ABCB4 Mutations in Adults Cause a Spectrum Cholestatic Disorder Histologically Distinct from Other Biliary Disease

Sinha, Amil; Bhuva, Meha; Grant, Claire; Gimson, Alexander; Thompson, Eop; Duckworth, Adam; Davies, Susan; Aithal, Guruprasad P.; Griffiths, William J.

doi:10.1007/s10620-022-07416-9

Cited by 5 publications

(10 citation statements)

References 21 publications

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“…Alterations within the ABCB4 transporter have been described to cause cholestatic liver disease. [2][3][4][5][6][7][8][9] Our previous study also revealed altered expression of ABCB4, as well as ABCB11, which is another ABC transporter mitigating bile acid transport between hepatocytes and the bile Ó 2023 The Authors. Histopathology published by John Wiley & Sons Ltd., Histopathology, 83, 559-568.…”

Section: Discussionmentioning

confidence: 92%

“…ABC transporters are important regulators of bile excretion between hepatocytes and the bile canalicular system and alterations result in cholestasis and liver damage 1–9 . The ABC transporter ABCB4 is crucial for phosphatidylcholine secretion into the bile 2,24 .…”

Section: Discussionmentioning

confidence: 99%

“…Alterations in various ATP‐binding cassette transporters at the bile canalicular membrane of hepatocytes have been reported in hereditary cholestatic liver diseases. For example, mutations within the ATP8B1 , ABCB4 , ABCB11 genes result in progressive intrahepatic familial cholestasis (PFIC type 1–3), mutations within the ABCC2 gene causes Dubin‐Johnson syndrome and mutations within the ABCG5/ABCG8 genes lead to sitosterolemia 2–7 . Moreover, altered expression of ABCB4 and ABCB11 have been reported in intrahepatic cholestasis during pregnancy as well as primary sclerosing cholangitis (PSC) 8–10 .…”

Section: Introductionmentioning

confidence: 99%

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Analysis of various ATP‐binding cassette transporters revealed quantification of ABCB4 as a potential diagnostic tool in primary sclerosing cholangitis (PSC)

Thoeni,

Perciani,

Nakib

et al. 2023

Histopathology

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AimsATP‐binding cassette transporters are important proteins in regulating bile constituent transport between hepatocytes and the bile canalicular system. Dysfunctional transporters lead to accumulation of toxic bile components within hepatocytes or the biliary system, known as cholestasis, resulting in liver damage. It has been previously reported that two particular ATP‐binding cassette transporters, ABCB4 and ABCB11, have altered expression in patients with primary sclerosing cholangitis (PSC). Interested in further analysis of expression patterns of ATP‐binding cassette transporters in PSC patients, we investigated liver samples from 201 patients, including 43 patients with PSC and 51 patients with primary biliary cholangitis patients (PBC). In addition to ABCB4 and ABCB11, we also included other ATP‐binding cassette transporters, to determine if upregulation of ABCB4 and ABCB11 is specifically found in the liver of patients with PSC.Methods and resultsRetrospectively, formalin‐fixed and paraffin‐embedded liver biopsies, resections, and explants were selected to investigate the expression of ABCB1, ABCB4, ABCB11, ABCG5/8, and FXR1 using nanoString nCounter and immunohistochemistry for validation of differently expressed transporters seen in PSC liver samples in comparison to non‐PSC liver specimens. Strikingly, ABCB4 was the only ATP‐binding cassette transporter showing increased gene and protein expression in hepatocytes of PSC livers when compared to non‐PSC liver specimens. Furthermore, ABCB4 protein expression also correlated with disease stage in PSC.ConclusionOur study concluded that altered ABCB4 expression is specifically seen in liver specimens of PSC patients. Therefore, quantitative ABCB4 analysis may be an additional useful tool for the histopathological diagnosis of PSC to distinguish this entity from other cholangiopathies.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analysis of various ATP‐binding cassette transporters revealed quantification of ABCB4 as a potential diagnostic tool in primary sclerosing cholangitis (PSC)

Thoeni,

Perciani,

Nakib

et al. 2023

Histopathology

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“…Clinicopathological correlation in seven patients with ABCB4 disease presenting with cholestatic liver disease in adulthood [30] showed a distinct histological picture, including ductopenia of the smaller tracts, mild non-ductocentric portal inflammation, bilirubinostasis, significant copperassociated protein deposition and variable fibrosis.…”

Section: Familial Cholestatic Disordersmentioning

confidence: 98%

Histological evaluation in biliary diseases

Saffioti

Motta

Quaglia

2023

Current Opinion in Gastroenterology

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Purpose of reviewThis review focuses on recent developments of histopathology in the most common biliary disorders affecting adults. The reader is referred to other sources for the specialized topics on paediatric populations and post liver transplantation.Recent findingsFibrosis stage at diagnosis is an independent predictor of liver transplant-free survival in patients with primary biliary cholangitis. Immunohistochemistry might have an important role in predicting response to treatment. New histological scoring systems with excellent correlation with long-term clinical outcomes are being developed in primary sclerosing cholangitis (PSC). Quantification of fibrosis with collagen proportionate area can improve risk stratification and could be particularly useful to assess treatment response in PSC.Gene sequencing on cytology and intrabiliary biopsy may improve risk stratification for cholangiocarcinoma. Genetic variants of ATP8B1, ABCB11 and ABCB4 are relatively common in adults with cholestatic liver disease. New causes of cholestatic liver injury have recently been described.SummaryHistology is often not necessary for the diagnosis of biliary disease, but can provide important information that may assist the clinician in patients’ management. Histopathology remains crucial to confirm a diagnosis of cholangiocarcinoma, and to identify the pattern of biliary injury in immune-mediated cholangiopathies and rarer pathological entities.

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“…Next-generation sequencing revealed the ABCB4 variants: c.959C>T, p.S320F previously reported, likely pathogenic and c.2301dupT, p.T768Yfs*26 previously predicted, likely pathogenic combined to c.3149T>A p.I1050K)—VUS in ATP8B1 , responsible for PFIC1. At histology, mild fibrosis, ductular reaction, ductopenia, and cholestatic rosettes were found [ 102 ].…”

Section: Canalicular Efflux Transport Proteins and Compounds Involved...mentioning

confidence: 99%

Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis

Vitale

Mattiaccio

Conti

et al. 2023

IJMS

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Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver’s metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (ABCB11); 2. the multidrug resistance protein-2 (MRP2, ABCC2) regulating the bile salts’ independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, ABCB1) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, ABCB4). Two of the most known proteins involved in bile acids’ (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs’ secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the ABCB4 gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs.

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ABCB4 Mutations in Adults Cause a Spectrum Cholestatic Disorder Histologically Distinct from Other Biliary Disease

Cited by 5 publications

References 21 publications

Analysis of various ATP‐binding cassette transporters revealed quantification of ABCB4 as a potential diagnostic tool in primary sclerosing cholangitis (PSC)

Analysis of various ATP‐binding cassette transporters revealed quantification of ABCB4 as a potential diagnostic tool in primary sclerosing cholangitis (PSC)

Histological evaluation in biliary diseases

Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis

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