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1.  AB083. A cause of cholestasis and hepatic failure in children: neonatal intrahepatic cholestasis cause by citrin deficiency 
Annals of Translational Medicine  2015;3(Suppl 2):AB083.
Background and objective
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is rare disease. It is a novel metabolism disease which caused by deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier encoded by the SLC25A13 gene. Citrin deficiency causes NICCD and adult-onset type II citrullinemia (CTLN2) with severe hepatic-neurology syndrome. The study presents some clinical features, laboratory finding, results molecular analysis and following process of 96 NICCD.
Prospective description study.
Two hundred and thirty-six patients, who had hepatic troubles and were diagnosed SLC25A13 mutations by PCR/PCR-RFLP enrolled in this study. There were 96 in 236 patients were diagnosed NICCD by molecular analysis. Some NICCD clinical manifestations include: Jaundice (95.8%), hepatomegaly (31.3%), steatorrhea (89.6%), chubby face (88.5%), splenomegaly (29.4%), and faint (2.1%). Laboratory finding: Hyperbilirubinemia (95.8%), increase AST (100%), ALT (88.5%), AST/ALT ratio >2.5 (89.6%), coagulation disorder (87.5%), hypoproteinemia (82.3%), hypoalbuminemia (84.4%), hyperammonemia (92.7%), 100% patients had elevation of AFP and 70.8% had increase of citrullin. DNA analysis of SLC25A13 revealed combinations of 851del4, 1638ins23, IVS6 + 5G > A and IVS16ins3kb with 5 genotypes, 89 homozygous and 7 compound heterozygous. No relation between phenotype and genotype has been found. With supportive treatment and nutritional manipulation most of patients in group recovered completely by the age 18 months. However, there were eight patients had died of uncompensative hepatic failure.
NICCD should be considered in the differential diagnosis of cholestatic and hepatic failure infants. Phenotype of NICCD is very polymorphic and not always benign. All NICCD should be long term followed up.
PMCID: PMC4563457
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD); SLC25A13; cholestasis; hepatic failure
2.  Biochemical characteristics of neonatal cholestasis induced by citrin deficiency 
AIM: To explore differences in biochemical indices between neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and that with other etiologies.
METHODS: Patients under 6 mo of age who were referred for investigation of conjugated hyperbilirubinaemia from June 2003 to December 2010 were eligible for this study. After excluding diseases affecting the extrahepatic biliary system, all patients were screened for the two most common SLC25A13 mutations; the coding exons of the entire SLC25A13 gene was sequenced and Western blotting of citrin protein performed in selected cases. Patients in whom homozygous or compound heterozygous SLC25A13 mutation and/or absence of normal citrin protein was detected were defined as having NICCD. Cases in which no specific etiological factor could be ascertained after a comprehensive conjugated hyperbilirubinaemia work-up were defined as idiopathic neonatal cholestasis (INC). Thirty-two NICCD patients, 250 INC patients, and 39 infants with cholangiography-confirmed biliary atresia (BA) were enrolled. Laboratory values at their first visit were abstracted from medical files and compared.
RESULTS: Compared with BA and INC patients, the NICCD patients had significantly higher levels of total bile acid (TBA) [all measures are expressed as median (inter-quartile range): 178.0 (111.2-236.4) μmol/L in NICCD vs 112.0 (84.9-153.9) μmol/L in BA and 103.0 (70.9-135.3) μmol/L in INC, P = 0.0001]. The NICCD patients had significantly lower direct bilirubin [D-Bil 59.6 (43.1-90.9) μmol/L in NICCD vs 134.0 (115.9-151.2) μmol/L in BA and 87.3 (63.0-123.6) μmol/L in INC, P = 0.0001]; alanine aminotransferase [ALT 34.0 (23.0-55.0) U/L in NICCD vs 108.0 (62.0-199.0) U/L in BA and 84.5 (46.0-166.0) U/L in INC, P = 0.0001]; aspartate aminotransferase [AST 74.0 (53.5-150.0) U/L in NICCD vs 153.0 (115.0-239.0) U/L in BA and 130.5 (81.0-223.0) U/L in INC, P = 0.0006]; albumin [34.9 (30.7-38.2) g/L in NICCD vs 38.4 (36.3-42.2) g/L in BA and 39.9 (37.0-42.3) g/L in INC, P = 0.0001]; glucose [3.2 (2.0-4.4) mmol/L in NICCD vs 4.1 (3.4-5.1) mmol/L in BA and 4.0 (3.4-4.6) mmol/L in INC, P = 0.0014] and total cholesterol [TCH 3.33 (2.97-4.00) mmol/L in NICCD vs 4.57 (3.81-5.26) mmol/L in BA and 4.00 (3.24-4.74) mmol/L in INC, P = 0.0155] levels. The D-Bil to total bilirubin (T-Bil) ratio was significantly lower in NICCD patients [all measures are expressed as median (inter-quartile range): 0.54 (0.40-0.74)] than that in BA patients [0.77 (0.72-0.81), P = 0.001] and that in INC patients [0.74 (0.59-0.80), P = 0.0045]. A much higher AST/ALT ratio was found in NICCD patients [2.46 (1.95-3.63)] compared to BA patients [1.38 (0.94-1.97), P = 0.0001] and INC patients [1.48 (1.10-2.26), P = 0.0001]. NICCD patients had significantly higher TBA/D-Bil ratio [3.36 (1.98-4.43) vs 0.85 (0.72-1.09) in BA patients and 1.04 (0.92-1.14) in INC patients, P = 0.0001], and TBA/TCH ratio [60.7 (32.4-70.9) vs 24.7 (19.8-30.2) in BA patients and 24.2 (21.4-26.9) in INC patients, P = 0.0001] compared to the BA and INC groups.
CONCLUSION: NICCD has significantly different biochemical indices from BA or INC. TBA excretion in NICCD appeared to be more severely disturbed than that of bilirubin and cholesterol.
PMCID: PMC3482648  PMID: 23112554
Cholestasis; Biliary atresia; Infants; Idiopathic neonatal cholestasis; SLC25A13
3.  Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency in Korean Infants 
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.
PMCID: PMC2694627  PMID: 18162705
Cholestasis; Citrin; Citrullinemia; SLC25A13; Mutation
4.  AB089. Postnatal and prenatal diagnosis for neonatal intrahepatic cholestasis caused by citrin deficiency 
Annals of Translational Medicine  2015;3(Suppl 2):AB089.
Background and objective
Neonatal 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, prolong jaundice, chronic liver disease and so on. This study aimed to identify mutations of SLC25A13 for 649 NICCD and 46 siblings, from September 2009 to December 2014 and prenatal diagnosis for pregnancies with high risk of NICCD.
Detection four common termed as 851del4, IVS6 + 5G > A, 1638ins23, IVS16ins3kb for NICCD patients by DNA analysis (PCR-RFLP) and confirm by directly sequencing. The NICCD parents who had fetus then enrolled in DNA testing for the carrier. Prenatal diagnosis for their fetus was performed by PCR-RFLP following by amniocentesis and amniocyte culture.
In 695 patients, 169 (24.3%) patients have identified mutations, of which 93 patients were 851del4 homozygote, 62 patients were 851del4 heterozygote, three patients were heterozygote of single mutation 1638ins23, one patient was heterozygote of single mutation IVS6 + 5G > A and two patients were compound heterozygote of 1638ins23 + 851del4, two patients were compound heterozygote (851del4 + IVS6 + 5G > A), six patients were compound heterozygote of (851del4 + IVS16ins3kb); 851del4 was the major mutation type, accounting for 76.3% in mutant allele, followed by c.1638ins23 (1.5%), IVS16ins3kb (1.8%), and IVS6 + 5G > A (0.9%); out of 10 couple enrolled DNA testing, two fathers revealed that they were homozygous mutation without any clinical figure and the others were carrier. Among four pregnancies having prenatal diagnosis, two fetuses were homozygote, one fetu was heterozygote and the remaining was normal.
851del4 was the most common mutation in Vietnamese NICCD patients. Moreover, citrin deficiency prenatal diagnosis might open a novel area of clinical management for citrin deficiency in Vietnam.
PMCID: PMC4563537
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD); SLC25A13 gene; mutation; DNA analysis; citrin deficiency; Vietnam
5.  AB087. Most common SLC25A13 mutation in 695 Vietnamese patients with NICCD 
Annals of Translational Medicine  2015;3(Suppl 2):AB087.
Background and objective
Neonatal 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, prolong jaundice, chronic liver disease and so on. This study aimed to identify four mutations of SLC25A13.
Four common mutations termed as 851del4, IVS6 + 5G > A, 1638ins23, IVS16ins3kb in the NICCD patients were detected by DNA analysis.
851del4 was accounting for 90.5% in mutant allele. One hundred and sixty-nine patients have identified mutations, including 93 patients were 851del4 homozygotes, 62 patients were 851del4 heterozygotes, three patients was heterozygotes of single mutation 1638ins23, one patient was heterozygotes of single mutation IVS6+5G > A and two patients was compound heterozygotes of 1638ins23+851del4, two patients were compound heterozygotes (851del4 + IVS6 + 5G > A), six patients were compound heterozygotes (851del4 + IVS16ins3kb). Genotype of NICCD in Vietnam were 851del/851del4, 851del/1638ins23, 851del/IVS6 + 5G > A. 851del/IVS16ins3kb.
851del4 was the most common mutation type and 851del/851del4 is the major genotype. We recommend that this mutation should be firstly screen for Vietnamese patients suspected NICCD caused by citrin deficiency.
PMCID: PMC4563449
Citrin deficiency; neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD); citrullinemia; Vietnam
6.  SLC25A13 Gene Analysis in Citrin Deficiency: Sixteen Novel Mutations in East Asian Patients, and the Mutation Distribution in a Large Pediatric Cohort in China 
PLoS ONE  2013;8(9):e74544.
The human SLC25A13 gene encodes citrin, the liver-type mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), and SLC25A13 mutations cause citrin deficiency (CD), a disease entity that encompasses different age-dependant clinical phenotypes such as Adult-onset Citrullinemia Type II (CTLN2) and Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD). The analyses of SLC25A13 gene and its protein/mRNA products remain reliable tools for the definitive diagnoses of CD patients, and so far, the SLC25A13 mutation spectrum in Chinese CD patients has not been well-characterized yet.
Methods and Results
By means of direct DNA sequencing, cDNA cloning and SNP analyses, 16 novel pathogenic mutations, including 9 missense, 4 nonsense, 1 splice-site, 1 deletion and 1 large transposal insertion IVS4ins6kb (GenBank accession number KF425758), were identified in CTLN2 or NICCD patients from China, Japan and Malaysia, respectively, making the SLC25A13 variations worldwide reach the total number of 81. A large NICCD cohort of 116 Chinese cases was also established, and the 4 high-frequency mutations contributed a much larger proportion of the mutated alleles in the patients from south China than in those from the north (χ2 = 14.93, P<0.01), with the latitude of 30°N as the geographic dividing line in mainland China.
This paper further enriched the SLC25A13 variation spectrum worldwide, and formed a substantial contribution to the in-depth understanding of the genotypic feature of Chinese CD patients.
PMCID: PMC3777997  PMID: 24069319
7.  Treatment with Lactose (Galactose)-Restricted and Medium-Chain Triglyceride-Supplemented Formula for Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency 
JIMD Reports  2011;2:37-44.
Citrin plays a role in the transfer of NADH-reducing equivalent from cytosol to mitochondria as part of the malate–aspartate shuttle in liver. Citrin deficiency may cause an impairment of glycolysis due to an increase in the cytosolic NADH/NAD ratio leading to an energy shortage in the liver. Mutations of the SLC25A13 gene are responsible for neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Most patients with NICCD show a resolution of symptoms within the first year of life, but some patients present with severe symptoms and require liver transplantation. We treated four patients including three siblings with NICCD by lactose (galactose)-restricted and medium-chain triglyceride (MCT)-supplemented formula. This formula rapidly improved the clinical condition and laboratory findings. Early treatment was more effective and did not require long-term administration. Lactose (galactose)-restriction can avoid further increase in the cytosolic NADH/NAD ratio in the liver and MCT supplementation can provide energy to hepatic cells by producing an excess of acetyl-CoA in mitochondria. Early treatment with lactose (galactose)-restricted and MCT-supplemented formula is recommended for patients with NICCD and possibly for patients with CTLN2.
PMCID: PMC3509838  PMID: 23430852
8.  Inspissated bile syndrome in an infant with citrin deficiency and congenital anomalies of the biliary tract and esophagus: Identification and pathogenicity analysis of a novel SLC25A13 mutation with incomplete penetrance 
Biallelic mutations of the SLC25A13 gene result in citrin deficiency (CD) in humans. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is the major CD phenotype in pediatrics; however, knowledge on its genotypic and phenotypic characteristics remains limited. The present study aimed to explore novel molecular and clinical characteristics of CD. An infant suspected to have NICCD as well as her parents were enrolled as the research subjects. SLC25A13 mutations were investigated using various methods, including cDNA cloning and sequencing. The pathogenicity of a novel mutation was analyzed bioinformatically and functionally with a yeast model. Both the infant and her father were heterozygous for c.2T>C and c.790G>A, while the mother was only a c.2T>C carrier. The novel c.790G>A mutation proved bioinformatically and functionally pathogenic. The infant had esophageal atresia and an accessory hepatic duct, along with bile plug formation confirmed by laparoscopic surgery. However, the father seemed to be healthy thus far. The findings of the present study enrich the genotypic and phenotypic characteristics of CD patients, and provided clinical and molecular evidence suggesting the possible non-penetrance of SLC25A13 mutations and the likely involvement of this gene in primitive foregut development during early embryonic life.
PMCID: PMC4199400  PMID: 25216257
citrin deficiency; inspissated bile syndrome; esophageal atresia; functional analysis
9.  Citrin deficiency presenting as acute liver failure in an eight-month-old infant 
Citrin deficiency typically presents as neonatal intrahepatic cholestasis and resolves in late infancy. Here we report a case of citrin deficiency that presented as acute liver failure in late infancy in an apparently healthy child. The full-term male infant weighed 3400 g at birth, and exhibited normal development for eight months, at which time he contracted bronchial pneumonia. The infant developed jaundice and laboratory tests indicated elevated bilirubin and ammonia levels and an abnormal coagulation profile. Plasma amino acid analysis showed elevated levels of tyrosine, methionine, citrulline, and arginine. Citrin deficiency was suspected, and genomic DNA analysis revealed a mutation (IVS16ins3kb) in SLC25A13, which encodes a mitochondrial aspartate-glutamate carrier protein. The infant was immediately put on a lactose-free, medium-chain-triglyceride-enriched formula with ursodeoxycholic acid and lipid-soluble vitamins. However, cholestasis and abnormal laboratory indices persisted, and the infant died at the age of 11.5 mo, two days before a scheduled liver transplantation. This case demonstrates that citrin deficiency can present in late infancy as acute liver failure triggered by infection, and may require liver transplantation.
PMCID: PMC4476898  PMID: 26109823
Citrin deficiency; Infant; Liver failure; Respiratory infection; SLC25A13
10.  Screening of SLC25A13 mutation in the Thai population 
AIM: To determine the prevalence of SLC25A13 mutations in the Thai population.
METHODS: A total of 1537 subjects representing the Thai population were screened for a novel pathologic allele p.Met1? (c.2T > C) and six previously known common SLC25A13 mutations: [I] (c.851_854delGTAT), [II] (g.IVS11 + 1G > A), [III] (c.1638_1660dup), [IV] (p.S225X), [V] (IVS13 + 1G > A), and [XIX] (g.IVS16ins3kb) using a newly developed TaqMan and established HybProbe assay, respectively. Sanger sequencing was employed for specimens showing an aberrant peak to confirm the targeted mutation as well as the unknown aberrant peaks detected. Frequencies of the mutations identified were compared in each region. Carrier frequency and disease prevalence of citrin deficiency caused by SCL25A13 mutations were estimated.
RESULTS: p.Met1? was identified in the heterozygous state in 85 individuals, giving a carrier frequency of 1/18, which suggests possible selective advantage of this variant. The question of p.Met1? homozygote lethality remains unanswered which may serve as an explanation as to why this homozygote has yet to be identified in patients/controls even with high allele frequency. The p.Met1? mutation has rarely been studied in populations other than Thai and Chinese; therefore, may have been overlooked. Development of the TaqMan assay in the present study would allow a simple, rapid, and cost-effective method for mass screening. Heterozygous mutations: [XIX] and [I] were identified in 17 individuals, giving a carrier rate of 1/90 and a calculated homozygote rate of 1/33000. Two novel variants, g.IVS11 + 17C > G and c.1311C > T, of unknown clinical significance were identified at low frequency.
CONCLUSION: This study highlighted the current underestimation of citrin deficiency and suggests the possible selective advantage of the p.Met1? allele.
PMCID: PMC3837273  PMID: 24282362
Aspartate-glutamate carrier; Isoform 2; Citrin deficiency; Type II citrullinemia; Neonatal intrahepatic cholestasis caused by citrin deficiency; SLC25A13
11.  Slc25a13-Knockout Mice Harbor Metabolic Deficits but Fail To Display Hallmarks of Adult-Onset Type II Citrullinemia 
Molecular and Cellular Biology  2004;24(2):527-536.
Adult-onset type II citrullinemia (CTLN2) is an autosomal recessive disease caused by mutations in SLC25A13, the gene encoding the mitochondrial aspartate/glutamate carrier citrin. The absence of citrin leads to a liver-specific, quantitative decrease of argininosuccinate synthetase (ASS), causing hyperammonemia and citrullinemia. To investigate the physiological role of citrin and the development of CTLN2, an Slc25a13-knockout (also known as Ctrn-deficient) mouse model was created. The resulting Ctrn−/− mice were devoid of Slc25a13 mRNA and citrin protein. Liver mitochondrial assays revealed markedly decreased activities in aspartate transport and the malate-aspartate shuttle. Liver perfusion also demonstrated deficits in ureogenesis from ammonia, gluconeogenesis from lactate, and an increase in the lactate-to-pyruvate ratio within hepatocytes. Surprisingly, Ctrn−/− mice up to 1 year of age failed to show CTLN2-like symptoms due to normal hepatic ASS activity. Serological measures of glucose, amino acid, and ammonia metabolism also showed no significant alterations. Nitrogen-loading treatments produced only minor changes in the hepatic ammonia and amino acid levels. These results suggest that citrin deficiency alone may not be sufficient to produce a CTLN2-like phenotype in mice. These observations are compatible, however, with the variable age of onset, incomplete penetrance, and strong ethnic bias seen in CTLN2 where additional environmental and/or genetic triggers are now suspected.
PMCID: PMC343808  PMID: 14701727
12.  Most common SLC25A13 mutation in 400 Chinese infants with intrahepatic cholestasis 
AIM: To establish the real time fluorescence polymerase chain reaction (RT-PCR) with dual labeled probes for fast detection of SLC25A13 gene mutation 851del4.
METHODS: Four hundred infants (< 1 year of age) with unexplained intrahepatic cholestasis from 18 provinces or municipalities in China were enrolled in this study for detecting their SLC25A13 gene mutation 851del4. Suitable primers and fluorescence-labeled probes for detecting SLC25A13 gene mutation 841del4 were designed. Normal and mutant sequences were detected by PCR with two fluorescence-labeled probes. After a single RT-PCR, results were obtained by analyzing the take-off curves. Twenty-four positive and 14 negative samples were retested by direct sequencing.
RESULTS: Eight homozygous and 30 heterozygous mutations were detected in 46 mutant alleles with a 851del4 mutation rate of 5.8% (46/800). Twenty-six and 20 mutant alleles were observed respectively, in 474 and 242 alleles from the intermediate and southern areas of China. No mutant allele was detected in 84 alleles from northern China. Twenty-four positive samples including 4 homozygous and 20 heterozygous mutations, and 14 negative samples were retested by direct sequencing, which confirmed that the accuracy of RT-PCR was 100%.
CONCLUSION: RT-PCR can detect the mutation 851del4 in infants with intrahepatic cholestasis with an accuracy of 100%.
PMCID: PMC2868222  PMID: 20458766
851del4 mutation; Neonatal intrahepatic cholestasis; Real-time fluorescent polymerase chain reaction; SLC25A13 gene
13.  Different regional distribution of SLC25A13 mutations in Chinese patients with neonatal intrahepatic cholestasis 
AIM: To investigate the differences in the mutation spectra of the SLC25A13 gene mutations from specific regions of China.
METHODS: Genetic analyses of SLC25A13 mutations were performed in 535 patients with neonatal intrahepatic cholestasis from our center over eight years. Unrelated infants with at least one mutant allele were enrolled to calculate the proportion of SLC25A13 mutations in different regions of China. The boundary between northern and southern China was drawn at the historical border of the Yangtze River.
RESULTS: A total of 63 unrelated patients (about 11% of cases with intrahepatic cholestasis) from 16 provinces or municipalities in China had mutations in the SLC25A13 gene, of these 16 (25%) were homozygotes, 28 (44%) were compound heterozygotes and 19 (30%) were heterozygotes. In addition to four well described common mutations (c.851_854del, c.1638_1660dup23, c.615+5G>A and c.1750+72_1751-4dup17insNM_138459.3:2667 also known as IVS16ins3kb), 13 other mutation types were identified, including three novel mutations: c.985_986insT, c.287T>C and c.1349A>G. According to the geographical division criteria, 60 mutant alleles were identified in patients from the southern areas of China, 43 alleles were identified in patients from the border, and 4 alleles were identified in patients from the northern areas of China. The proportion of four common mutations was higher in south region (56/60, 93%) than that in the border region (34/43, 79%, χ2 = 4.621, P = 0.032) and the northern region (2/4, 50%, χ2 = 8.288, P = 0.041).
CONCLUSION: The SLC25A13 mutation spectra among the three regions of China were different, providing a basis for the improvement of diagnostic strategies and interpretation of genetic diagnosis.
PMCID: PMC3725380  PMID: 23901231
Citrin deficiency; Mutation spectrum; Intrahepatic cholestasis; SLC25A13
14.  Clinical, Molecular and Functional Investigation on an Infant with Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD) 
PLoS ONE  2014;9(2):e89267.
Background and Objective
SLC25A13 analysis has provided reliable evidences for the definitive diagnosis of citrin deficiency (CD) in the past decade. Meanwhile, these studies generated some issues yet to be resolved, including the pathogenicity of SLC25A13 missense mutations and the mRNA product from the mutation c.615+5G>A. This study aims to investigate the effect of a novel missense mutation on the aspartate/glutamate carrier (AGC) function of citrin protein, and to explore the aberrant transcript from c.615+5G>A in the same CD infant.
Methods and Results
By means of screening for prevalent SLC25A13 mutations and exons sequencing, the patient proved a compound heterozygote of c.615+5G>A and a novel c.1064G>A (p.Arg355Gln) mutation. An aberrant transcript with retention of the entire intron 6, r.[615+1_615+1789ins; 615+5 g>a] (GenBank accession number KJ128074), which was resulted from c.615+5G>A, was detected by RT-PCR and cDNA sequencing. After bioinformatic analyses of the novel missense mutation c.1064G>A, the growth abilities of three agc1Δ yeast strains were tested, which had been transformed with recombinant or empty vectors, respectively. Besides the bioinformatically pathogenic evidences, the growth ability of the agc1Δ strains transformed with mutant recombinant was the same as with empty vector, but significantly lower than that with normal control in functional analysis.
A CD infant was definitely diagnosed in this paper by a genetic, transcriptional and functional analysis of SLC25A13 gene. This study provided direct laboratory evidences supporting the splice-site nature of the c.615+5G>A mutation, and the novel c.1064G>A variation, which proved a pathogenic mutation bioinformatically and functionally, enriched the SLC25A13 mutation spectrum.
PMCID: PMC3931723  PMID: 24586645
15.  Diversity of Disorders Causing Neonatal Cholestasis – The Experience of a Tertiary Pediatric Center in Germany 
Background and Objective: Rapidly establishing the cause of neonatal cholestasis is an urgent matter. The aim of this study was to report on the prevalence and mortality of the diverse disorders causing neonatal cholestasis in an academic center in Germany.
Methods: Clinical chemistry and cause of disease were retrospectively analyzed in 82 infants (male n = 42, 51%) that had presented with neonatal cholestasis to a tertiary medical center from January 2009 to April 2013.
Results: Altogether, 19 disorders causing neonatal cholestasis were identified. Biliary atresia was the most common diagnosis (41%), followed by idiopathic cases (13%), progressive familial intrahepatic cholestasis (PFIC, 10%), cholestasis in preterm infants (10%), α1AT deficiency, Alagille syndrome, portocaval shunts, mitochondriopathy, biliary sludge (all 2%), and others. Infants with biliary atresia were diagnosed with a mean age of 62 days, they underwent Kasai portoenterostomy ~66 days after birth. The majority of these children (~70%) received surgery within 10 weeks of age and 27% before 60 days. The 2-year survival with their native liver after Kasai procedure was 12%. The time span between Kasai surgery and liver transplantation was 176 ± 73 days. Six children (7%), of whom three patients had a syndromic and one a non-syndromic biliary atresia, died prior to liver transplantation. The pre- and post-transplant mortality rate for children with biliary atresia was ~12 and ~17%, respectively.
Conclusion: Neonatal cholestasis is a severe threat associated with a high risk of complications in infancy and it therefore requires urgent investigation in order to initiate life saving therapy. Although in the last 20 years new causes such as the PFICs have been identified and newer diagnostic tools have been introduced into the clinical routine biliary atresia still represents the major cause.
PMCID: PMC4066316  PMID: 25003101
neonatal cholestasis; neonatal jaundice; biliary atresia; Kasai procedure; ERCP
16.  Cholestatic jaundice in infancy. The importance of familial and genetic factors in aetiology and prognosis. 
Archives of Disease in Childhood  1981;56(8):622-627.
One hundred and twenty-four infants admitted to hospitals in Norway between 1955 and 1974 during the first 3 months of life with cholestatic jaundice were studied retrospectively. Sixty-four infants had had extrahepatic atresia of the biliary tree and 60 had had intrahepatic cholestasis. This gives an incidence of about 1:9000 live births for cholestasis. In 4 of the 64 infants with extra-hepatic atresia a bile duct-to-bowel anastomosis had been performed but this was successful in only 2. Sixty of these infants had died by their 2nd birthday. Twenty-six of the infants with intrahepatic cholestasis had died by 1978 and the most common causes of death were cholestasis complicated by infection, bleeding, or hepatoma. The survivors aged between 4 and 23 years were followed up in 1978. In about two-thirds of them aetiological factors--such as alpha-1-antitrypsin deficiency, arteriohepatic dysplasia, cholestasis with lymphoedema--and other familial or genetic factors, or infections were found. Four of the 34 survivors are known to have cirrhosis. Twenty patients had biochemical abnormalities, and 12 had normal liver function tests. Two patients could not be examined. Of the 19 patients with familial or genetic aetiological factors, 4 had cirrhosis, 14 had biochemical abnormalities, and only 5 had normal liver function tests. Of 11 survivors with idiopathic disease or septicaemia, none had cirrhosis and only 4 had abnormal liver function tests.
PMCID: PMC1627279  PMID: 7271301
17.  Novel ABCB11 mutations in a Thai infant with progressive familial intrahepatic cholestasis 
Progressive familial intrahepatic cholestasis (PFIC) type 2 is caused by mutations in ABCB11, which encodes bile salt export pump (BSEP). We report a Thai female infant who presented with progressive cholestatic jaundice since 1 mo of age, with normal serum γ-glutamyltransferase. Immunohistochemical staining of the liver did not demonstrate BSEP along the canaliculi, while multidrug resistance protein 3 was expressed adequately. Novel mutations in ABCB11, a four-nucleotide deletion in exon 3, c.90_93delGAAA, and a single-nucleotide insertion in exon 5, c.249_250insT, were identified, with confirmation in her parents. These mutations were predicted to lead to synthesis of truncated forms of BSEP. Immunostaining and mutation analysis thus established the diagnosis of PFIC type 2.
PMCID: PMC2744194  PMID: 19750581
ABCB11; Bile salt export pump; Progressive familial intrahepatic cholestasis
18.  Evaluation of cholestasis in Iranian infants less than three months of age 
Aim: The aim of this study is to find-out the possible etiologies in Iranian infants less than three months in Shiraz, South of Iran.
Background: Cholestatic jaundice most probably occurs due to a pathological condition and the most frequent causes in early infancy are neonatal hepatitis and biliary atresia. Early diagnosis and treatment of infantile cholestasis can improve prognosis of liver diseases by prevention of the complications of these disorders.
Patients and methods: In this retrospective study, 122 infants under 3 months of age with cholestasis were studied in Nemazee Hospital (affiliated to Shiraz University of Medical Sciences) during the years 2001-2011. Demographic data, duration of jaundice, liver biopsy and the causes of cholestasis were recorded.
Results: There were 76 males (62.3%) and 46 females (37.7%) with a mean age of 54.4 ± 23.7 days. The most common clinical finding was jaundice that was seen in all patients (100%).The onset of jaundice was the first day to the fifty two days of age, with an average age of 15.6 ± 16.1 days. Other findings included hepatomegaly in 92 patients (76.4%), clay-color stool in 54 (44.3%), and splenomegaly in 29 patients (23.8%). In this study, the most common causes of cholestasis were biliary atresia (30=24.6%), idiopathic neonatal hepatitis (30= 24.6%) and bile ducts paucity (16=10.3).
Conclusion: The results of this study showed that biliary atresia and neonatal hepatitis are the most common causes of infantile cholestasis in this area. It is recommended that biliary atresia should be discriminated from other forms of neonatal cholestasis.
PMCID: PMC4285931  PMID: 25584175
Cholestasis; Biliary atresia; Neonatal jaundice
19.  Biopsy-driven diagnosis in infants with cholestatic jaundice in Iran 
AIM: To determine the frequencies of diagnoses confirmed by liver biopsy in infants with cholestasis in an Iranian pediatric hospital.
METHODS: This was a retrospective study conducted in a tertiary referral children’s hospital in Iran. We retrieved all pathology reports of liver biopsies from children less than two years of age who had presented for evaluation of cholestatic jaundice from March 2001 to March 2011. Additional specimen samples obtained from archived pathology blocks were reviewed by a pathologist blinded to the final diagnosis. These results were compared with the pathology reports from chart records to ensure consensus and eliminate any inconsistencies in final diagnoses. A structured checklist was used to gather information on multiple variables including age, sex, gestational age at birth, birth weight, age at which hyperbilirubinemia manifested, presence and identification of associated anomalies, clinical manifestations, and histological findings from liver biopsies. The baseline data are reported using descriptive statistics, and differences between groups were assessed by Fisher’s exact test and Student’s t test when indicated.
RESULTS: Fifty-five cases (28 females; 27 males) of infantile cholestasis (IC) were included in this study. The mean serum total bilirubin and direct bilirubin at presentation were 13.6 ± 5.9 and 7.3 ± 3.4, respectively. Forty cases (72.7%) were the product of term pregnancies. Common associated clinical findings were acholic stool in 33 cases (60.0%), hepatomegaly in 30 cases (54.5%), and dark-colored urine in 21 cases (38.2%). Biliary atresia (BA) was the most frequent diagnosis, found in 32 cases (58.2%), followed by intrahepatic bile duct paucity found in 6 cases (10.9%), metabolic disease in 6 cases (10.9%), idiopathic neonatal hepatitis in 5 cases (9.1%), choledochal cyst in 2 cases (3.6%), liver cirrhosis in 2 cases (3.6%), and progressive familial intrahepatic cholestasis and portal fibrosis each in 1 case (1.8%). The mean times for jaundice onset and liver biopsy were 43.8 and 102.0 d, respectively. In BA, the mean age at jaundice presentation was 21 d and for liver biopsy was 87.5 d, representing a mean delay of 66.5 d.
CONCLUSION: A significant delay was found between IC presentation and liver biopsy, which is detrimental in conditions that can cause irreversible liver damage, such as BA.
PMCID: PMC3921528  PMID: 24574777
Cholestasis; Neonate; Hepatitis; Biliary atresia; Neonatal hepatitis; Infant; Conjugated hyperbilirubinemia; Liver biopsy
20.  Bile salts and liver disease in childhood 
Postgraduate Medical Journal  1974;50(584):354-360.
Recognition of neonatal liver disease has been heavily dependent on the occurrence of jaundice. In most instances the jaundice is related to specific disturbances in bilirubin transport and other tests of liver function are normal. In contrast, hepatitis and other liver diseases not specifically affecting bilirubin transport often go undetected unless jaundice occurs.
The development of practical methods for the estimation of bile acids in serum has permitted an evaluation of hepatic excretory function in neonates and children independent of bilirubin excretion. Since bile acid excretion by the liver each day greatly exceeds bilirubin excretion it was not surprising to find that elevations in serum bile acids occur regularly in anicteric hepatitis. Because the excretion of bile acids generates canalicular bile flow a reduction in the capacity to excrete bile acids intimates the presence of cholestasis. Early cholestasis is not associated with hyperbilirubinaemia but as cholestasis becomes more severe, jaundice occurs and the possibility of biliary atresia arises in neonates. Serum bile acid patterns in neonates being evaluated for biliary atresia indicate two distinctive patterns. Those infants with severe cholestasis and patent bile ducts usually have pre-dominantly cholic acid in serum. This observation is consistent with the bile acid patterns found in intrahepatic and extrahepatic cholestasis occurring in adult life. Infants found to have extrahepatic biliary atresia have marked elevations in the proportion of chenodeoxycholate in serum. Since elevations of chenodeoxycholate in serum are associated with hepatitis, the findings are consistent with the view that extrahepatic atresia is a rare sequalae of hepatitis.
Studies of bile acid metabolism and excretion give promise of providing further insight on the pathogenesis of cholestatic liver disease.
PMCID: PMC2495736  PMID: 4464509
21.  Neonatal Cholestasis – Differential Diagnoses, Current Diagnostic Procedures, and Treatment 
Cholestatic jaundice in early infancy is a complex diagnostic problem. Misdiagnosis of cholestasis as physiologic jaundice delays the identification of severe liver diseases. In the majority of infants, prolonged physiologic jaundice represent benign cases of breast milk jaundice, but few among them are masked and caused by neonatal cholestasis (NC) that requires a prompt diagnosis and treatment. Therefore, a prolonged neonatal jaundice, longer than 2 weeks after birth, must always be investigated because an early diagnosis is essential for appropriate management. To rapidly identify the cases with cholestatic jaundice, the conjugated bilirubin needs to be determined in any infant presenting with prolonged jaundice at 14 days of age with or without depigmented stool. Once NC is confirmed, a systematic approach is the key to reliably achieve the diagnosis in order to promptly initiate the specific, and in many cases, life-saving therapy. This strategy is most important to promptly identify and treat infants with biliary atresia, the most common cause of NC, as this requires a hepatoportoenterostomy as soon as possible. Here, we provide a detailed work-up approach including initial treatment recommendations and a clinically oriented overview of possible differential diagnoses in order to facilitate the early recognition and a timely diagnosis of cholestasis. This approach warrants a broad spectrum of diagnostic procedures and investigations including new methods that are described in this review.
PMCID: PMC4470262  PMID: 26137452
neonatal cholestasis; neonatal jaundice; conjugated hyperbilirubinemia; biliary atresia; kasai procedure
22.  Etiologies of conjugated hyperbilirubinemia in infancy: a systematic review of 1692 subjects 
BMC Pediatrics  2015;15:192.
The etiologies of conjugated hyperbilirubinemia in infancy are diverse.
Determine the prevalence rates of the specific etiologies of conjugated hyperbilirubinemia in infancy.
Data sources
EMBASE and Pubmed were searched electronically and the bibliographies of selected studies were search manually. The search was conducted independently by two authors.
Study selection
(1) prospective or retrospective case series or cohort study with 10 or more subjects; (2) consecutive infants who presented with conjugated hyperbilirubinemia; (3) subjects underwent appropriate diagnostic work-up for conjugated hyperbilirubinemia; (4) no specific diagnoses were excluded in the studied cohort.
Data extraction
Patient number, age range, country of origin, and categorical and specific etiologies.
From 237 studies identified, 17 studies encompassing 1692 infants were selected. Idiopathic neonatal hepatitis (INH) occurred in 26.0 % of cases; the most common specific etiologies were extrahepatic biliary atresia (EHBA) (25.89 %), infection (11.47 %), TPN- associated cholestasis (6.44 %), metabolic disease (4.37 %), alpha-1 anti-trypsin deficiency (4.14 %), and perinatal hypoxia/ischemia (3.66 %). CMV was the most common infection identified (31.51 %) and galactosemia (36.49 %) was the most common metabolic disease identified.
Major limitations are: (1) inconsistencies in the diagnostic evaluations among the different studies and (2) variations among the sample populations.
INH is the most common diagnosis for conjugated hyperbilirubinemia in infancy while EHBA and infection are the most commonly identified etiologies. The present review is intended to be a guide to the differential diagnosis and evaluation of the infant presenting with conjugated hyperbilirubinemia.
PMCID: PMC4654877  PMID: 26589959
Conjugated hyperbilirubinemia; Cholestatic jaundice; Newborn; Differential diagnosis
23.  Atypical causes of cholestasis 
Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have “silent” progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.
PMCID: PMC4110573  PMID: 25071336
Cholestasis; Benign recurrent intrahepatic cholestasis; Progressive familial intrahepatic cholestasis; Alagille syndrome; Biliary atresia; Total parenteral nutrition; Drug induced liver injury
24.  Neonatal cholestasis as the presenting feature in cystic fibrosis. 
Between 1960 and 1994 cystic fibrosis was found in nine out of 1474 infants investigated for neonatal cholestasis. Four had delay in passing meconium. In all patients cholestatic jaundice was present during the first 48 hours and in three patients cholestasis was complete, mimicking biliary atresia. Serum cholesterol concentrations were normal in all but two children. Sweat chloride was repeatedly above 95 mmol/l in all instances. Three children had another condition enhancing the risk of cholestasis (alpha1-antitrypsin deficiency, hypopituitarism, perinatal asphyxia, and total parenteral nutrition). Liver histology displayed portal fibrosis and inflammation with bile duct proliferation; mucous plugs in bile ducts were observed in only one patient. Only one child died from cirrhosis. These results indicate that cystic fibrosis is not a major cause of neonatal cholestasis. However early signs of intestinal obstruction and low concentrations of serum cholesterol may indicate cystic fibrosis, regardless of liver histology. Neonatal cholestasis has no prognostic value concerning evolution to cirrhosis.
PMCID: PMC1511658  PMID: 8813874
25.  Screening of newborn infants for cholestatic hepatobiliary disease with tandem mass spectrometry 
BMJ : British Medical Journal  1999;319(7208):471-477.
To assess the feasibility of screening for cholestatic hepatobiliary disease and extrahepatic biliary atresia by using tandem mass spectrometry to measure conjugated bile acids in dried blood spots obtained from newborn infants at 7-10 days of age for the Guthrie test.
Three tertiary referral clinics and regional neonatal screening laboratories.
Unused blood spots from the Guthrie test were retrieved for infants presenting with cholestatic hepatobiliary disease and from the two cards stored on either side of each card from an index child. Concentrations of conjugated bile acids measured by tandem mass spectrometry in the two groups were compared.
Main outcome measures
Concentrations of glycodihydroxycholanoates, glycotrihydroxycholanoates, taurodihydroxycholanoates, and taurotrihydroxycholanoates. Receiver operator curves were plotted to determine which parameter (or combination of parameters) would best predict the cases of cholestatic hepatobiliary disease and extrahepatic biliary atresia. The sensitivity and specificity at a selection of cut off values for each bile acid species and for total bile acid concentrations for the detection of the two conditions were calculated.
218 children with cholestatic hepatobiliary disease were eligible for inclusion in the study. Two children without a final diagnosis and five who presented at <14 days of age were excluded. Usable blood spots were obtained from 177 index children and 708 comparison children. Mean concentrations of all four bile acid species were significantly raised in children with cholestatic hepatobiliary disease and extrahepatic biliary atresia compared with the unaffected children (P<0.0001). Of 177 children with cholestatic hepatobiliary disease, 104 (59%) had a total bile acid concentration >33 μmol/l (97.5th centile value for comparison group). Of the 61 with extrahepatic biliary atresia, 47 (77%) had total bile acid concentrations >33 μmol/l. Taurotrihydroxycholanoate and total bile acid concentrations were the best predictors of both conditions. For all cholestatic hepatobiliary disease, a cut off level of total bile acid concentration of 30 μmol/l gave a sensitivity of 62% and a specificity of 96%, while the corresponding values for extrahepatic biliary atresia were 79% and 96%.
Most children who present with extrahepatic biliary atresia and other forms of cholestatic hepatobiliary disease have significantly raised concentrations of conjugated bile acids as measured by tandem mass spectrometry at the time when samples are taken for the Guthrie test. Unfortunately the separation between the concentrations in these infants and those in the general population is not sufficient to make mass screening for cholestatic hepatobiliary disease a feasible option with this method alone.
Key messagesThe prognosis of cholestatic hepatobiliary disease in infancy, in particular biliary atresia, is improved by early detectionInfants destined to present with cholestatic jaundice in the first few months of life have raised concentrations of bile acids in the blood spots obtained at 7-10 days for current neonatal screening programmesTandem mass spectrometry can be used to detect this marker of neonatal cholestasisUnfortunately there is too much overlap between bile acid concentrations in infants with cholestasis and those in control infants for this to be used as a single screening test for cholestatic hepatobiliary disease in general and biliary atresiaTandem mass spectrometry is a powerful tool for neonatal screening but every potential application must be carefully assessed
PMCID: PMC28198  PMID: 10454398

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