequencing for coding exons and flanking regions of the target genes. Suspected variants were verified by Sanger sequencing and bioinformatic analysis. RESULTS: Among the 16 NICCD cases, 15 were found to harbor pathogenic variants. Among these, IVS14-9A>G, c.1640G>A, c.762T>A, c.736delG, c.1098Tdel and c.851G>A were previously unreported. CONCLUSION Six novel SLC25A13 variants were found by high-throughput sequencing, which has enriched the spectrum of SLC25A13 gene variants and provided a basis for genetic counseling and prenatal diagnosis.
Calcium-Binding Proteins/genetics* ; Cholestasis, Intrahepatic/genetics* ; Citrullinemia/genetics* ; Humans ; Infant ; Infant, Newborn ; Mitochondrial Membrane Transport Proteins/genetics* ; Mutation ; Organic Anion Transporters/genetics* ; Protein Deficiency