Intrahepatic Cholestasis: Summary of an American Association for the Study of Liver Diseases Single-Topic Conference *

Balistreri, William F.; Bezerra, Jorge A.; Jansen, Petér L. M.; Karpen, Saul J.; Shneider, Benjamin L.; Suchy, Frederick J.

doi:10.1002/hep.20729

Cited by 79 publications

(75 citation statements)

References 101 publications

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“…Under physiological conditions, the fetus presents a low serum BA pool (0.1 mM) that increases postnatally (1‐2 mM). These drastic changes after birth indicate that BA clearance compensatory activity by the placenta is lost in the fetus and that liver clearance functions are insufficient in most neonates 28, 32. Clinical evidence shows in most cases that serum BA levels reach adult values (0.5 mM) only after 1 year of age, again supporting the increase in NTCP glycosylation demonstrated in our study (Figs.…”

Section: Discussionsupporting

confidence: 88%

Age‐dependent glycosylation of the sodium taurocholate cotransporter polypeptide: From fetal to adult human livers

Sargiacomo

El-Kehdy

Pourcher

et al. 2018

Hepatology Communications

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Sodium taurocholate cotransporter polypeptide (NTCP), mainly expressed on the sinusoidal membrane of hepatocytes, is one of the major transporters responsible for liver bile acid (BA) re‐uptake. NTCP transports conjugated BA from the blood into hepatocytes and is crucial for correct enterohepatic circulation. Studies have shown that insufficient hepatic clearance of BA correlates with elevated serum BA in infants younger than 1 year of age. In the current study, we investigated human NTCP messenger RNA and protein expression by using reverse‐transcription quantitative polymerase chain reaction and immunoblotting in isolated and cryopreserved human hepatocytes from two different age groups, below and above 1 year of age. Here, we show that NTCP messenger RNA expression is not modulated whereas NTCP protein posttranslational glycosylation is modulated in an age‐dependent manner. These results were confirmed by quantification analysis of NTCP 55‐kDa N‐glycosylated bands, which showed significantly less total NTCP protein in donors below 1 year of age compared to donors older than 1 year. NTCP tissue localization was also analyzed by means of immunofluorescence. This revealed that NTCP cellular localization in fetal samples was mainly perinuclear, suggesting that NTCP is not glycosylated, while its postnatal localization on the plasma membrane is age dependent compared to multidrug resistant protein 2, which is apical starting in fetal life. Conclusion: After birth, the NTCP age‐dependent maturation process requires approximately 1 year to complete NTCP glycosylation in human hepatocytes. Therefore, NTCP late posttranslational glycosylation appears to be important for correct NTCP membrane localization, which might explain physiologic cholestasis in neonatal life and might play a central role for HBV infection after birth. (Hepatology Communications 2018;2:693‐702)

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Section: Discussionsupporting

confidence: 88%

Age‐dependent glycosylation of the sodium taurocholate cotransporter polypeptide: From fetal to adult human livers

Sargiacomo

El-Kehdy

Pourcher

et al. 2018

Hepatology Communications

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“…: cardiovascular and renal defects). 4,7,8,23,[37][38][39] In view of such variability in clinical presentation, the ability to analyze the nucleotide sequence facilitates studies of phenotypegenotype relationship for individual genes. In addition, we chose to add SERPINA1 to the chip as an investigative tool for studies examining how α1AT polymorphisms may serve as disease modifiers in subjects harboring mutations in one of the other cholestatic genes, or in subjects with other forms of liver disease in a fashion described for patients with chronic pulmonary diseases.…”

Section: Discussionmentioning

confidence: 99%

“…2, 3 Subsequent studies led to the recognition of the inherited nature of syndromic and non-syndromic forms of cholestasis. 4 For example, patients with the Alagille syndrome have chronic cholestasis and variable syndromic features that may be shared by family members. 5, 6 Application of genetic mapping approaches to study these patients discovered disease-causing mutations in the JAG1 gene.…”

Section: Introductionmentioning

confidence: 99%

Novel Resequencing Chip Customized to Diagnose Mutations in Patients With Inherited Syndromes of Intrahepatic Cholestasis

et al. 2007

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Background and Aims-Inherited syndromes of intrahepatic cholestasis commonly result from mutations in the genes SERPINA1 (α1-antitrypsin deficiency), JAG1 (Alagille syndrome), ATP8B1 (Progressive Familial Intrahepatic Cholestasis type 1/PFIC1), ABCB11 (PFIC2), and ABCB4 (PFIC3). However, the large gene sizes and lack of mutational hotspots make it difficult to survey for disease-causing mutations in clinical practice. Here, we aimed to develop a technological tool that reads out the nucleotide sequence of these genes rapidly and accurately.

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“…So far, clear genotype-phenotype correlation data are missing and remain to be defined in order to identify those PFIC2 patients who could benefit from UDCA or biliary diversion. Preliminary data suggest that PFIC2 patients with some specific missense mutations may respond well to biliary diversion 16 and/or UDCA therapy. 7 In vitro studies showed that some missense BSEP mutations affect protein processing/ trafficking causing retention in the endoplasmic reticulum and subsequent endoplasmic reticulum-associated degradation.…”

Section: Therapy (Please Describe)mentioning

confidence: 99%

Clinical utility gene card for: Progressive familial intrahepatic cholestasis type 2

Gonzalès¹,

Spraul

Jacquemin³

2013

Eur J Hum Genet

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Intrahepatic Cholestasis: Summary of an American Association for the Study of Liver Diseases Single-Topic Conference *

Cited by 79 publications

References 101 publications

Age‐dependent glycosylation of the sodium taurocholate cotransporter polypeptide: From fetal to adult human livers

Age‐dependent glycosylation of the sodium taurocholate cotransporter polypeptide: From fetal to adult human livers

Novel Resequencing Chip Customized to Diagnose Mutations in Patients With Inherited Syndromes of Intrahepatic Cholestasis

Clinical utility gene card for: Progressive familial intrahepatic cholestasis type 2

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