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Objective:To investigate the clinical and genetic characteristics of genetic and metabolic infantile cholestatic hepatopathy (ICH), and to provide evidence for its diagnosis and treatment.Methods:Clinical data and follow-up outcomes of hospitalized children diagnosed with ICH in the Department of Gastroenterology, Children′s Hospital, Capital Institute of Pediatrics from January 2014 to December 2019 were retrospectively analyzed.Among the 80 children, 27 were female and 53 were male, with a mean age of onset of (39±18) days old.Children with confirmed etiology by high-throughput sequencing analysis were included in the genetic metabolic group (44 cases), and those with idiopathic neonatal cholestasis(INC) of unknown etiology after the systematic examination were included in the INC group (36 cases). The t-test or independent sample rank sum test was used to compare the laboratory test results and biochemical indexes.The infection rate of cytomegalovirus was compared by the Chi- square test. Results:(1) A total of 80 cases were included, and 44 cases (55.0%)were confirmed as INC by high-throughput sequencing.Among those with a positive molecular diagnosis, there were 23 cases of citrin deficiency (CD), 10 cases of Alagille syndrome (ALGS), 6 cases of progressive familial intrahepatic cholestasis (PFIC), 2 cases of congenital bile acid synthesis defect, 2 cases of Nieman Pick disease, and 1 case of cystic fibrosis.(2) Serum total bile acid (TBA) and activated partial prothrombin time (APTT) levels in the genetic metabolic group were significantly higher than those in the INC group (all P<0.05). TBA and APTT levels in genetic metabolites were 180.6 (115.5, 271.6) μmol/L and 40.6 (37.1, 45.2) s, respectively, which were 123.3 (98.8, 163.4) μmol/L and 34.8 (31.7, 40.1) s in INC group, respectively.There was no significant difference in the cytomegalovirus infection rate between the 2 groups ( P>0.05). (3)The pathological examination of liver tissue in the genetic metabolic group was worse than that in the INC group, with spot-like and fusion focal-like necrosis, and 5 cases (4 cases of ALGS and 1 case of CD) showed a reduced number of bile ducts in the portal area and lumen stenosis. Conclusions:CD, ALGS and PFIC are the common causes of genetic and metabolic ICH.Fundamental cause of cholestasis should be actively examined in children with cytomegalovirus infection.High-throughput sequencing is of great significance in the accurate diagnosis of ICH.
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Citrin deficiency is an autosomal recessive disorder caused by mutation of the SLC25A13 gene, and is one of the most important causes of infant cholestasis in China. The metabolic mechanism of CD is complex, involving the urea cycle, the malate aspartate cycle, the citrate malate cycle, fatty acid metabolism, carbohydrate motabolism and other metabolic pathways. Metabolomics has some applications in CD by analyzing metabolite alterations. This article provides a review for research progress of metabolomics in CD.
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OBJECTIVES@#To study the physical and neuropsychological development of children with Citrin deficiency (CD).@*METHODS@#A total of 93 children, aged 1.9-59.8 months, who were diagnosed with CD by @*RESULTS@#For the 93 children with CD, the incidence rate of failure to thrive was 25% (23 children) and the proportion of small for gestational age was 47% (44 children). For the 100 cases of CD, the incidence rates of growth retardation, underweight, emaciation, overweight, and microcephalus were 23% (23 cases), 14% (14 cases), 4% (4 cases), 8% (8 cases), and 9% (9 cases), respectively. The incidence rate of neuropsychological developmental delay was 25% (25 cases), and the incidence rates of development delay in the five domains of adaptability, gross motor, fine motor, language, and social ability were 7% (7 cases), 15% (15 cases), 7% (7 cases), 9% (9 cases), and 7% (7 cases), respectively.@*CONCLUSIONS@#Physical and neuropsychological developmental delay can be observed in children with CD, and physical and neuropsychological development should be regularly assessed.
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Criança , Humanos , Lactente , Citrulinemia , Proteínas de Transporte da Membrana Mitocondrial , Estudos RetrospectivosRESUMO
Objective@#To investigate the profiles of blood amino acid and acylcarnitine in early neonates with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and the sensitivity of newborn screening, and to explore potential biochemical metabolic markers for newborn screening program.@*Methods@#Amino acid and acylcarnitine profiles in dried blood spots of newborn screening program were analyzed by tandem mass spectrometry (MS/MS). A total of 158 651 neonates born in Guangzhou from January 1, 2015 to June 30, 2019 were enrolled in this newborn screening program, and additionally 55 patients with NICCD confirmed by SLC25A13 gene analysis in Guangzhou Women and Children Medical Center were included in this study. NICCD screen-positive was defined as the cutoff value of citrulline (Cit) ≥ 30 μmol/L. The values of blood sampling time of the true positive group and those of the false negative group were compared by t-test. The levels of amino acid and acylcarnitine among different groups, including true positive group (Cit≥30 μmol/L), false negative group (Cit 21-<30 μmol/L and Cit<21 μmol/L) and the normal control group, were analyzed by F test, respectively.@*Results@#Among 158 651 neonates, 39 neonates were positive for NICCD screening. Three of them were confirmed NICCD and 4 cases were found to be false negatives. The positive predictive value was 7.7% and the sensitivity was about 43.0%. Among 55 patients with NICCD, 18 cases (18/55, 32.7%) were true positives and 37 cases (37/55, 67.3%) were false negatives based on the cutoff value of citrulline in the dried blood spots for newborn screening. The blood sampling time was significantly different between true positive group and false negative group ((4.28±1.6) vs. (2.98±0.74) d, t=4.06, P<0.01). The increased levels of tyrosine((176.0±98.4) μmol/L), methionine ((37.0±26.9) μmol/L) and phenylalanine ((133.0±80.9)μmol/L) in Cit≥30 μmol/L group (n=18) were significantly different as compared with those in the other three groups, respectively (F=117.0, 58.5, 135.0, P<0.01). The levels of arginine ( (10.0±9.2) , (11.0±9.3) , (9.0±17.8) μmol/L), valine ( (119.0±29.8) , (107.6±14.1) , (102±68) μmol/L) and leucine ( (167.0±37.1) , (161.0±37.7) , (163.5±180.6) μmol/L) were not statistically significant among groups of Cit≥30 μmol/L(n=18), Cit21-<30 μmol/L(n=7) and Cit<21μmol/L(n=30,P>0.05), but they were significantly higher than those of the normal control group ((4±3), (78±21), (114.0±31.5) μmol/L, n=1 000), respectively(F=30.1, 23.0, 29.8, P<0.01). Alanine (Ala) ( (150±50) , (156.0±30.2), (168±105), (152±52) μmol/L) levels showed no significant difference (F=0.86, P>0.05) but the ratios of Ala/Cit (1.52±1.44, 6.82±1.56, 12.06±7.71, 19.42±6.27) decreased significantly among the four groups (F=69.0, P<0.05). The acylcarnitine levels showed no statistically significant results among the different groups (P>0.05). With Cit≥30 μmol/L and Ala/Cit<7.5 as cutoff values, the number of screen-positive cases reduced from 39 to 22 cases with no additional false negative case. With Cit≥21 μmol/L and Ala/Cit<7.5 as cutoff values the number of screen-positive cases increased to 117 cases with 1 additional true positive.@*Conclusions@#The profiles of blood amino acid in early neonates with NICCD present the increased levels of multiple amino acids including citrulline, tyrosine, methionine and phenylalanine, and decreased ratio of Ala/Cit. Taking citrulline and ratio of Ala/Cit as screening markers can improve the positive predictive value appropriately. The limited sensitivity of NICCD newborn screening may be related to early blood sampling time.
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The elevated NADH/ NAD + ratio in the plasma of the hepatocyte is a key pathophysiologic altera-tion for the development of neonatal intrahepatic cholestasis caused by Citrin deficiency (NICCD). The elevated ratio results in energy shortage in hepatocytes and impairs the function of the ATP - dependent canalicular transporters,in-cluding BSEP,MDR3,FIC1,Sterolin 1 / 2 and MRP2,leading to intrahepatic cholestasis in NICCD patients. On the other hand,the increased NADH/ NAD + ratio inhibits galactose metabolism and thus gives rise to secondary galactosemia, damaging the hepatocyte as well as extrahepatic organs including the lens of the eyes. The lactose - free and medium -chain triglyceride - enriched formulas can rapidly correct the energy shortage of the hepatocyte and alleviate secondary galactosemia,hence improving the clinical presentations effectively in NICCD patients.
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Objective Early detection is the most effective way to improve the clinical outcome of biliary atresia(BA).Emerging metabolomics provides a powerful platform for discovering novel biomarkers and biochemical pathways to improve early diagnosis.The aim of this study is to find the potential biomarkers to distinguish BA from neonatal hepatitis syndrome(NHS) by using a metabolomics method.Methods We comprehensively analyzed the serum metabolites in a total of 26 blood samples from patients with BA or neonatal hepatitis syndrome(NHS) and from normal individuals using advanced metabolomic approaches.Results The levels of propanoic acid,hexadecanoic acid,eicosanoic acid,octadecenoic acid and cholesterol significantly increased in the BA group.Conclusion The levels of L-Tyrosine(Tyr)were reduced in the BA group compared to those in the NHS group,but still higher than the normal controls.The levels of L-Proline(Pro) in the NHS group were significantly elevated compared to those in the BA group.And at the same time,we find 5 patients with cirin deficiency.This study demonstrates the possibility of metabolomics as non-invasive biomarkers for the early detection of BA and also provides new insight into pathophysiologic mechanisms for BA.
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Cholestasis is defined as a conjugated bilirubin level >1 mg/dL(17.1 μmol/L)if total serum bilirubin is ≤5 mg/dL(85.5 μmol/L),or conjugated bilirubin fraction >20％of total bilirubin when the total bilirubin is >5 mg/dL(85.5 μmol/L).In the recent years,the diagnosis and management of genetic cholestasis have caused considerable attention in the pediatric world,in pace with the development,maturation,and clinical application of the theories and techniques in genomics as well as molecular genetics.With a diversity of causative genes,genetic cholestasis usually demonstrates nonpathognomonic clinical manifestations.The etiology diagnosis such a disease relies on genetic tests,the treatment is often difficult,and the prognosis varies disparately,usually causing tremendous pain and burden on the affected patient and the family as well.Taking citrin deficiency,mitochondrial DNA depletion syndrome,microvi-llus inclusion disease and sodium taurocholate cotransporting polypeptide deficiency as samples,the recent advances in the diagnosis and treatment of genetic cholestasis are addressed.
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Objective To analyze the main clinical manifestations,laboratory features and prognosis of neonatal intrahepatic cholestasis caused by Citrin defiency (NICCD).Methods Twenty-nine NICCD infants were diagnosed by blood tandem mass spectrometry (MS-MS)analysis and/or SLC25A13 mutation analysis from July 2012 to February 2015 in Children's Hospital of Chongqing Medical University.Clinical data of 29 cases were analyzed retrospectively which included manifestations,laboratory features and prognosis.The general situation,feeding,liver function,growth were followed up.Results Twenty-nine infants suffering from NICCD presented jaundice in an early time,and some clinical manifestations were investigated such as hepatomegaly (20/29 cases),splenomegaly (3/29 cases),anemia (14/29 cases),and failure to thrive (9/29 cases).Laboratory data suggested that all of 29 patients had increased conjugated bilirubin,total bile acid,γ-glutamyl transferase and alkaline phosphatase.Some patients also showed abnormal coagulation function (20/22 cases),dyslipidemia (9/20 cases),increased blood lactic acid (22/26 cases) and alpha-fetoprotein (14/14 cases),decreased albumin (24/29 cases),blood glucose (17/22 cases) and ceruloplasmin (4/4 cases).The pathological analysis of one patient's liver indicated the edema and degeneration of liver cells,intrahepatic cholestasis and a small amount of fibrous tissue hyperplasia in portal area.MS-MS analysis of blood samples revealed distinctive increase in methionine,tyrosine,threonine,citrulline,arginine and free carnitine,long chain acyl-carnitine in most patients.Gas chromatography-mass spectrometer (GC-MS) analysis of urine samples mainly showed elevated 4-hydroxyphenyllactic acid and 4-hydroxyphenylpyruvic acid.Prognosis showed that most of the NICCD patients (8/29 cases) could recover in one-year old with a lactose-free,medium chain triglyceride-enriched formula,and one patient died of liver cirrhosis.Three patients at over one-year old had the preference of a high protein and low carbohydrate diet.Conclusions Infants might be considered to have NICCD if they have jaundice in an early time,with the clinical characteristics of hepatomegaly,splenomegaly,abnormal coagulation function,anemia,failure to thrive,dyslipidemia,decresed albumin and blood glucose,increased blood lactic acid and alpha-fetoprotein.After that further tests of MS-MS,GC-MS and gene analysis of this disease are needed to confirm diagnosis.
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Objective To explore the clinical manifestations and the characteristics of neonatal intrahepatic cholestasis caused by Citrin deficiency(NICCD)in Hubei province. Methods The biochemical indicators including liver function,blood lipid,lactic acid,blood ammonia,total bile acid,alpha feto protein,coagulogram,blood amino spec-trum,acylcrnitine spectrum,urine organic acid and SLC25A13 gene analysis of 20 cases with NICCD,who came from Wuhan Children's Hospital,during September 2010 to January 2013,were collected before treatment,then followed up for 1 year. Results Laboratory results of NICCD patients showed high blood bilirubin,elevated liver enzymes and bile acid,hyperlipidemia,high alpha feto protein,high lactic acidosis,high ammonia,hypoalbuminemia,hypoglycemia,disor-der of blood coagulation mechanism,variety of amino acids increase,mainly citrulline rose. Mainly long - chain acyl carnitine increased among acyl of carnitine. Abnormal increase of urine 4 - hydroxy benzene acetic acid,4 - hydroxy benzene lactic acid and 4 - hydroxy benzene pyruvic acid. Six mutations were detected in SLC25A13 gene analysis,and L477R,G639S of them were novel mutations,851del4,1638ins23,IVS6 + 5G ﹥ A were hot mutation. All the patients were eased in jaundice before they were 1 year old. Conclusions The early clinical criterion of the patients is disor-der. Hyperlipidemia has been detected in the early course of the disease,and L477R,G639S are the novel mutations.
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Objective To investigate the incidence of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD)in neonates with idiopathic neonatal cholestasis (INC)in Nanjing,China,SLC25A13 gene mutations in these neonates,and clinical features.Methods A total of 152 neonates with INC,who were admitted to the Affiliated Nanjing Children's Hospital of Nanjing Medical University from Sep-tember 2009 to August 2013,underwent gene analysis for detecting SLC25A13 gene mutations.The neonates were divided into NICCD group,who had been diagnosed definitely,and INC group at a ratio of 1∶2,considering the age and gender.Several biochemical indices were compared between the two groups.Comparison of continuous data between the two groups was made by Mann-Whitney U test after Bonferroni correction.Results There were 21 confirmed cases of NICCD (21/152,13.82%)among the 152 neonates with INC;five types of SLC25A13 mutations were identified in the 21 neonates with NICCD,including 851_854del (27/42,64.29%),IVS6+5 G→A (7/42, 16.67%),1638ins23 (5/42,11.90%),IVS11 +1 G→A (2/42,4.76%),and Q259X (1/42,2.38%).The alanine aminotransferase (ALT)level,aspartate aminotransferase (AST)level,bile acid concentration,albumin level,fasting blood glucose,blood ammonia,and prothrombin time for the NICCD group were 39.42 ±23.40 U/L,124.85 ±92.65 U/L,142.43 ±24.34μmol/L,30.66 ±2.70 g/L,2.79 ± 0.54 mmol/L,117.57 ±27.88 μmol/L,and 14.03 ±2.79 s,respectively,versus 136.02 ±113.67 U/L,226.12 ±129.26 U/L,80.47 ± 31.53 μmol/L,36.87 ±4.96 g/L,3.14 ±0.45 mmol/L,76.43 ±20.80 μmol/L,and 11.40 ±1.55 s for the INC group.The NICCD group had significantly lower ALT and AST levels than the INC group (Z=-5.02,P=0.000;Z=-3.66,P=0.000);the NICCD group had a significantly higher bile acid concentration than the INC group (Z=-5.58,P=0.000);the NICCD group had significantly lower albumin level and fasting blood glucose than the INC group (Z=-4.52,P=0.000;Z=-2.56,P=0.010);the NICCD group had a significantly higher blood ammonia level than the INC group (Z=-4.75,P=0.000);the NICCD group had a significantly longer prothrombin time than the INC group (Z=-4.10,P=0.000).Conclusion Citrin deficiency due to SLC25A13 gene mutations is an im-portant cause of INC in Nanjing.The three most common mutations are 851_854del,IVS6+5 G>A,and 1638_1660dup23,which account for 92.86% of the SLC25A13 gene mutations.More attention should be paid to clinical analysis and detection of SLC25A13 gene mutations to confirm the diagnosis of NICCD.
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Neonatal intrahepatic cholestasis caused by Citrin deficiency(NICCD) is one of phenotypes of Citrin deficiency.It's an autosomal recessive disorder which was mainly seen in East Asia,including China.Case of NICCD was reported firstly by Japanese in 2001.In south area of China,the morbidity of NICCD is higher than that in north area of China.Most of the patients with NICCD has benign prognosis.Symptoms resolve within the first year of life,thus making a diagnosis difficult after this time.But few of patients will develop liver failure,even be fatal to life.Early diagnosis,regular follow-up and proper management may improve the prognosis.
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Citrin deficiency,caused by mutations in SLC25A13,is an autosomal recessive genetic disorder with two age-related phenotypes:adult-oneset type Ⅱ citrullinemia and neonatal intrahepatic cholestasis.Recently,it has been found mostly in individuals of East Asian ancestry.In south China,there is a high mutation carrier frequency especially.There is still a lack of criteria for clinical or biochemical diagnosis of this disease,gene analysis is the main basis of the current diagnosis consequently.Surging number of case reports indicate that Citrin deficiency is not a self-limited disease.Early diagnosis and proper treatments may improve the prognosis.This paper focuses on the current researches in order to make further comprehensiom.
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Objective To investigate the changing pattern of diagnosis of infantile cholestasis after screening the inherited metabolic diseases in infants with cholestasis. Methods Infants under 12 months with cholestasis were identified retrospectively from hospital records from Jan. 1996 to Dec. 2007. The data were retrieved from the medical records and analyzed by focusing particularly on the changing etiology of cholestasis and inherited metabolic diseases in these infants after performing routine screening and diagnostic procedures. Results Among 421 infants identified as having cholestasis during 12-years study period, the common causes of infantile cholestasis were cytomegalovirus (CMV) infection (36. 11% ), bile duct hypoplasia or congenital biliary atresia (31.59%), metabolic disease (8.08%), miscellaneous (10.69%), and unknown ( 13.54% ). The proportion of infants with metabolic diseases after screening increased 16 folds compared with before screening( 15.76% vs 0. 92% ,P<0. 01 ), whereas the proportion of infants with unknown cause decreased from 17.43% to 9.36% (P<0.05). There was no significant change in the proportions of CMV infection, congenital biliary atresia, and miscellaneous causes. The major metabolic diseases of 34 infants included citrin deficiency (41. 18% ) and tyrosinemia (23.53%), followed by galactosemia and progressive familial intrahepatic cholestasis (8. 82% )etc. Conclusions Inherited metabolic disease has become an important cause of infantile cholestasis, which is mainly due to citrin deficiency. Therefore, it is necessary to set a routing screening of citrin deficiency in infants with cholestasis.
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Citrin deficiency is an autosomal recessive disorder caused by mutations of the SLC25A13 gene.As a calcium binding mitochondrial aspartate glutamate carrier,Citrin plays an important role not only in the urea synthesis but NADH shuttle as well.Citrin deficiency has two phenotypes:adult-onset typeⅡcitrullinemia and neonatal intrahepatic cholestasis.Citrin deficiency is a common congenital metabolic defect first found in Japan and now is considered as a global disease.