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BACKGROUND: Patients with acid sphingomyelinase deficiency (ASMD) may be referred to a hepatologist for liver manifestations. This study summarized the liver manifestations of patients with ASMD in the early disease course. METHODS: This study enrolled ASMD patients diagnosed by genetic tests between July 2016 and December 2020 in a national pediatric liver center. The significance of low High-density lipoprotein cholesterol (HDL-C) for aid diagnosis of ASMD in infancy was explored by reviewing 160 consecutive infants with liver manifestations, who underwent both genetic tests and lipid profile studies, between January 2020 and December 2020. RESULTS: A total of 7 patients were diagnosed as ASMD, and 10 known disease-causing variants were identified. Hepatosplenomegaly, elevated transaminases, and liver foam cells were observed in all the 7 patients at age ranging from 4 to 31 months. Low HDL-C was detected in 5 patients, cherry red spot in 4 patients, development delay in 3 patients, and interstitial lung diseases in 1 patient. Three ASMD patients developed cholestasis around 1 month of age, and bilirubin levels normalized at age ranging from 3 to 10 months. They had persistently elevated transaminases and hepatosplenomegaly, and died within 4 years of age. Among the 160 infants with liver manifestations, 125 (78.1%) had low HDL-C. Fifty-four had both low HDL-C and splenomegaly, including 48 cholestatic infants, but only 1 (1.9%, 1/54) infant without cholestasis was diagnosed as ASMD. CONCLUSIONS: ASMD can manifest as neonatal cholestasis in the early disease course. Cholestasis is a pitfall when low HDL-C is used for aid diagnosis of ASMD in infants with splenomegaly.
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Colestasis , Hepatopatías , Enfermedad de Niemann-Pick Tipo A , Enfermedades de Niemann-Pick , Preescolar , Hepatomegalia/etiología , Humanos , Lactante , Enfermedades de Niemann-Pick/genética , Esplenomegalia/etiología , TransaminasasRESUMEN
BACKGROUND: Genetic defects account for a substantial proportion of pediatric cholestasis. This study explored the molecular findings in a large cohort of Chinese patients with inherited cholestasis. METHODS: Between January 2012 and June 2016, 809 Chinese pediatric patients with suspected inherited intrahepatic cholestasis were evaluated by Sanger sequencing and/or panel sequencing. RESULTS: Of the 809 patients, 273 (33.7%) obtained a genetic diagnosis. The rate of positive genetic diagnosis in patients with disease onset at 0-3 month of age was higher than that in patients with disease onset at 4 month of age or later. There were 17 distinct genetic defects diagnosed. The top 4 resulted from mutations in SLC25A13 (44.3%), JAG1 (24.5%), ABCB11 (11.0%), and ATP8B1 (5.9%). All 17 genetic disorders were diagnosed in patients with disease onset at 0-3 months of age; but only 5 were diagnosed in patients with disease onset beyond 4 months of age. A total of 217 distinct pathogenic variants, including 41 novel variants, were identified. Ten recurrent mutations were detected in SLC25A13, ATP8B1, and CYP27A1. They accounted for 48.2% of the total 477 mutant alleles. CONCLUSIONS: There were 17 distinct genetic disorders diagnosed in Chinese pediatric patients with inherited cholestasis.
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Colestasis Intrahepática/genética , Mutación , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP/genética , Adenosina Trifosfatasas/genética , Adolescente , Pueblo Asiatico/genética , Niño , Preescolar , China , Colestanotriol 26-Monooxigenasa/genética , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/etnología , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , Lactante , Proteína Jagged-1/genética , Masculino , Proteínas de Transporte de Membrana Mitocondrial/genética , Linaje , Fenotipo , Medición de Riesgo , Factores de RiesgoRESUMEN
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 (2.85â±â1.50 vs 1.49â±â0.70âµmol/L, Pâ=â0.00008). 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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Bilirrubina , Transportadores de Anión Orgánico Sodio-Dependiente , Simportadores , Niño , Homocigoto , Humanos , Recién Nacido , Transportadores de Anión Orgánico Sodio-Dependiente/deficiencia , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Simportadores/deficiencia , Simportadores/genéticaRESUMEN
BACKGROUND: Long waiting times result in low satisfaction. Although several methods are used to shorten the actual waiting time (AWT) in large hospitals of China, the outpatients still have a long actual waiting time. This study aimed to explore whether satisfaction could be improved by extending the expected waiting time (EWT) instead of shortening the AWT. METHODS: In October 2016, 257 students in grade one voluntarily participated in this study. They came from 6 classes, which were randomly divided into two groups: 3 classes comprised the control group (n = 125) and 3 classes comprised the experimental group (n = 132). Unfavorable information (UI) was given to the experimental group alone. Six distinct questionnaires were designed to explore the effects of UI on EWT and the effects of an extended EWT on satisfaction. Satisfaction scores ranged from 0 to 100: 0-25, very dissatisfied; 26-50, dissatisfied; 51-75, satisfied; 76-100, very satisfied. Each participant finished one of the 6 questionnaires online. Of the 257 questionnaires, 233 were valid. RESULTS: Before UI was given, the initial EWT (T0) was similar between the control and experimental groups (Z = -1.924, P = 0.054). Under the effects of UI, individuals in the experimental group extended their EWT (T1) from 121.0 to 180.0 min (Z = -6.367, P < 0.001). Females prolonged their EWT longer than males did (Z = -2.239, P = 0.025). Then, this study defined T0 = 1.5 h and T1 = 2.5 h, and compared the satisfaction scores between the control and experimental groups: a significant difference was found when AWT =2.0 h (t = - 3.568, P = 0.001), but not when AWT =3.0 h (t = - 0.718, P = 0.475) or when AWT =1.0 h (t = - 1.088, P = 0.280). When AWT =3.0 h, fewer individuals felt "very dissatisfied" in the experimental group (21.2%) than in the control group (44.7%) (χ2 = 4.368, P = 0.037). CONCLUSIONS: EWT was found to be extended greatly by UI. An extended EWT could improve satisfaction scores.
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Encuestas de Atención de la Salud , Pacientes Ambulatorios/psicología , Satisfacción del Paciente/estadística & datos numéricos , Listas de Espera , Adolescente , Femenino , Humanos , Masculino , Factores de Tiempo , Adulto JovenRESUMEN
Hereditary cholestasis in childhood and infancy with normal serum gamma-glutamyltransferase (GGT) activity is linked to several genes. Many patients, however, remain genetically undiagnosed. Defects in myosin VB (MYO5B; encoded by MYO5B) cause microvillus inclusion disease (MVID; MIM251850) with recurrent watery diarrhea. Cholestasis, reported as an atypical presentation in MVID, has been considered a side effect of parenteral alimentation. Here, however, we report on 10 patients who experienced cholestasis associated with biallelic, or suspected biallelic, mutations in MYO5B and who had neither recurrent diarrhea nor received parenteral alimentation. Seven of them are from two study cohorts, together comprising 31 undiagnosed low-GGT cholestasis patients; 3 are sporadic. Cholestasis in 2 patients was progressive, in 3 recurrent, in 2 transient, and in 3 uncategorized because of insufficient follow-up. Liver biopsy specimens revealed giant-cell change of hepatocytes and intralobular cholestasis with abnormal distribution of bile salt export pump (BSEP) at canaliculi, as well as coarse granular dislocation of MYO5B. Mass spectrometry of plasma demonstrated increased total bile acids, primary bile acids, and conjugated bile acids, with decreased free bile acids, similar to changes in BSEP-deficient patients. Literature review revealed that patients with biallelic mutations predicted to eliminate MYO5B expression were more frequent in typical MVID than in isolated-cholestasis patients (11 of 38 vs. 0 of 13). CONCLUSION: MYO5B deficiency may underlie 20% of previously undiagnosed low-GGT cholestasis. MYO5B deficiency appears to impair targeting of BSEP to the canalicular membrane with hampered bile acid excretion, resulting in a spectrum of cholestasis without diarrhea. (Hepatology 2017;65:1655-1669).
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Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Colestasis Intrahepática/genética , Cadenas Pesadas de Miosina/genética , Miosina Tipo V/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/sangre , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP , Transportadoras de Casetes de Unión a ATP/metabolismo , Ácidos y Sales Biliares/sangre , Colestasis Intrahepática/sangre , Colestasis Intrahepática/patología , Análisis Mutacional de ADN , Exoma , Femenino , Humanos , Lactante , Recién Nacido , Hígado/metabolismo , Hígado/patología , Masculino , Cadenas Pesadas de Miosina/metabolismo , Miosina Tipo V/metabolismo , Estudios RetrospectivosRESUMEN
BACKGROUND & AIMS: Genetic defects causing dysfunction in bile salt export pump (BSEP/ABCB11) lead to liver diseases. ABCB11 mutations alter the bile acid metabolome. We asked whether profiling plasma bile acids could reveal compensatory mechanisms and track genetic and clinical status. METHODS: We compared plasma bile acids in 17 ABCB11-mutated patients, 35 healthy controls and 12 genetically undiagnosed cholestasis patients by ultra-high-performance liquid chromatography/multiple-reaction monitoring-mass spectrometry (UPLC/MRM-MS). We developed an index to rank bile acid hydrophobicity, and thus toxicity, based on LC retention times. We recruited 42 genetically diagnosed hereditary cholestasis patients, of whom 12 were presumed to have impaired BSEP function but carried mutations in genes other than ABCB11, and 8 healthy controls, for further verification. RESULTS: The overall hydrophobicity indices of total bile acids in both the ABCB11-mutated group (11.89 ± 1.07 min) and the undiagnosed cholestasis group (11.46 ± 1.07 min) were lower than those of healthy controls (13.69 ± 0.77 min) (both p < 0.005). This was owing to increased bile acid modifications. Secondary bile acids were detected in patients without BSEP expression, suggesting biliary bile acid secretion through alternative routes. A diagnostic panel comprising lithocholic acid (LCA), tauro-LCA, glyco-LCA and hyocholic acid was identified that could differentiate the ABCB11-mutated cohort from healthy controls and undiagnosed cholestasis patients (AUC=0.946, p < 0.0001) and, in non-ABCB11-mutated cholestasis patients, could distinguish BSEP dysfunction from normal BSEP function (9/12 vs 0/38, p < 0.0000001). CONCLUSIONS: Profiling of plasma bile acids has provided insights into cholestasis alleviation and may be useful for the clinical management of cholestatic diseases.
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Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP/genética , Ácidos y Sales Biliares/sangre , Colestasis Intrahepática/sangre , Colestasis Intrahepática/genética , Estudios de Casos y Controles , Preescolar , China , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Lactante , Masculino , MutaciónRESUMEN
AIM: The aim of this study was to analyze the pathogenicity of rare/novel synonymous or intronic variants identified in ABCB11 heterozygotes presenting as progressive intrahepatic cholestasis with low γ-glutamyltransferase. METHODS: The enrolled variants were identified in ABCB11 between October 2009 and June 2016. The effects on pre-RNA splicing were analyzed by in silico tools and minigene splicing assay. RESULTS: There were three intronic (c.908 + 5G > A, c.2815-8A > G, and c.612-15_-6del10bp) and two synonymous (c.1809G > A, p.K603 K and c.2418C > T, p.G806G) variants with unknown significance identified in ABCB11 of five ABCB11 heterozygotes. Parental studies were carried out for four patients, and revealed that the variants with unknown significance were compound heterozygous with other pathogenic variants. The five variants with unknown significance had minor allele frequency <0.1% or were absent from controls, and had positive prediction results by in silico tools. The effects on pre-RNA splicing were further confirmed by minigene splicing assay. c.908 + 5A caused abnormal splicing in at least 78.5 ± 3.8% of products using a cryptic splice site (ss) 22 nucleotides (nt) upstream of the wild-type (WT) 5'ss. Seven nucleotides of intron 22 upstream of the WT 3'ss was retained for all products from c.2815-8G. c.612-15_-6del caused exon 8 skipping in 24.8 ± 7.7% of products, and 55 nt of exon 8 downstream of the WT 3'ss removal in remaining products. c.1809A led to exon 15 skipping. c.2418 T removed exon 20 and 62 nt of exon 21 downstream of the WT 3'ss by using a cryptic ss. CONCLUSIONS: We successfully identified five pathogenic synonymous or intronic variants with some common features. These features might help to choose the right variant for further functional assay.
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OBJECTIVES: 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 cholestasis assess the cholestasis as transient, with patient survival. Our experience differs. METHODS: Homozygous or compound heterozygous CYP27A1 mutations were detected in 8 neonatal cholestasis patients by whole exome sequencing, panel sequencing, or Sanger sequencing. Their clinical and biochemical data were retrospectively reviewed. Immunostaining for CYP27A1 was conducted in liver of 4 patients. Mass spectrometry was used to analyze patients' urine samples. RESULTS: All 8 infants had severe cholestasis. Five died from, or were transplanted for, liver failure; 3 cleared their jaundice eventually. Marking for CYP27A1 was weak or absent in 3 of the 4 patient specimens. Mass spectrometry of urine revealed a predominance of sulfated and doubly conjugated (sulfated-glucuronidated) bile alcohols. No patient harbored a putatively pathogenic mutation in genes other than CYP27A1 that have been implicated in cholestatic liver disease. CONCLUSIONS: CTX manifest as neonatal cholestasis has a bile acid profile different from CTX manifest in later life, and thus may be overlooked. Immunostaining, mass spectrometry of urine, and genetic studies can support one another in making the diagnosis. A substantial proportion of CTX patients with severe neonatal cholestasis may die or need liver transplantation. CTX manifest in infancy as severe cholestasis warrants further investigation of biochemical diagnostic criteria and best management.
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Colestasis/etiología , Xantomatosis Cerebrotendinosa/diagnóstico , Colestanotriol 26-Monooxigenasa/genética , Colestanotriol 26-Monooxigenasa/metabolismo , Colestasis/diagnóstico , Colestasis/mortalidad , Colestasis/cirugía , Femenino , Marcadores Genéticos , Humanos , Recién Nacido , Hígado/metabolismo , Trasplante de Hígado , Masculino , Espectrometría de Masas , Mutación , Estudios Retrospectivos , Análisis de Secuencia de ADN/métodos , Índice de Severidad de la Enfermedad , Xantomatosis Cerebrotendinosa/complicaciones , Xantomatosis Cerebrotendinosa/genética , Xantomatosis Cerebrotendinosa/metabolismoRESUMEN
BACKGROUND: Fibrinogen storage disease (FSD) is a rare autosomal-dominant disorder caused by mutation in FGG, encoding the fibrinogen gamma chain. Here we report the first Han Chinese patient with FSD, caused by de novo fibrinogen Aguadilla mutation, and his response to pharmacologic management. CASE PRESENTATION: Epistaxis and persistent clinical-biochemistry test-result abnormalities prompted liver biopsy in a boy, with molecular study of FGG in him and his parents. He was treated with the autophagy enhancer carbamazepine, reportedly effective in FSD, and with ursodeoxycholic acid thereafter. Inclusion bodies in hepatocellular cytoplasm stained immune-histochemically for fibrinogen. Selective analysis of FGG found the heterozygous mutation c.1201C > T (p.Arg401Trp), absent in both parents. Over more than one year's follow-up, transaminase and gamma-glutamyl transpeptidase activities have lessened but not normalized. CONCLUSION: This report expands the epidemiology of FSD and demonstrates idiosyncrasy in response to oral carbamazepine and/or ursodeoxycholic acid in FSD.
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Afibrinogenemia/tratamiento farmacológico , Afibrinogenemia/genética , Pueblo Asiatico/genética , Carbamazepina/uso terapéutico , Fibrinógenos Anormales/genética , Ácido Ursodesoxicólico/uso terapéutico , Preescolar , Genes Dominantes , Humanos , Masculino , Mutación , Resultado del TratamientoRESUMEN
Background: The identification of vanishing bile duct syndrome (VBDS) is still challenging before liver biopsy. This study tried to explore non-invasive biomarkers for identification of VBDS among children with acute cholestatic hepatitis. Methods: Between January 2017 and December 2021, 192 children underwent native-liver biopsy for acute cholestatic hepatitis with onset after 6 months of age. VBDS was diagnosed by liver biopsy. Differences of liver biochemical indices were compared between children with and without VBDS. Diagnostic performances for VBDS were tested by receiver operating characteristic (ROC) curve analyses. Results: Among the 192 patients, 24 (12.5%) were diagnosed with VBDS based on liver biopsy. At biopsy, their levels of total bilirubin (TB), direct bilirubin (DB), γ-glutamyl transpeptidase (GGT), total bile acid, triglyceride, and total cholesterol (TCH) were higher than patients without VBDS (all P<0.05). However, only GGT and TCH could distinguish patients with VBDS from patients without VBDS with an area under ROC curve (AUC) >0.850. Using GGT >446 U/L as a cut-off value, the sensitivity was 87.5%, the specificity was 91.6%, and the AUC was 0.948 (P<0.001). Using TCH >6.4 mmol/L as a cut-off value, the sensitivity was 100.0%, the specificity was 89.8%, and the AUC was 0.983 (P<0.001). A total of 28 patients had both GGT >446 U/L and TCH >6.4 mmol/L, including 21 patients with VBDS and 7 without VBDS (21/28 vs. 3/143, P<0.0001). Three patients with VBDS would be missed for GGT <446 U/L. Conclusions: Both GGT and TCH can be used as non-invasive biomarkers for identification of VBDS among children with acute cholestatic hepatitis.
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Early diagnosis of Niemann-Pick disease type C (NP-C) in neonatal cholestasis is still challenging because splenomegaly is non-specific and oxysterol profiling studies also have a relatively low specificity. This study explores a method for identifying infants with a high clinical suspicion of NP-C in neonatal cholestasis. We reviewed the clinical findings of 9 neonatal cholestatic infants with NP-C genetically diagnosed between January 2015 and December 2020. Seven underwent liver biopsy at ages ranging from 35 to 112 d. Foam cells were only detected in 2 (28.6%, 2/7) liver tissues obtained beyond 3 months of age. However, vacuolated Kupffer cells were detected in all 7 liver tissues. Their significance was explored by using 168 neonatal cholestatic infants, who underwent genetic tests and liver biopsy between January 2018 and December 2020. Of them, 26 detected vacuolated Kupffer cells. Six (23.1%, 6/26) were diagnosed as NP-C, comparing to none of the 142 neonatal cholestatic infants without vacuolated Kupffer cells (χ 2 = 33.983, p < 0.001). The ratio of positive diagnosis of NP-C was 31.6% (6/19) in neonatal cholestatic infants with both vacuolated Kupffer cells and splenomegaly. Therefore, we conclude that the presence of vacuolated Kupffer cells can raise a high clinical suspicion of NP-C in neonatal cholestatic infants, especially in those with splenomegaly.
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BACKGROUND: Acute liver failure (ALF) can be a primary presentation of Wilson disease (WD). Mortality rates are high in WD with ALF (WDALF). Predictions of mortality in WDALF vary by model and are sometimes contradictory, perhaps because few patients are studied or WD diagnoses are questionable. AIM: To determine the outcomes among well-documented WDALF patients and assess mortality model performance in this cohort. METHODS: We reviewed the medical records of our pediatric WDALF patients (n = 41 over 6-years-old, single-center retrospective study) and compared seven prognostic models (King's College Hospital Criteria, model for end-stage liver disease/pediatric end-stage liver disease scoring systems, Liver Injury Unit [LIU] using prothrombin time [PT] or international normalized ratio [INR], admission LIU using PT or INR, and Devarbhavi model) with one another. RESULTS: Among the 41 Han Chinese patients with ALF, WD was established by demonstrating ATP7B variants in 36. In 5 others, Kayser-Fleischer rings and Coombs-negative hemolytic anemia permitted diagnosis. Three died during hospitalization and three underwent liver transplantation (LT) within 1 mo of presentation and survived (7.3% each); 35 (85.4%) survived without LT when given enteral D-penicillamine and zinc-salt therapy with or without urgent plasmapheresis. Parameters significantly correlated with mortality included encephalopathy, coagulopathy, and gamma-glutamyl transpeptidase activity, bilirubin, ammonia, and serum sodium levels. Area under the receiver operating curves varied among seven prognostic models from 0.981 to 0.748 with positive predictive values from 0.214 to 0.429. CONCLUSION: WDALF children can survive and recover without LT when given D-penicillamine and Zn with or without plasmapheresis, even after enlisting for LT.
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OBJECTIVE: To study the risk factors for neonatal ventilator-associated pneumonia (VAP) and the changes of isolated pathogens in the last eight years. METHODS: The clinical data of 230 neonates who were admitted into the neonatal intensive care unit (NICU) and received mechanical ventilation for equal to or longer than 48 hrs in 2008 were retrospectively reviewed. The isolated pathogens were compared with those of eight years ago. RESULTS: The incidence of VAP (25.2%) in the year 2008 was lower than that of eight years ago (36.1%; P<0.05). The development of VAP was negatively correlated with the gestational age and the birth weight, but positively correlated with the duration of mechanical ventilation, intubation times, duration of hospitalization, presence of gastrointestinal bleeding and need for blood products transfusion. The main isolated pathogens were opportunistic antibiotics resistant bacteria, and the majority was gram negative bacilli (77%). The most frequently detected gram negative bacilli were Klebsiella (20%), Stenotrophomonas maltophilia (18%) and Acinetobacter (13%). Streptococcus mitis was the most frequently detected gram positive bacilli (14%). The distribution pattern of pathogens isolated in the same NICU eight years ago was somewhat different: Klebsiella (23%), Pseudomonas aeruginosa (17%), Acinetobacter (16%), Streptococcus mitis (11%), Fungi (1%) and Candida albicans (1%). CONCLUSIONS: The incidence of VAP is correlated with gestational age, birth weight, duration of mechanical ventilation and hospitalization, intubation times, presence of gastrointestinal bleeding and need for blood products transfusion. The main isolated pathogens are usually antibiotic resistant opportunistic bacteria. The detection rate of Stenotrophomonas maltophilia increased and that of Pseudomonas aeruginosa decreased when compared with eight years ago.
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Bacterias Gramnegativas , Neumonía Asociada al Ventilador , Antibacterianos/uso terapéutico , Bacterias Gramnegativas/aislamiento & purificación , Humanos , Incidencia , Recién Nacido , Factores de RiesgoRESUMEN
BACKGROUND AND AIMS: Genetic defects in ATP8B1 or ABCB11 account for the majority of cholestasis with low GGT. But the ranges for GGT in patients with ATP8B1 or ABCB11 deficiency are unclear. This study tried to unravel the features of GGT in these patients that improve diagnostic efficiency. METHODS: This study enrolled 207 patients with chronic cholestasis who were ordered to test for ATP8B1 and/or ABCB11 from January 2012 to December 2015. Additional 17 patients with ATPB81 or ABCB11 deficiency diagnosed between January 2004 and December 2011 were also enrolled in this study. 600 population-matched children served as controls. Clinical data were obtained by retrospectively reviewing medical records. RESULTS: A total of 26 patients were diagnosed with ATP8B1 deficiency and 30 patients were diagnosed with ABCB11 deficiency. GGT levels were similar between the two disorders at any observed month of age, but varied with age. The peak GGT value was <70U/L in the 2nd~6th month of life, <60U/L in the 7th~12th month and <50U/L beyond one year. GGT levels in patients with a genetic diagnosis were different from that in patients without a genetic diagnosis and controls. Larger ranges for GGT were found in patients without a genetic diagnosis. Some controls had GGT≥70U/L in the 2nd~6th month. Of the 207 patients, 39 (18.8%) obtained a genetic diagnosis. 111 patients met the ranges described above, including all the 39 patients with ATP8B1 or ABCB11 deficiency. The sensitivity was 100.0%. The rate of a positive molecular diagnosis increased to 35.1% (39/111 vs. 39/207, X2 = 10.363, P = 0.001). The remaining 96 patients exceeded the ranges described above and failed to receive a genetic diagnosis. These patients accounted for 43.8% of sequencing cost. CONCLUSIONS: GGT levels in patients with ATP8B1 or ABCB11 deficiency varied with age. The peak GGT value was <70U/L in the 2nd~6th month of life, <60U/L in the 7th~12th month and <50U/L beyond one year.
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Transportadoras de Casetes de Unión a ATP/genética , Adenosina Trifosfatasas/genética , Colestasis/diagnóstico , gamma-Glutamiltransferasa/genética , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP , Adolescente , Estudios de Casos y Controles , Niño , Colestasis/genética , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
BACKGROUND AND AIMS: Large indels are commonly identified in patients but are not detectable by routine Sanger sequencing and panel sequencing. We specially designed a multi-gene panel that could simultaneously test known large indels in addition to ordinary variants, and reported the diagnostic yield in patients with intrahepatic cholestasis. METHODS: The panel contains 61 genes associated with cholestasis and 25 known recurrent large indels. The amplicon library was sequenced on Ion PGM system. Sequencing data were analyzed using a routine data analysis protocol and an internal program encoded for large indels test simultaneously. The validation phase was performed using 54 patients with known genetic diagnosis, including 5 with large insertions. At implement phase, 141 patients with intrahepatic cholestasis were evaluated. RESULTS: At validation phase, 99.6% of the variations identified by Sanger sequencing could be detected by panel sequencing. Following the routine protocol, 99.8% of false positives could be filtered and 98.8% of retained variations were true positives. Large insertions in the 5 patients with known genetic diagnosis could be correctly detected using the internal program. At implementation phase, 96.9% of the retained variations, following the routine protocol, were confirmed to be true. Twenty-nine patients received a potential genetic diagnosis when panel sequencing data were analyzed using the routine protocol. Two additional patients, who were found to harbor large insertions in SLC25A13, obtained a potential genetic diagnosis when sequencing data were further analyzed using the internal program. A total of 31 (22.0%) patients obtained a potential genetic diagnosis. Nine different genetic disorders were diagnosed, and citrin deficiency was the commonest. CONCLUSION: Specially designed multi-gene panel can correctly detect large indels simultaneously. By using it, we assigned a potential genetic diagnosis to 22.0% of patients with intrahepatic cholestasis.
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Colestasis Intrahepática/genética , Pruebas Genéticas/métodos , Mutación INDEL , Análisis de Secuencia de ADN/métodos , Niño , Diagnóstico Precoz , Femenino , Biblioteca de Genes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Proteínas de Transporte de Membrana Mitocondrial/genética , Sensibilidad y EspecificidadRESUMEN
Wilson disease is an autosomal recessive disorder of copper metabolism that can cause fatal neurological and hepatic disease if not diagnosed and treated. The youngest child with normal liver function reported so far is an 8-mo-old Japanese boy with low ceruloplasmin levels, and the youngest child with elevated aminotransferase ever reported so far is a 9-mo-old Korean boy with confirmed by genetic testing. Here we report an 8-mo-old Chinese boy presented with elevated liver enzymes, and low serum ceruloplasmin level. Genetic analysis of ATP7B gene detected two heterozygous disease causing mutations (c.2621C>T/p.A874V and c.3809A>G/p.N1270S), and parental origins were determined. Persistent elevation of serum aminotransferase in this infant was normalized after zinc therapy. To our best knowledge, this is the youngest patient with elevated liver enzymes ever reported worldwide. We hope that this will raise awareness among pediatricians, leading to earlier diagnosis, timely treatment, and better clinical outcome.