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Benjamin L Shneider - One of the best experts on this subject based on the ideXlab platform.
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initial assessment of the infant with Neonatal Cholestasis is this biliary atresia
PLOS ONE, 2017Co-Authors: Benjamin L Shneider, John C Magee, Saul J Karpen, Binita M Kamath, Jeffrey S Moore, Nanda Kerkar, Jean P Molleston, Jorge A Bezerra, Karen F MurrayAbstract:Author(s): Shneider, Benjamin L; Moore, Jeff; Kerkar, Nanda; Magee, John C; Ye, Wen; Karpen, Saul J; Kamath, Binita M; Molleston, Jean P; Bezerra, Jorge A; Murray, Karen F; Loomes, Kathleen M; Whitington, Peter F; Rosenthal, Philip; Squires, Robert H; Guthery, Stephen L; Arnon, Ronen; Schwarz, Kathleen B; Turmelle, Yumirle P; Sherker, Averell H; Sokol, Ronald J; Childhood Liver Disease Research Network | Abstract: IntroductionOptimizing outcome in biliary atresia (BA) requires timely diagnosis. Cholestasis is a presenting feature of BA, as well as other diagnoses (Non-BA). Identification of clinical features of Neonatal Cholestasis that would expedite decisions to pursue subsequent invasive testing to correctly diagnose or exclude BA would enhance outcomes. The analytical goal was to develop a predictive model for BA using data available at initial presentation.MethodsInfants at presentation with Neonatal Cholestasis (direct/conjugated bilirubin g2 mg/dl [34.2 μM]) were enrolled prior to surgical exploration in a prospective observational multi-centered study (PROBE-NCT00061828). Clinical features (physical findings, laboratory results, gallbladder sonography) at enrollment were analyzed. Initially, 19 features were selected as candidate predictors. Two approaches were used to build models for diagnosis prediction: a hierarchical classification and regression decision tree (CART) and a logistic regression model using a stepwise selection strategy.ResultsIn PROBE April 2004-February 2014, 401 infants met criteria for BA and 259 for Non-BA. Univariate analysis identified 13 features that were significantly different between BA and Non-BA. Using a CART predictive model of BA versus Non-BA (significant factors: gamma-glutamyl transpeptidase, acholic stools, weight), the receiver operating characteristic area under the curve (ROC AUC) was 0.83. Twelve percent of BA infants were misclassified as Non-BA; 17% of Non-BA infants were misclassified as BA. Stepwise logistic regression identified seven factors in a predictive model (ROC AUC 0.89). Using this model, a predicted probability of g0.8 (n = 357) yielded an 81% true positive rate for BA; l0.2 (n = 120) yielded an 11% false negative rate.ConclusionDespite the relatively good accuracy of our optimized prediction models, the high precision required for differentiating BA from Non-BA was not achieved. Accurate identification of BA in infants with Neonatal Cholestasis requires further evaluation, and BA should not be excluded based only on presenting clinical features.
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mutations in the nuclear bile acid receptor fxr cause progressive familial intrahepatic Cholestasis
Nature Communications, 2016Co-Authors: Natalia Gomezospina, Carol Potter, Kandamurugu Manickam, Benjamin L Shneider, Theodora Jacobson, Weimin He, Rui Xiao, Jennifer Picarsic, Jing Zhang, A S KniselyAbstract:Neonatal Cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic Cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with Neonatal Cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related Cholestasis include Neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.
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mr cholangiography in the evaluation of Neonatal Cholestasis initial results
Radiology, 2002Co-Authors: Karen I Norton, Ronald B J Glass, Debora Kogan, Jacob S Lee, Sukru Emre, Benjamin L ShneiderAbstract:PURPOSE: To retrospectively analyze prospective magnetic resonance (MR) cholangiographic interpretations of findings and compare them with clinical outcome and to determine the accuracy of MR cholangiography in depicting extrahepatic biliary atresia and helping to distinguish it from other causes of Neonatal jaundice. MATERIALS AND METHODS: Twenty-six infants (15 male, 11 female; median age, 2 months) underwent MR cholangiography with a 1.5-T MR imaging unit. Original interpretations were compared with clinical outcome. Statistical analysis was performed to determine the accuracy of MR cholangiography in depicting extrahepatic biliary atresia. Equivocal cases and any cases lost to follow-up were excluded. RESULTS: Findings in six of 26 infants were interpreted as normal, and none of five patients (one lost to follow-up) had biliary atresia or other surgical lesions; two were abnormal but not suggestive of biliary atresia (one false-negative finding); 12 were consistent with biliary atresia (three false-po...
A S Knisely - One of the best experts on this subject based on the ideXlab platform.
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biallelic variants in vps50 cause a neurodevelopmental disorder with Neonatal Cholestasis
Brain, 2021Co-Authors: Pauline E Schneeberger, A S Knisely, Sheela Nampoothiri, Tess Holling, Dhanya Yesodharan, Malik Alawi, Thomas Muller, Barbara Plecko, Andreas R Janecke, Kerstin KutscheAbstract:Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes are membrane-tethering heterotetramers located at the trans-Golgi network and recycling endosomes, respectively. GARP and EARP share the three subunits VPS51, VPS52, and VPS53, while VPS50 is unique to EARP and VPS54 to GARP. Retrograde transport of endosomal cargos to the TGN is mediated by GARP and endocytic recycling by EARP. Here we report two unrelated individuals with homozygous variants in VPS50, a splice variant (c.1978-1G>T) and an in-frame deletion (p.Thr608del). Both patients had severe developmental delay, postnatal microcephaly, corpus callosum hypoplasia, seizures and irritability, transient Neonatal Cholestasis, and failure to thrive. Light and transmission electron microscopy of liver from one revealed absence of gamma-glutamyltransferase at bile canaliculi, with mislocalization to basolateral membranes, and abnormal tight junctions. Using patient-derived fibroblasts, we identified reduced VPS50 protein accompanied by reduced levels of VPS52 and VPS53. While transferrin-receptor internalization rate was normal in cells of both patients, recycling of the receptor to the plasma membrane was significantly delayed. These data underscore the importance of VPS50 and/or the EARP complex in endocytic recycling and suggest an additional function in establishing cell polarity and trafficking between basolateral and apical membranes in hepatocytes. Individuals with biallelic hypomorphic variants in VPS50, VPS51 or VPS53 show an overarching neurodegenerative disorder with severe developmental delay, intellectual disability, microcephaly, early-onset epilepsy, and variable atrophy of the cerebellum, cerebrum, and/or brainstem. The term "GARP/EARP deficiency" designates disorders in such individuals.
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abcb11 deficiency presenting as transient Neonatal Cholestasis correlation with genotypes and bsep expression
Liver International, 2020Co-Authors: Ye Yang, A S Knisely, Xinbao Xie, Lian Chen, Jiayan Feng, Jianshe WangAbstract:Background & aims ABCB11 deficiency presenting in infancy is believed generally to manifest as persistent/progressive Cholestasis. We describe a group of patients with biallelic ABCB11 variants whose disorder manifested as transient Neonatal Cholestasis (TNC). Methods Neonatal intrahepatic Cholestasis in 68 children (31 males) with biallelic predictedly pathogenic variants (PPV) in ABCB11 was classified as transient (TNC group, n = 23, 11 males), intermittent (benign recurrent intrahepatic Cholestasis [BRIC] group, n = 3, 1 male) or persistent/ progressive (progressive familial intrahepatic Cholestasis [PFIC] group, n = 42, 19 males). Clinical, genetic and bile salt export pump (BSEP) expression information was correlated with outcomes. Results The median onset age of jaundice was 3 days (birth to 2 months) for the TNC group and 10.5 days (birth to 3 months) for the PFIC group (P = .034). The median length of follow-up of TNC patients was 44 months (12 months-168 months). At presentation, hepatobiliary-injury biomarker values were similar between the groups (P > .05). TNC patients (17/23) more often than PFIC patients (20/42, P = .041) harboured biallelic non-null variants (predicted not to terminate translation prematurely). TNC patient livers (7/7) more often than PFIC patient livers (5/16, P = .005) expressed immunohistochemically detectable BSEP. Kaplan-Meier analysis showed better prognosis for patients with BSEP expression (P = .009). Too few BRIC patients were available for statistical study. Conclusions Neonatal Cholestasis associated with biallelic PPV in ABCB11 can resolve temporarily or persistently in one third of cases. Resolution is more likely in patients with biallelic non-null PPV or with liver BSEP expression.
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severe Neonatal Cholestasis in cerebrotendinous xanthomatosis genetics immunostaining mass spectrometry
Journal of Pediatric Gastroenterology and Nutrition, 2017Co-Authors: Jing Yu Gong, Kenneth D R Setchell, A S Knisely, Neng Li Wang, Jing Zhao, Wujuan Zhang, Brian Wolfe, Karolin Lackner, Chenzhi Hao, Meihong ZhangAbstract:ABSTRACTObjectives:Cerebrotendinous xanthomatosis (CTX) is caused by defects in sterol 27-hydroxylase (CYP27A1, encoded by CYP27A1), a key enzyme in the bile acid synthesis pathway. CTX usually presents as neurologic disease in adults or older children. The rare reports of CTX manifest as Neonatal c
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mutations in the nuclear bile acid receptor fxr cause progressive familial intrahepatic Cholestasis
Nature Communications, 2016Co-Authors: Natalia Gomezospina, Carol Potter, Kandamurugu Manickam, Benjamin L Shneider, Theodora Jacobson, Weimin He, Rui Xiao, Jennifer Picarsic, Jing Zhang, A S KniselyAbstract:Neonatal Cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic Cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with Neonatal Cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related Cholestasis include Neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.
James E Heubi - One of the best experts on this subject based on the ideXlab platform.
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longitudinal outcomes in young patients with alpha 1 antitrypsin deficiency with native liver reveal that Neonatal Cholestasis is a poor predictor of future portal hypertension
The Journal of Pediatrics, 2020Co-Authors: Jeffrey Teckman, John C Magee, Saul J Karpen, Nanda Kerkar, Karen F Murray, Philip J Rosenthal, Kieran Hawthorne, Cathie Spino, Lee M Bass, James E HeubiAbstract:Objectives To identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere. Study design The Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected. Results We enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding Neonatal Cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for Neonatal Cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score. Conclusions Portal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of Neonatal Cholestasis is a weak predictor of severe disease.
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inborn errors of bile acid metabolism
Clinics in Liver Disease, 2018Co-Authors: James E Heubi, Kenneth D R Setchell, Kevin E. BoveAbstract:: Inborn errors of bile acid metabolism are rare causes of Neonatal Cholestasis and liver disease in older children and adults. The diagnosis should be considered in the context of hyperbilirubinemia with normal serum bile acids and made by urinary liquid secondary ionization mass spectrometry or DNA testing. Cholic acid is an effective treatment of most single-enzyme defects and patients with Zellweger spectrum disorder with liver disease.
Björn Fischler - One of the best experts on this subject based on the ideXlab platform.
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cd13 autoantibodies are elevated in sera from mothers of infants with Neonatal Cholestasis of different causes
Journal of Pediatric Gastroenterology and Nutrition, 2017Co-Authors: Afsar Rahbar, Björn Fischler, Antal Nemeth, Soley Omarsdottir, Jonas Teng, Cecilia SoderbergnauclerAbstract:Objectives Human cytomegalovirus (HCMV) infection induces production of CD13-specific autoantibodies, which may promote inflammation and tissue damage. HCMV infection has been suggested as a cause of biliary atresia (BA), but little is known of its role in other forms of Neonatal Cholestasis. We studied serum levels of CD13-specific autoantibodies in mothers of infants with Neonatal Cholestasis of different causes, including BA, and in mothers of healthy, term infants without Cholestasis, as well as in healthy blood donors. Methods Using fluorescence-activated cell sorting, we measured CD13-specific autoantibody levels in serum from the above-mentioned groups. In addition, the effect of serum from mothers of infants with Neonatal Cholestasis was tested on the differentiation of monocytes into macrophages. Results CD13-specific autoantibodies were found in mothers of infants with Neonatal Cholestasis, but not in mothers of infants without Cholestasis and healthy blood donors, and were associated with HCMV seropositivity. Sera from mothers of infants with all forms of Neonatal Cholestasis inhibited differentiation of monocytes into macrophages, but this was not dependent on CD13-specific autoantibodies. Conclusions The significantly higher frequency of CD13-specific autoantibodies in mothers of infants with Neonatal Cholestasis of all forms compared with mothers of healthy infants without Cholestasis suggests an association, but does not prove that they are pathogenic. The presence of CD13-specific autoantibodies does not correlate with HCMV IgG serostatus, suggesting a more complicated mechanism that possibly reflects active HCMV infection in these individuals. Further studies are needed to elucidate whether these autoantibodies contribute to the development of Cholestasis or represent an epiphenomenon.
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population based study of incidence and clinical outcome of Neonatal Cholestasis in patients with down syndrome
The Journal of Pediatrics, 2012Co-Authors: Henrik Arnell, Björn FischlerAbstract:Objective To study the incidence and outcome of Down syndrome–associated Neonatal Cholestasis in a population-based cohort. Study design This retrospective study included all neonates diagnosed with Down syndrome born between January 2005 and September 2011 in the County of Stockholm, Sweden. Clinical and biochemical data related to Cholestasis, early gastrointestinal (GI) involvement, congenital heart defects (CHD), and bone marrow disease were obtained from the computer-based hospital chart system. Results A total of 206 newborns with Down syndrome were identified, for an incidence of 1 in 880 newborns. Prevalences of other diseases in these newborns included 47% for CHD, 11.2% for GI involvement, 3.9% for Neonatal Cholestasis, and 3.4% for bone marrow disease. Neonatal Cholestasis was more common in the newborns with GI involvement (3 of 23 vs 5 of 183 of those without GI involvement; P = .047), CHD (8 of 96 vs 0 of 110 of those without CHD; P = .0019), and bone marrow disease (3 of 7 vs 5 of 199 of those without bone marrow disease; P = .0013). Cholestasis was severe in 3 patients (all of whom had bone marrow disease, with liver failure and early death in 2), and transient in 5 patients. Conclusion Neonatal Cholestasis occurs in a significant percentage of patients with Down syndrome and is always associated with involvement of other organs. The outcome is variable, being most severe in newborns with the combination of Neonatal Cholestasis and bone marrow disease.
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clinical aspects on Neonatal Cholestasis based on observations at a swedish tertiary referral centre
Acta Paediatrica, 2007Co-Authors: Björn Fischler, Nikos Papadogiannakis, Antal NemethAbstract:UNLABELLED The aim of the study was to investigate the clinical aspects of Neonatal Cholestasis. The medical records of 85 cholestatic infants were retrospectively reviewed. A majority of the patients were referred from other parts of the country. The most common diagnoses were extrahepatic biliary atresia (n = 30 patients), alpha1-antitrypsin deficiency (n = 11) and progressive familial intrahepatic Cholestasis (n = 11). On presentation, the biliary atresia group had higher mean serum values of bilirubin, G-GT and cholesterol than the patients with intrahepatic Cholestasis, with no significant differences noticed for any other biochemical parameter. A lack of excretion on hepatobiliary scintigraphy was noticed in all investigated patients with biliary atresia, but also in 9 of 34 patients with intrahepatic Neonatal Cholestasis. There was no statistical correlation between the age at portoenterostomy and the outcome in patients with biliary atresia. However, both the detection of a partial flow on perioperative cholangiogram and the establishment of a non-icteric phase within 6 mo after the portoenterostomy correlated to a good outcome. Eight of 11 patients with progressive familial intrahepatic Cholestasis were treated with a biliary diversion procedure, five of eight experienced a sustained cholestatic remission. CONCLUSIONS Progressive familial intrahepatic Cholestasis may be a more common cause of Neonatal Cholestasis in Sweden than reported elsewhere and that the experience with biliary diversion is positive. While early referral in patients with extrahepatic biliary atresia remains important, a portoenterostomy should be attempted also in patients referred after 3 mo of age.
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Aetiological factors in Neonatal Cholestasis
Acta paediatrica (Oslo Norway : 1992), 2001Co-Authors: Björn Fischler, Nikos Papadogiannakis, Antal NemethAbstract:UNLABELLED: The aim of the study was to investigate factors of possible importance for the aetiology of Neonatal Cholestasis. The medical records of 85 cholestatic infants were retrospectively reviewed. The most common diagnoses were extrahepatic biliary atresia (n = 30 patients), alpha1-antitrypsin deficiency (n = 11) and progressive familial intrahepatic Cholestasis (n = 11). The mothers of the patients with biliary atresia had a higher mean age and were more commonly treated for gestational diabetes than the mothers of patients with intrahepatic Neonatal Cholestasis. The morbidity and mortality in the siblings of patients with biliary atresia were also greater than expected. There was a seasonal variation of the birth months in the biliary atresia group. possibly indicating an association to viral infections. Signs of ongoing cytomegalovirus infection were more common in both the extrahepatic and the intrahepatic group. CONCLUSIONS: Progressive familial intrahepatic Cholestasis may be a more common cause of Neonatal Cholestasis in Sweden than reported elsewhere. A maternal vulnerability, of genetic or other origin, is suggested in the aetiology of biliary atresia. The true pathogenetic importance of cytomegalovirus infection in patients with Neonatal Cholestasis of different origins remains to be established.
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cytomegalovirus dna detection on guthrie cards in patients with Neonatal Cholestasis
Archives of Disease in Childhood-fetal and Neonatal Edition, 1999Co-Authors: Björn Fischler, Antal Nemeth, Pia Rodensjo, Marianne Forsgren, Ilona LewensohnfuchsAbstract:AIM—To time the onset of cytomegalovirus (CMV) infection in patients (n=39) with CMV associated Neonatal Cholestasis by analysing CMV DNA on Guthrie cards sampled at 3 days of age. METHODS—CMV infection was diagnosed by serology/urine isolation or by CMV DNA detection (polymerase chain reaction) in liver biopsy specimens. In order to time the infection dry blood filter paper discs were punched out from stored Guthrie cards. After phenol-chloroform extraction CMV DNA was detected by nested polymerase chain reaction. RESULTS—All cards from control children (n=8) with congenital CMV tested positive; none of the negative controls (n=4) did so. Two of 39 cholestatic infants were CMV DNA positive; their mothers had serological signs compatible with infection during the second half of the pregnancy. All other cholestatic infants tested negative. CONCLUSIONS—CMV DNA was not detected in most of the children using Guthrie cards, suggesting that infection developed at or soon after birth.
Jianshe Wang - One of the best experts on this subject based on the ideXlab platform.
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abcb11 deficiency presenting as transient Neonatal Cholestasis correlation with genotypes and bsep expression
Liver International, 2020Co-Authors: Ye Yang, A S Knisely, Xinbao Xie, Lian Chen, Jiayan Feng, Jianshe WangAbstract:Background & aims ABCB11 deficiency presenting in infancy is believed generally to manifest as persistent/progressive Cholestasis. We describe a group of patients with biallelic ABCB11 variants whose disorder manifested as transient Neonatal Cholestasis (TNC). Methods Neonatal intrahepatic Cholestasis in 68 children (31 males) with biallelic predictedly pathogenic variants (PPV) in ABCB11 was classified as transient (TNC group, n = 23, 11 males), intermittent (benign recurrent intrahepatic Cholestasis [BRIC] group, n = 3, 1 male) or persistent/ progressive (progressive familial intrahepatic Cholestasis [PFIC] group, n = 42, 19 males). Clinical, genetic and bile salt export pump (BSEP) expression information was correlated with outcomes. Results The median onset age of jaundice was 3 days (birth to 2 months) for the TNC group and 10.5 days (birth to 3 months) for the PFIC group (P = .034). The median length of follow-up of TNC patients was 44 months (12 months-168 months). At presentation, hepatobiliary-injury biomarker values were similar between the groups (P > .05). TNC patients (17/23) more often than PFIC patients (20/42, P = .041) harboured biallelic non-null variants (predicted not to terminate translation prematurely). TNC patient livers (7/7) more often than PFIC patient livers (5/16, P = .005) expressed immunohistochemically detectable BSEP. Kaplan-Meier analysis showed better prognosis for patients with BSEP expression (P = .009). Too few BRIC patients were available for statistical study. Conclusions Neonatal Cholestasis associated with biallelic PPV in ABCB11 can resolve temporarily or persistently in one third of cases. Resolution is more likely in patients with biallelic non-null PPV or with liver BSEP expression.
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abnormal bilirubin metabolism in patients with sodium taurocholate cotransporting polypeptide deficiency
Journal of Pediatric Gastroenterology and Nutrition, 2020Co-Authors: Yan Yan Yan, Kenneth D R Setchell, Xinbao Xie, Meng Xuan Wang, Jing Yu Gong, Lang Li Liu, Neng Li Wang, Jianshe WangAbstract:OBJECTIVES The aim of the study was to explore the significance of sodium taurocholate cotransporting polypeptide (NTCP) deficiency and its clinical features in Chinese children presenting with isolated persistent hypercholanemia. METHODS The exon and adjacent regions of SLC10A1, the gene encoding NTCP, were sequenced in 33 Chinese children presenting with isolated hypercholanemia. Clinical history and medical data were reviewed. Growth milestones were compared with the national standard. The serum direct bilirubin concentration at last follow-up was compared with age- and sex-matched controls. RESULTS A variant, c.800C>T, p. S267F of SLC10A1 was detected in all subjects; 30 patients were homozygotes and 3 were compound heterozygotes. Nine patients presented with transient Neonatal Cholestasis, and 1 with a persistent mild conjugated hyperbilirubinemia. The serum direct bilirubin level in NTCP-deficient patients was significantly higher than age- and sex-matched controls even after the Neonatal Cholestasis stage (2.85 ± 1.50 vs 1.49 ± 0.70 μmol/L, P = 0.00008). No growth delay or other severe long-term clinical consequences were observed. CONCLUSIONS NTCP deficiency is the exclusive or major cause of isolated hypercholanemia in Han Chinese children, with c.800C>T the major contributing genetic variation. The defect may affect bilirubin metabolism and present as transient Neonatal Cholestasis and/or persistent mild conjugated hyperbilirubinmia, but with no apparent long-term clinical consequences.
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association of variants of abcb11 with transient Neonatal Cholestasis
Pediatrics International, 2013Co-Authors: Liyan Liu, Xiaohong Wang, Qirong Zhu, Jianshe WangAbstract:Background The significance of ABCB11 variants have been studied in some cholestatic diseases, but this is not clear in transient Neonatal Cholestasis (TNC). The aim of the present study was to explore the association between ABCB11 variants and TNC. Methods This was a case–control study. A total of 192 children with TNC referred to a tertiary referral hospital in eastern China were enrolled as subjects, and 196 healthy children were selected as controls. Part of the promoter and exons of the ABCB11 gene were sequenced directly. The single nucleotide polymorphism (SNP) site of V444A was tested using fluorescent quantitative polymerase chain reaction. Potential consequences of variants were predicted using bioinformatics software. The biochemistry indices were compared between the patients with or without possibly pathogenic variants/mutations. Results Twenty-eight variants, including 14 novel ones, were detected. Four novel, possibly pathogenic mutations (I416I, K436N, R928Q and IVS7+5G>A) were detected in six subjects. The γ-glutamyltransferase level of these six was lower than in the others (P = 0.054). The genotype distribution of the four common SNP sites, V444A, A535A, A865V and A1082A, was not significantly different between TNC patients and controls. Conclusions Approximately 3% of TNC cases can be attributed to ABCB11 mutations.
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biochemical characteristics of Neonatal Cholestasis induced by citrin deficiency
World Journal of Gastroenterology, 2012Co-Authors: Jianshe Wang, Xiaohong Wang, Yingjie Zheng, Rui Chen, Lingjuan Fang, Takeyori Saheki, Keiko KobayashiAbstract: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.
