Neonatal Dubin–Johnson syndrome: biochemical parameters, characteristics, and genetic variants study

Fu, Haiyan; Zhao, Ruizhi; Jia, Xiaoyun; Li, Xiaolei; Li, Gui-Gui; Yin, Chunlan

doi:10.1038/s41390-021-01583-7

Cited by 7 publications

(5 citation statements)

References 18 publications

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“…Twenty-two of the variations we observed had been previously reported, 10,11,[13][14][15][16] and thirty-three were novel (Table 2). Of the novel variants, six were canonical splicing variants, two were noncanonical splicing variants, five were nonsense variants, thirteen were missense variants, and seven were frameshift variants.…”

Section: Identification Of Novel Abcc2 Variants and In Silico Assessmentmentioning

confidence: 52%

Neonatal Dubin-Johnson Syndrome and its Differentiation from Biliary Atresia

Liu¹,

Zhao²,

Feng³

et al. 2022

J Clin Transl Hepatol

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Background and Aims:The aim was to determine if liver biochemistry indices can be used as biomarkers to help differentiate patients with neonatal Dubin-Johnson syndrome (nDJS) from those with biliary atresia (BA). Methods: Patients with genetically-confirmed nDJS or cholangiographically confirmed BA were retrospectively enrolled and randomly assigned to discovery or verification cohorts. Their liver chemistries, measured during the neonatal period, were compared. Predictive values were calculated by receiver operating characteristic curve analysis. Results: A cohort of 53 nDJS patients was recruited, of whom 13 presented with acholic stools, and 14 underwent diagnostic cholangiography or needle liver biopsy to differentiate from BA. Thirty-five patients in the cohort, with complete biochemical information measured during the neonatal period, were compared with 133 infants with cholangiographically confirmed BA. Total and direct bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acids, alkaline phosphatase, and gamma-glutamyl transferase were significantly lower in nDJS than in BA. In the discovery cohort, the areas under the curve for ALT and AST were 0.908 and 0.943, respectively. In the validation cohort, 13/15 patients in the nDJS group were classified as nDJS, and 10/53 in the BA control group were positive (p<0.00001) with an ALT biomarker cutoff value of 75 IU/L. Thirteen of 15 patients were classified as nDJS and none were classified positive in the BA group (13/15 vs. 0/53, p<0.00001) with an AST cutoff of 87 IU/L. Conclusions: Having assembled and investigated the largest cohort of nDJS patients reported to date, we found that nDJS patients could be distinguished from BA patients using the serum AST level as a biomarker. The finding may be clinically useful to spare cholestatic nDJS patients unnecessary invasive procedures.

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Section: Identification Of Novel Abcc2 Variants and In Silico Assessmentmentioning

confidence: 52%

Neonatal Dubin-Johnson Syndrome and its Differentiation from Biliary Atresia

Liu¹,

Zhao²,

Feng³

et al. 2022

J Clin Transl Hepatol

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“…Hereditary elevations of bilirubin can cause unconjugated hyperbilirubinemia, including Crigler-Najjar syndrome ( 23 , 24 ) and Gilbert syndrome ( 25 ), as well as conjugated hyperbilirubinemia, including Dubin-Johnson syndrome ( 26 ) and Rotor syndrome ( 27 ). It turns out that both Crigler-Najjar and Gilbert syndromes are caused by a lack of glucuronosyltransferase (UGT1A1), which is responsible for the conversion of bilirubin to bilirubin diglycosidic acid, making bilirubin less soluble in water ( 23 – 25 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic prediction of causal association between serum bilirubin and hematologic malignancies: a two-sample Mendelian randomized and bioinformatics study

Lu,

Luo,

et al. 2024

Front. Oncol.

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IntroductionAn increasing number of cohort studies have shown a correlation between serum bilirubin and tumors, but no definitive causal relationship has been established between serum bilirubin and hematological malignancies.Therefore, the aim of the present study was to assess the causal relationship of serum bilirubin, including total bilirubin (TBIL) and direct bilirubin (DBIL), with hematological malignancies, including leukemia, lymphoma, and myeloma.MethodsWe used a genome-wide association study (GWAS) collection of TBIL, DBIL, and hematological malignancies data. Using two-sample Mendelian randomization(MR), we assessed the impact of TBIL and DBIL on hematological malignancies. For this study, the inverse variance weighting method (IVW) was the primary method of MR analysis. In the sensitivity analysis, the weighted median method, MR Egger regression, and MR-PRESSO test were used. To understand the mechanisms behind TBIL and DBIL, we used three different approaches based on screening single nucleotide polymorphisms (SNPs) and their associated genes, followed by bioinformatics analysis.ResultsThe IVW test results showed evidence of effects of TBIL (odds ratio [OR]: 4.47, 95% confidence interval [CI]: 1.58-12.62) and DBIL (OR: 3.31, 95% CI: 1.08-10.18) on the risk of acute myeloid leukemia (AML).The findings from bioinformatics indicated that TBIL could potentially undergo xenobiotic metabolism through cytochrome P450 and contribute to chemical carcinogenesis.DiscussionIn this study, two-sample MR analysis revealed a causal relationship between TBIL, DBIL, and AML.

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“…Canalicular PFIC1 ATP8B1 FIC1 canalicular P type [19] ATPase, aminophospholipid flippase PFIC2 ABCB11 BSEP conjugated bile acid transporter [20] PFIC3 ABCB4 MDR3 phospholipid transporter [102] Dubin-Johnson ABCC2 MRP2 organic anions and bilirubin glucuronide transporter [98] Basolateral NTCP deficiency SLC10A1 NTCP bile acid importer [103] Rotor syndrome SLCO1B1, SLCO1B3 OATP1B1 or OATP1B3 bilirubin glucuronide reuptake [104] Organic solute transporter deficiency SLC51A, SLC51B OSTα/β organic solute heterodimeric exporter (congenital diarrhea) [105,106] Disorders of nuclear receptors PFIC5 NR1H4 FXR nuclear bile acids receptor [107] Disorders of intracellular trafficking…”

Section: Disorders Of Membrane Transporter or Polaritymentioning

confidence: 99%

“…Further, the use of cholestasis gene panels can expand our current understanding of phenotypes associated with certain variants, for instance, the diverse hepatic presentations associated with ABCB4 mutations or recently described cases of cholestasis associated with Dubin‐Johnson variants. [ 98 ] Finally, the use of genetic panels may highlight the role of variants that can modify hepatic phenotypes, though caution must be exercised in overinterpretation and underinterpretation of potential genetic modifiers because definitive data remain scant. So, genotype before phenotype may well become the modern mantra in the diagnostic workup of a cholestatic child, though careful phenotypic evaluation cannot be put to rest.…”

Section: Gaps In Knowledge and Future Directionsmentioning

confidence: 99%

Cholestatic liver diseases of genetic etiology: Advances and controversies

et al. 2022

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With the application of modern investigative technologies, cholestatic liver diseases of genetic etiology are increasingly identified as the root cause of previously designated “idiopathic” adult and pediatric liver diseases. Here, we review advances in the field enhanced by a deeper understanding of the phenotypes associated with specific gene defects that lead to cholestatic liver diseases. There are evolving areas for clinicians in the current era specifically regarding the role for biopsy and opportunities for a “sequencing first” approach. Risk stratification based on the severity of the genetic defect holds promise to guide the decision to pursue primary liver transplantation versus medical therapy or nontransplant surgery, as well as early screening for HCC. In the present era, the expanding toolbox of recently approved therapies for hepatologists has real potential to help many of our patients with genetic causes of cholestasis. In addition, there are promising agents under study in the pipeline. Relevant to the current era, there are still gaps in knowledge of causation and pathogenesis and lack of fully accepted biomarkers of disease progression and pruritus. We discuss strategies to overcome the challenges of genotype–phenotype correlation and draw attention to the extrahepatic manifestations of these diseases. Finally, with attention to identifying causes and treatments of genetic cholestatic disorders, we anticipate a vibrant future of this dynamic field which builds upon current and future therapies, real‐world evaluations of individual and combined therapeutics, and the potential incorporation of effective gene editing and gene additive technologies.

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Neonatal Dubin–Johnson syndrome: biochemical parameters, characteristics, and genetic variants study

Cited by 7 publications

References 18 publications

Neonatal Dubin-Johnson Syndrome and its Differentiation from Biliary Atresia

Neonatal Dubin-Johnson Syndrome and its Differentiation from Biliary Atresia

Genetic prediction of causal association between serum bilirubin and hematologic malignancies: a two-sample Mendelian randomized and bioinformatics study

Cholestatic liver diseases of genetic etiology: Advances and controversies

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