Inherited Cholestatic Diseases in the Era of Personalized Medicine

Goldberg, Alyssa; Mack, Cara L.

doi:10.1002/cld.872

Cited by 10 publications

(8 citation statements)

References 13 publications

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“…Progressive familial intrahepatic cholestasis associated diseases (van Wessel et al, 2020(van Wessel et al, , 2021Maddirevula et al, 2019;Goldberg and Mack, 2020) Thus, molecular chaperone therapy is potentially effective in patients with mutations causing misfolding of BSEP proteins. In FIC1 deficiency, a study by Van der Woerd et al showed that several CFTR correctors were able to improve trafficking of FIC1 to the plasma membrane in vitro (van der Woerd et al, 2016).…”

Section: Tablementioning

confidence: 99%

The spectrum of Progressive Familial Intrahepatic Cholestasis diseases: Update on pathophysiology and emerging treatments

Felzen

Verkade

2021

European Journal of Medical Genetics

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Section: Tablementioning

confidence: 99%

The spectrum of Progressive Familial Intrahepatic Cholestasis diseases: Update on pathophysiology and emerging treatments

Felzen

Verkade

2021

European Journal of Medical Genetics

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“…The single most common cause of cholestasis in neonates and infants is biliary atresia (BA), a deficiency of the extrahepatic bile ducts with an unclear aetiology [8]. Following this, it is estimated that 25-50% of cases of cholestasis occur due to identifiable genetic mutations [9][10][11][12]. These mutations involve a wide variety of genes which have either a direct or indirect effect on the synthesis, transport and flow of bile.…”

Section: Genetic Causes Of Cholestasis In Neonates and Infantsmentioning

confidence: 99%

The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges

Jeyaraj

Bounford

Ruth

et al. 2021

Genes

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Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved our understanding of physiological bile secretion and flow. By helping to define the molecular basis of certain cholestatic disorders, these methods have also identified new targets for therapy as well patient subgroups more likely to benefit from specific therapies. At the same time, sequencing methods have presented new diagnostic challenges, such as the interpretation of single heterozygous genetic variants. This article discusses those challenges in the context of neonatal and infantile cholestasis, focusing on difficulties in predicting variant pathogenicity, the possibility of other causal variants not identified by the genetic screen used, and phenotypic variability among patients with variants in the same genes. A prospective, observational study performed between 2010–2013, which sequenced six important genes (ATP8B1, ABCB11, ABCB4, NPC1, NPC2 and SLC25A13) in an international cohort of 222 patients with infantile liver disease, is given as an example of potential benefits and challenges that clinicians could face having received a complex genetic result. Further studies including large cohorts of patients with paediatric liver disease are needed to clarify the spectrum of phenotypes associated with, as well as appropriate clinical response to, single heterozygous variants in cholestasis-associated genes.

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“…As matter of fact then, several genes involved in the development of inherited cholestasis are linked to the risk of HCC and CCA in pediatric and not pediatric populations: ABCB11 , ABCB4 , TJP2 , FXR , MYO5B , SLC51B , SLC25A13 , NOTCH2 , JAG1 , TGR5 and HNF1B [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature

Vitale

Mattiaccio

Conti

et al. 2022

Cancers

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The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the NR1H4 gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). NR1H4 gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as ABCB11, ABCB4 and TJP2. Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.

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Inherited Cholestatic Diseases in the Era of Personalized Medicine

Abstract: http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-reading-mack a video presentation of this article

Cited by 10 publications

References 13 publications

The spectrum of Progressive Familial Intrahepatic Cholestasis diseases: Update on pathophysiology and emerging treatments

The spectrum of Progressive Familial Intrahepatic Cholestasis diseases: Update on pathophysiology and emerging treatments

The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges

Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature

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