Comprehensive bile acid profiling in hereditary intrahepatic cholestasis: Genetic and clinical correlations

Liu, Teng; Wang, Ren‐Xue; Han, Jun; Hao, Chenzhi; Qiu, Yi‐Ling; Yan, Yanyan; Li, Li‐Ting; Wang, Neng‐Li; Gong, Jing‐Yu; Lu, Yi; Zhang, Meihong; Xie, Xin‐Bao; Yang, Juncong; You, Yijie; Li, Jia‐qi; Knisely, A. S.; Borchers, Christoph H.; Ling, Victor; Wang, Jianshe

doi:10.1111/liv.13714

Cited by 15 publications

(29 citation statements)

References 28 publications

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“…Among these genes, we found ABCB11, which encodes the bile salt export pump (BSEP), was involved in bile secretion, cholesterol metabolism, bile acid and bile salt metabolism, and recycling of bile acids and salts based on the pathway analysis. BSEP mediates the secretion of bile acids across the canicular membrane of hepatocytes into bile to provide the osmotic pressure for bile flow [50, 51]. Strautnieks et al found that BSEP is typically absent or greatly reduced due to ABCB11 mutations, and 15% of patients with BSEP deficiency developed hepatocellular carcinoma or CCA [52].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of DNA methylation and gene expression profiles in cholangiocarcinoma

Zhang

Meng

et al. 2019

Cancer Cell Int

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Background: The incidence of cholangiocarcinoma (CCA) has risen in recent years, and it has become a significant health burden worldwide. However, the mechanisms underlying tumorigenesis and progression of this disease remain largely unknown. An increasing number of studies have demonstrated crucial biological functions of epigenetic modifications, especially DNA methylation, in CCA. The present study aimed to identify and analyze methylationregulated differentially expressed genes (MeDEGs) involved in CCA tumorigenesis and progression by bioinformatics analysis. Methods:The gene expression profiling dataset (GSE119336) and gene methylation profiling dataset (GSE38860) were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) were identified using the limma packages of R and GEO2R, respectively. The MeDEGs were obtained by overlapping the DEGs and DMGs. Functional enrichment analyses of these genes were then carried out. Protein-protein interaction (PPI) networks were constructed using STRING and visualized in Cytoscape to determine hub genes. Finally, the results were verified based on The Cancer Genome Atlas (TCGA) database. Results:We identified 98 hypermethylated, downregulated genes and 93 hypomethylated, upregulated genes after overlapping the DEGs and DMGs. These genes were mainly enriched in the biological processes of the cell cycle, nuclear division, xenobiotic metabolism, drug catabolism, and negative regulation of proteolysis. The top nine hub genes of the PPI network were F2, AHSG, RRM2, AURKB, CCNA2, TOP2A, BIRC5, PLK1, and ASPM. Moreover, the expression and methylation status of the hub genes were significantly altered in TCGA. Conclusions:Our study identified novel methylation-regulated differentially expressed genes (MeDEGs) and explored their related pathways and functions in CCA, which may provide novel insights into a further understanding of methylation-mediated regulatory mechanisms in CCA.

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Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of DNA methylation and gene expression profiles in cholangiocarcinoma

Zhang

Meng

et al. 2019

Cancer Cell Int

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“…Twenty patients with primary defect of bile salt export pump (BSEP) and 37 healthy controls in bile acid profiling investigations were described in former studies (Liu et al, ; Qiu et al, ).…”

Section: Methodsmentioning

confidence: 99%

“…Serum sample was separated from blood by routine centrifugation, ali‐quoted (50 μl), freeze‐dried and stored at −80°C until bile acid analysis was performed by reversed‐phase ultrahigh‐performance liquid chromatography/multiple‐reaction monitoring‐mass spectrometry (UPLC/MRM‐MS) with negative ion detection as described previously (Han et al, ; Liu et al, ; Qiu et al, ). The quantitation of bile acids utilized standard substances of 60 bile acids included all of the major bile acids and some minor species with 14 deuterium‐labeled analogs of bile acids as internal standards.…”

Section: Methodsmentioning

confidence: 99%

Novel missense mutation in VPS33B is associated with isolated low gamma‐glutamyltransferase cholestasis: Attenuated, incomplete phenotype of arthrogryposis, renal dysfunction, and cholestasis syndrome

et al. 2019

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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 gammaglutamyltransferase (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. K E Y W O R D S ARC, incomplete phenotype, isolated cholestasis, Novel, VPS33B Human Mutation. 2019;40:2247-2257.wileyonlinelibrary.com/journal/humu

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“…Notes: Case numbers in boldface indicate subjects of previous reports. 7,[9][10][11][12][13][14][15] Variants in boldface are novel.…”

Section: Discussionmentioning

confidence: 99%

ABCB11 deficiency presenting as transient neonatal cholestasis: Correlation with genotypes and BSEP expression

Yong

et al. 2020

Liver International

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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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Comprehensive bile acid profiling in hereditary intrahepatic cholestasis: Genetic and clinical correlations

Abstract: Profiling of plasma bile acids has provided insights into cholestasis alleviation and may be useful for the clinical management of cholestatic diseases.

Cited by 15 publications

References 28 publications

Comprehensive analysis of DNA methylation and gene expression profiles in cholangiocarcinoma

Comprehensive analysis of DNA methylation and gene expression profiles in cholangiocarcinoma

Novel missense mutation in VPS33B is associated with isolated low gamma‐glutamyltransferase cholestasis: Attenuated, incomplete phenotype of arthrogryposis, renal dysfunction, and cholestasis syndrome

ABCB11 deficiency presenting as transient neonatal cholestasis: Correlation with genotypes and BSEP expression

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