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1.
Hum Mutat ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31696999

RESUMO

To assess the spectrum of pediatric clinical phenotypes in TJP2 disease, we reviewed records of our seven patients in whom intrahepatic cholestasis was associated with biallelic TJP2 variants (13; 12 novel) and correlated clinical manifestations with mutation type. The effect of a splicing variant was analyzed with a minigene assay. The effects of three missense variants were analyzed with protein expression in vitro. Our patients had both remitting and persistent cholestasis. Three exhibited growth retardation. Six responded to treatment with cholestyramine, ursodeoxycholic acid, or both. Two had cholecystolithiasis. None required liver transplantation or developed hepatocellular or cholangiocellular malignancy. None manifested extrahepatic disease not attributable to effects of cholestasis. The variant c.2180-5T>G resulted in exon 15 skipping with in-frame deletion of 32 amino acid residues in TJP2. The three missense variants decreased but did not abolish TJP2 expression. Patients with truncating or canonical splice-site variants had clinically more severe disease. TJP2 disease in children includes a full clinical spectrum of severity, with mild or intermittent forms as well as the severe and minimal forms hitherto described. Biallelic TJP2 variants must be considered in children with clinically intermittent or resolved intrahepatic cholestasis.

2.
Hum Mutat ; 40(12): 2247-2257, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31479177

RESUMO

The typical phenotype of arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome involves three cardinal symptoms as the name describes, harboring biallelic mutations on VPS33B or VIPAS39. Except for ARC syndrome, low gamma-glutamyltransferase (GGT) cholestasis often implies hereditary hepatopathy of different severity; however, some remain undiagnosed. Several monogenic defects typically with multiorgan manifestations may only present liver dysfunction at times, such as DGUOK defect and AGL defect. Previously, four VPS33B mutated cases were reported without arthrogryposis, or with less severe symptoms and longer lifespan, indicating the possibility of incomplete ARC phenotype of isolated hepatopathy. So we retrospectively reviewed all patients with confirmed VPS33B/VIPARS39 defect in our center and identified three presenting isolated low-GGT cholestasis with intractable pruritus. Distinguished from others with typical ARC phenotype, these patients did not suffer the other two typical characteristics, survived much longer, and shared a novel missense VPS33B variation c.1726T>C, p.Cys576Arg, causing declined protein expression and abolished interaction with VIPAS39 in-vitro. Serum bile acid profiles of our VPS33B/VIPAS39 mutated patients revealed similar changes to primary defect of bile salt export pump, among which those with isolated cholestasis phenotype had a higher level of total secondary bile acids than that with typical ARC phenotype, indicating the partial residual function of VPS33B.

3.
Pediatr Res ; 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31450232

RESUMO

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.

4.
BMC Gastroenterol ; 19(1): 120, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288754

RESUMO

BACKGROUND: Zinc therapy is considered an effective and safe treatment for Wilson's disease. Hypocupremia-related anemia is rarely reported after long-term zinc administration or combination therapy with copper-chelating agent. CASE PRESENTATION: We herein report a 12-year-old girl with pre-symptomatic Wilson's disease diagnosed 5 years ago who presented with severe anemia after high-dose oral zinc for 4 years and 4 months. Her hemoglobin was gradually restored to the normal range after the adjustment of zinc dose and diet therapy for 4 months. A review of the literature revealed eight patients with hypocupremia-associated anemia following zinc therapy for Wilson's disease, including 7 adults and 1 child. The only child patient was a 16-year-old boy, in whom the zinc therapy was succession to penicillamine administration. CONCLUSIONS: This is the first report worldwide that a child developed severe anemia following high-dose single zinc administration for Wilson's disease. It highlights the importance of regular follow-up during zinc treatment and the involvement of specialists in the long-term management of Wilson's disease. We hope that this will alert pediatricians the issue of zinc over-treatment.

5.
World J Clin Cases ; 7(4): 494-499, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30842961

RESUMO

BACKGROUND: Pediatric recurrent acute liver failure (RALF) with recovery between episodes is rare. Causes include autoimmune disease, which may flare and subside; intermittent exposure to toxins, as with ingestions; and metabolic disorders, among them the fever-associated crises ascribed to biallelic mutations in SCYL1, with RALF beginning in infancy. SCYL1 disease manifest with RALF, as known to date, includes central and peripheral neurologic and muscular morbidity (hepatocerebellar neuropathy syndrome). Primary ventilatory and skeletal diseases also have been noted in some reports. CASE SUMMARY: We describe a Han Chinese boy in whom fever-associated RALF began at age 14 mo. Bilateral femoral head abnormalities and mild impairment of neurologic function were first noted aged 8 years 6 mo. Liver biopsy after the third RALF episode (7 years) and during resolution of the fourth RALF episode (8 years 6 mo) found abnormal architecture and hepatic fibrosis, respectively. Whole-exome sequencing revealed homozygosity for the novel frameshift mutation c.92_93insGGGCCCT, p.(H32Gfs*20) in SCYL1 (parental heterozygosity confirmed). CONCLUSION: Our findings expand the mutational and clinical spectrum of SCYL1 disease. In our patient a substantial neurologic component was lacking and skeletal disease was identified relatively late.

6.
World J Gastroenterol ; 25(7): 859-869, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30809085

RESUMO

BACKGROUND: Disorders of primary bile acid synthesis may be life-threatening if undiagnosed, or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-oxosteroid 5ß-reductase (AKR1D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral bile acid replacement therapy with chenodeoxycholic acid (CDCA) in patients with this bile acid synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration (FDA) approved drug cholic acid, which is currently unavailable in China. AIM: To evaluate the therapeutic responses of patients with AKR1D1 deficiency to oral bile acid therapy, specifically CDCA. METHODS: Twelve patients with AKR1D1 deficiency, confirmed by fast atom bombardment ionization-mass spectrometry analysis of urine and by gene sequencing for mutations in AKR1D1, were treated with differing doses of CDCA or ursodeoxycholic acid (UDCA). The clinical and biochemical responses to therapy were monitored over a period ranging 0.5-6.4 years. Dose adjustment, to optimize the therapeutic dose, was based on changes in serum biochemistry parameters, notably liver function tests, and suppression of the urinary levels of atypical hepatotoxic 3-oxo-Δ4-bile acids measured by mass spectrometry. RESULTS: Physical examination, serum biochemistry parameters, and sonographic findings improved in all 12 patients during bile acid therapy, except one who underwent liver transplantation. Urine bile acid analysis confirmed a significant reduction in atypical hepatotoxic 3-oxo-Δ4 bile acids concomitant with clinical and biochemical improvements in those patients treated with CDCA. UDCA was ineffective in down-regulating endogenous bile acid synthesis as evidenced from the inability to suppress the urinary excretion of atypical 3-oxo-Δ4-bile acids. The dose of CDCA required for optimal clinical and biochemical responses varied from 5.5-10 mg/kg per day among patients based on maximum suppression of the atypical bile acids and improvement in serum biochemistry parameters, and careful titration of the dose was necessary to avoid side effects from CDCA. CONCLUSION: The primary bile acid CDCA is effective in treating AKR1D1 deficiency but the therapeutic dose requires individualized optimization. UDCA is not recommended for long-term management.


Assuntos
Ácido Quenodesoxicólico/administração & dosagem , Fármacos Gastrointestinais/administração & dosagem , Doenças Metabólicas/tratamento farmacológico , Oxirredutases/deficiência , Ácido Ursodesoxicólico/administração & dosagem , Administração Oral , Ácido Quenodesoxicólico/efeitos adversos , Análise Mutacional de DNA , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Recém-Nascido , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/urina , Mutação , Oxirredutases/genética , Estudos Retrospectivos , Resultado do Tratamento , Ácido Ursodesoxicólico/efeitos adversos
7.
Medicine (Baltimore) ; 97(49): e13576, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30544479

RESUMO

To retrospectively analyze and quantitatively correlate UGT1A1 (bilirubin UDP- glucuronosyltransferase gene) genotypes and unconjugated hyperbilirubinemia (UCH) phenotypes among Chinese children.We retrospectively reviewed UCH patients, quantitatively analyzed genotype-phenotype correlation by comparing with healthy controls. Pfam database, SWISS-model, and Pymol were used for UGT1A1 protein domain analysis and protein modeling for assessing the effect of novel missense variants on protein structure.Seventy four cases, including 21 prolonged unconjugated hyperbilirubinemia (PUCH), 30 Gilbert syndrome (GS), 22 Crigler-Najjar syndrome type II (CNS-II), and 1 Crigler-Najjar syndrome type I (CNS-I) phenotypes were analyzed. Total of 21 variants, including 7 novel variants (c.764T>A/p.L255Q, c.1112C>T/p.T371I, c.1028C>A/p.S343X, c.1047delG/p.I350YfsX16, c.996 + 5G>C/g.6923G>C, c.287G>A/p.G96E, and c.1142G>A/p.S381N) were found. In the multiple regression model, heterozygous A(TA)7TAA, G71R/P364L, and Y486D/other mutations were significantly associated with increased risk of GS, PUCH, and CNS-II, respectively. Total allele number is significantly associated with GS and CNS-II, with each increase in total allele number, the odds ratio (OR) of having GS and CNS-II increased by 1.46 and 4.47 fold, respectively. Having only functional polymorphisms in UGT1A1 gene is associated with increased risk of PUCH, and GS with OR values of 5.67 (95% CI: 1.52-21.13), and 3.88 (95% CI: 1.02-14.78), respectively. Having only mutation is associated with significantly increased risk of having GS phenotype (OR: 34.00, 95% CI: 4.65-248.37), but not CNS-II. Polymorphism plus mutation had the strongest association with CNS-II with OR value of 64.80 (95% CI: 7.68-546.41), followed by GS (OR: 4.53, 95% CI: 1.08-19.08).We detected 7 novel variants, and quantitatively calculated risks of having specific phenotypes using genetic data. Among Chinese children, G71R and P364L is independently associated with PUCH, A(TA)7TAA is associated with GS, and Y486D or other disease-causing mutations were associated with CNS-II. Multiple alleles were associated with more severe phenotypes. Combined variant of G71R+Y486D is a common occurrence among Chinese children with UCH.


Assuntos
Glucuronosiltransferase/genética , Hiperbilirrubinemia Hereditária/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , China , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Humanos , Lactente , Masculino , Fenótipo , Estudos Retrospectivos
8.
Liver Int ; 38(9): 1676-1685, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29412511

RESUMO

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.


Assuntos
Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Ácidos e Sais Biliares/sangue , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/genética , Estudos de Casos e Controles , Pré-Escolar , China , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Lactente , Masculino , Mutação
9.
J Pediatr Gastroenterol Nutr ; 65(5): 561-568, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28937538

RESUMO

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.


Assuntos
Colestase/etiologia , Xantomatose Cerebrotendinosa/diagnóstico , Colestanotriol 26-Mono-Oxigenase/genética , Colestanotriol 26-Mono-Oxigenase/metabolismo , Colestase/diagnóstico , Colestase/mortalidade , Colestase/cirurgia , Feminino , Marcadores Genéticos , Humanos , Recém-Nascido , Fígado/metabolismo , Transplante de Fígado , Masculino , Espectrometria de Massas , Mutação , Estudos Retrospectivos , Análise de Sequência de DNA/métodos , Índice de Gravidade de Doença , Xantomatose Cerebrotendinosa/complicações , Xantomatose Cerebrotendinosa/genética , Xantomatose Cerebrotendinosa/metabolismo
10.
BMC Gastroenterol ; 17(1): 77, 2017 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-28629372

RESUMO

BACKGROUND: Underlying causes in Chinese children with recurrent acute liver failure (RALF), including liver crises less than full acute liver failure, are incompletely understood. We sought to address this by searching for genes mutated in such children. METHODS: Five unrelated Chinese boys presenting between 2012 and 2015 with RALF of unexplained etiology were studied. Results of whole exome sequencing were screened for mutations in candidate genes. Mutations were verified in patients and their family members by Sanger sequencing. All 5 boys underwent liver biopsy. RESULTS: NBAS was the only candidate gene mutated in more than one patient (biallelic mutations, 3 of 5 patients; 5 separate mutations). All NBAS mutations were novel and predictedly pathogenic (frameshift insertion mutation c.6611_6612insCA, missense mutations c.2407G > A and c.3596G > A, nonsense mutation c.586C > T, and splicing-site mutation c.5389 + 1G > T). Of these mutations, 3 lay in distal (C-terminal) regions of NBAS, a novel distribution. Unlike the 2 patients without NBAS mutations, the 3 patients with confirmed NBAS mutations all suffered from a febrile illness before each episode of liver crisis (fever-related RALF), with markedly elevated alanine aminotransferase and aspartate aminotransferase activities 24-72 h after elevation of body temperature, succeeded by severe coagulopathy and mild to moderate jaundice. CONCLUSIONS: As in other countries, so too in China; NBAS disease is a major cause of fever-related RALF in children. The mutation spectrum of NBAS in Chinese children seems different from that described in other populations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Febre/genética , Falência Hepática Aguda/genética , Mutação , Proteínas de Neoplasias/genética , Criança , Pré-Escolar , China , Humanos , Lactente , Falência Hepática Aguda/complicações , Masculino , Recidiva , Estudos Retrospectivos
11.
Hepatology ; 65(5): 1655-1669, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28027573

RESUMO

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).


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Colestase Intra-Hepática/genética , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Ácidos e Sais Biliares/sangue , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/patologia , Análise Mutacional de DNA , Exoma , Feminino , Humanos , Lactente , Recém-Nascido , Fígado/metabolismo , Fígado/patologia , Masculino , Cadeias Pesadas de Miosina/metabolismo , Miosina Tipo V/metabolismo , Estudos Retrospectivos
12.
PLoS One ; 11(10): e0164058, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27706244

RESUMO

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.


Assuntos
Colestase Intra-Hepática/genética , Testes Genéticos/métodos , Mutação INDEL , Análise de Sequência de DNA/métodos , Criança , Diagnóstico Precoce , Feminino , Biblioteca Gênica , Predisposição Genética para Doença , Humanos , Masculino , Proteínas de Transporte da Membrana Mitocondrial/genética , Sensibilidade e Especificidade
13.
BMC Gastroenterol ; 16(1): 92, 2016 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-27520927

RESUMO

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.


Assuntos
Afibrinogenemia/tratamento farmacológico , Afibrinogenemia/genética , Grupo com Ancestrais do Continente Asiático/genética , Carbamazepina/uso terapêutico , Fibrinogênios Anormais/genética , Ácido Ursodesoxicólico/uso terapêutico , Pré-Escolar , Genes Dominantes , Humanos , Masculino , Mutação , Resultado do Tratamento
14.
PLoS One ; 11(4): e0153114, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27050426

RESUMO

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.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Adenosina Trifosfatases/genética , Colestase/diagnóstico , gama-Glutamiltransferase/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Adolescente , Estudos de Casos e Controles , Criança , Colestase/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
15.
World J Gastroenterol ; 21(23): 7331-4, 2015 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-26109823

RESUMO

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.


Assuntos
Citrulinemia/complicações , Falência Hepática Aguda/etiologia , Broncopneumonia/complicações , Broncopneumonia/diagnóstico , Broncopneumonia/microbiologia , Citrulinemia/sangue , Citrulinemia/diagnóstico , Citrulinemia/dietoterapia , Citrulinemia/genética , Análise Mutacional de DNA , Evolução Fatal , Predisposição Genética para Doença , Humanos , Lactente , Icterícia/etiologia , Falência Hepática Aguda/sangue , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/cirurgia , Transplante de Fígado , Masculino , Proteínas de Transporte da Membrana Mitocondrial/genética , Mutação , Fenótipo , Pneumonia Bacteriana/complicações , Pneumonia Bacteriana/diagnóstico , Pneumonia Bacteriana/microbiologia
16.
Pediatr Crit Care Med ; 12(2): e73-8, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20453706

RESUMO

OBJECTIVE: To evaluate the effect of continuous veno-venous hemodialysis filtration (CVVHDF) on cardiopulmonary function and clearance of inflammatory mediators in piglets with endotoxin-induced acute lung injury. DESIGN: A randomized controlled trial. SETTING: An animal laboratory in a tertiary care pediatric center. SUBJECTS: : Eighteen piglets, weighing 6-8 kg. INTERVENTIONS: The piglets were anesthetized, ventilated, and received an intravenous infusion of 150 µg/kg of endotoxin. They were then randomly divided into three groups: control group (n = 6) received Ringer's lactate solution; the heparin group (n = 6) received heparin infusion plus Ringer's lactate solution; and the CVVHDF group (n = 6) received CVVHDF plus heparin infusion and Ringer's lactate solution. MEASUREMENTS AND MAIN RESULTS: Parameters measured simultaneously were: heart rate, mean arterial blood pressure, central venous pressure, pulse contour cardiac index, cardiac function index, left ventricular contractile index, and systemic vascular resistance index; extra vascular lung water index, respiratory rate, dynamic pulmonary compliance, airway resistance, Pao2/Fio2 ratio, serum tumor necrosis factor-α, and soluble tumor necrosis factor receptor. Lung tissue was obtained for pathologic lung injury scoring and wet/dry weight ratio. Endotoxin challenge decreased oxygenation and pulmonary mechanics, suppressed cardiac function, increased extravascular lung water, and elevated serum inflammatory mediators (tumor necrosis factor-α and soluble tumor necrosis factor receptor). After CVVHDF, pulmonary function and oxygenation improved (Pao2/Fio2, 291.5 ± 75.9 vs. 217.2 ± 45.4, respectively, p < .05); arterial blood pressure and cardiac function were restored (pulse contour cardiac index, 3.95 ± 0.52 L/min/m(2) vs. 2.69 ± 0.49 L/min/m(2), respectively, p < .05); extravascular lung water decreased, and serum inflammatory markers also decreased. Lung injury score improved and wet/dry weight ratio decreased. CONCLUSION: Early CVVHDF has a beneficial effect on acute lung injury in piglets and is associated with a reduction in inflammatory cytokines, improving pulmonary function and hemodynamics and decreasing extravascular lung water and lung damage.


Assuntos
Lesão Pulmonar Aguda/etiologia , Endotoxinas/efeitos adversos , Escherichia coli , Hemodiafiltração/métodos , Lesão Pulmonar Aguda/fisiopatologia , Animais , Endotoxinas/administração & dosagem , Escherichia coli/patogenicidade , Feminino , Masculino , Monitorização Fisiológica , Antígenos O/efeitos adversos , Distribuição Aleatória , Sus scrofa , Resultado do Tratamento
17.
Pediatr Pulmonol ; 45(7): 700-7, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20672361

RESUMO

OBJECTIVES: Partial liquid ventilation (PLV) with perfluorocarbons (PFC) seems not superior to conventional ventilation clinically. We hypothesized that a combination of continuous tracheal gas insufflation (TGI) with protective strategy of PLV (low dose of PFC, low inflation pressure, moderate inhalation of oxygen and moderate anesthesia) would improve cardiopulmonary function in acute lung injury. METHODS: Twenty-four healthy juvenile piglets were anesthetized and mechanically ventilated at PEEP of 2 cmH(2)O with a peak inspiratory pressure of 10 cmH(2)O and FIO(2) of 0.4. The piglets were challenged with lipopolysaccharide and randomly assigned to four groups (n = 6 each): (1) mechanical ventilation alone (MV); (2) PLV with perfluorodecalin (10 ml/kg); (3) TGI with continuous airway flow 2 L/min; and (4) combination of PLV and TGI. The outcome was assessed functionally and histologically. RESULTS: All treatments except MV improved pH, PaO(2)/FIO(2), PaCO(2), ventilation efficacy index (VEI) and tidal volume. Both PLV-associated treatments also improved heart rate, respiratory rate, pulse contour cardiac output, systemic vascular resistance, dynamic lung compliance, mean airway resistance and mean airway pressure. The combination group resulted in higher PaO(2)/FIO(2), VEI and a better lung histology score than any other treatments. CONCLUSIONS: The new protective strategy may provide a better treatment for sepsis-induced acute lung injury.


Assuntos
Lesão Pulmonar Aguda/terapia , Insuflação , Ventilação Líquida/métodos , Lesão Pulmonar Aguda/imunologia , Resistência das Vias Respiratórias , Animais , Débito Cardíaco , Feminino , Fluorcarbonetos/uso terapêutico , Frequência Cardíaca , Lipopolissacarídeos/imunologia , Pulmão/anatomia & histologia , Pulmão/fisiopatologia , Complacência Pulmonar , Masculino , Ventilação Pulmonar , Respiração Artificial/métodos , Taxa Respiratória , Suínos , Traqueia , Resistência Vascular
18.
World J Emerg Med ; 1(1): 59-64, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-25214943

RESUMO

BACKGROUND: Low tidal volume mechanical ventilation is difficult to correct hypoxemia, and prolonged inhalation of pure oxygen can lead to oxygen poisoning. We suggest that continuous tracheal gas insufflation (TGI) during protective mechanical ventilation could improve cardiopulmonary function in acute lung injury. METHODS: Totally 12 healthy juvenile piglets were anesthetized and mechanically ventilated at PEEP of 2 cmH2O with a peak inspiratory pressure of 10 cmH2O. The piglets were challenged with lipopolysaccharide and randomly assigned into two groups (n=6 each group): mechanical ventilation (MV) alone and TGI with continuous airway flow 2 l/min. FIO2 was set at 0.4 to avoid oxygen toxicity and continuously monitored with an oxygen analyzer. RESULTS: Tidal volume, ventilation efficacy index and mean airway resistant pressure were significantly improved in the TGI group (P<0.01 or P<0.05). At 4 hours post ALI, pH decreased to below 7.20 in the MV group, and improved in the TGI group (P<0.01). Similarly, PaCO2 was stable and was significantly lower in the TGI group than in the MV group (P<0.01). PaO2 and PaO2/FIO2 increased also in the TGI group (P<0.05). There was no significant difference in heart rate, respiratory rate, mean artery pressure, central venous pressure, dynamic lung compliance and mean resistance of airway between the two groups. Lung histological examination showed reduced inflammation, reduced intra-alveolar and interstitial patchy hemorrhage, and homogenously expanded lungs in the TGI group. CONCLUSION: Continuous TGI during MV can significantly improve gas exchange and ventilation efficacy and may provide a better treatment for acute lung injury.

19.
Respir Physiol Neurobiol ; 167(3): 221-6, 2009 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-19394451

RESUMO

To investigate the effect of partial liquid ventilation (PLV) at low inflation pressures on acute lung injury (ALI), endotoxin was administered to healthy anesthetized juvenile piglets. The animals were randomly assigned to two groups, n=6 each: (1) conventional mechanical ventilation (MV) and (2) PLV with perfluorodecalin (10 mL kg(-1)). Compared with MV, PLV improved each cardiopulmonary variable measured. These variables included pulse contour cardiac output, heart rate, blood pH, breathing rate, both partial pressure of arterial oxygen (PaO2) and PaO2/FIO2 (fraction of inspired oxygen), partial pressure of arterial carbon dioxide (PaCO2), dynamic lung compliance, tidal volume, and ventilation efficacy index. Lung morphology also showed less damage in the PLV group, even in non-dependent regions (P<0.05). Our data support the hypothesis that PLV can decrease pulmonary damage, improve gas exchange and cardiac output, and may lead to a better prognosis in endotoxin-induced ALI.


Assuntos
Endotoxinas/toxicidade , Ventilação Líquida , Pneumopatias/induzido quimicamente , Pneumopatias/prevenção & controle , Doença Aguda , Animais , Gasometria , Feminino , Hemodinâmica/fisiologia , Pulmão/patologia , Pneumopatias/patologia , Masculino , Mecânica Respiratória/fisiologia , Suínos
20.
Zhonghua Er Ke Za Zhi ; 46(5): 340-3, 2008 May.
Artigo em Chinês | MEDLINE | ID: mdl-19099749

RESUMO

OBJECTIVE: To investigate the effect of continuous veno-venous hemodiafiltration (CVVHDF) on endotoxin-induced acute lung injury (ALI) of piglets. METHODS: Eighteen piglets were randomly divided into three groups: control group (n = 6); heparin group (n = 6) and CVVHDF treatment group (n = 6). All the animals were anesthetized by muscle injection of ketamine (30 mg/kg), then placed in supine position, received continuous intravenous infusion of ketamine with the rate of 10 mg/(kgxh). After placing a 4.5 cm (inner diameter) tracheal tube via tracheostoma, controlled mechanical ventilation was established using the assisted-controlled ventilation option of the NEWPORT 200. Respiratory rate at 30 breath/min; PIP at 10 cm H2O (1 cm H2O = 0.098 kPa); PEEP at 2 cm H2O and fraction of inspired oxygen at 0.3. A vein catheter was placed into right vena jugularis interna to administer a Ringer's solution. Initially, at a rate of 10 ml/kg, followed by a rate of 15 ml/kg when the mean arterial blood pressure was below 70 mm Hg (1 mm Hg = 0.133 kPa), the rate of 20 ml/kg was used when the mean arterial blood pressure was below 60 mm Hg. An 8Fr double-lumen catheter was inserted into left femoral vein and served as the pathway for CVVHDF. A Pulsiocath Pcco catheter was positioned into left femoral artery to monitor the circulatory parameters. All catheters were flushed with heparinized saline to prevent clotting. Then all the animals were given intravenous infusion of 150 microg/kg endotoxin within 30 minutes to induce ALI. When the oxygenation index < 300 and pulmonary compliance < 30% of the baseline, the animals of heparin group received heparin infusion to maintain blood active coagulation time (ACT) 180 - 250 s, the animals of treatment group received CVVHDF with the blood flow of 50 ml/min, replacement rate of 300 ml/h, dialysis rate of 600 ml/h and the ultrafiltrate rate of 350 ml/h for six hours, heparin infusion to keep blood ACT 180 - 250 s. The circulatory parameters: heart rate (HR), mean arterial blood pressure (MABP), central venous pressure (CVP), pulse contour cardiac output index (PCCI); systemic venous resistance index (SVRI), cardiac function index (CFI), external venous lung water index (EVLWI), left ventricular contractile index (dPmx); respiratory parameters: respiratory rate (RR), pulmonary compliance (Cdyn) were monitored; arterial blood gas analysis was performed and oxygenation index (PaO2/FiO2) was calculated. All the parameters were recorded at baseline (B), onset of ALI (A 0 h), two hours (A 2 h), four hours (A 4 h), six hours (A 6 h) after ALI. RESULTS: No significant difference in circulatory parameters, respiratory parameters and blood gas analysis were found at B and A 0 h among the three groups. When the ALI occurred, PaO2/FiO2, Cdyn, MABP and PCCI of the three groups decreased; HR, RR, EVLWI, SVRI increased. After four hours of ALI, the RR, EVLWI, SVRI, CFI and dPmx of treatment group were improved, the differences were significant compared with the other two groups (P < 0.05). After six hours of ALI, the HR, PCCI, MABP, PaO2/FiO2 and Cdyn of treatment group were significantly improved, compared with control group and heparin group (P < 0.05). There were no significant differences in any of the parameters between control group and heparin group. The difference in CVP among three groups was not significant. CONCLUSION: CVVHDF has a good effect on hemodynamics of the endotoxin-induced ALI of the piglets.


Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Lesão Pulmonar Aguda/terapia , Hemodiafiltração , Lesão Pulmonar Aguda/etiologia , Animais , Endotoxinas/efeitos adversos , Hemodinâmica , Suínos
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