Case report: progressive familial intrahepatic cholestasis type 3 with compound heterozygous ABCB4 variants diagnosed 15 years after liver transplantation.

Published on Nov 30, 2020in BMC Medical Genetics1.585
· DOI :10.1186/S12881-020-01173-0
Mariam Goubran1
Estimated H-index: 1
(University of Alberta Hospital),
Ayodeji Aderibigbe1
Estimated H-index: 1
(University of Alberta Hospital)
+ 4 AuthorsAndrew L. Mason54
Estimated H-index: 54
(U of A: University of Alberta)
Progressive familial intrahepatic cholestasis (PFIC) type 3 is an autosomal recessive disorder arising from mutations in the ATP-binding cassette subfamily B member 4 (ABCB4) gene. This gene encodes multidrug resistance protein-3 (MDR3) that acts as a hepatocanalicular floppase that transports phosphatidylcholine from the inner to the outer canalicular membrane. In the absence of phosphatidylcholine, the detergent activity of bile salts is amplified and this leads to cholangiopathy, bile duct loss and biliary cirrhosis. Patients usually present in infancy or childhood and often progress to end-stage liver disease before adulthood. We report a 32-year-old female who required cadaveric liver transplantation at the age of 17 for cryptogenic cirrhosis. When the patient developed chronic ductopenia in the allograft 15 years later, we hypothesized that the patient’s original disease was due to a deficiency of a biliary transport protein and the ductopenia could be explained by an autoimmune response to neoantigen that was not previously encountered by the immune system. We therefore performed genetic analyses and immunohistochemistry of the native liver, which led to a diagnosis of PFIC3. However, there was no evidence of humoral immune response to the MDR3 and therefore, we assumed that the ductopenia observed in the allograft was likely due to chronic rejection rather than autoimmune disease in the allograft. Teenage patients referred for liver transplantation with cryptogenic liver disease should undergo work up for PFIC3. An accurate diagnosis of PFIC 3 is key for optimal management, therapeutic intervention, and avoidance of complications before the onset of end-stage liver disease.
#1Elodie Mareux (Université Paris-Saclay)H-Index: 2
#2Martine Lapalus (Université Paris-Saclay)H-Index: 2
Last. Emmanuel Jacquemin (Université Paris-Saclay)H-Index: 23
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#1Nicholas D. WeberH-Index: 1
#1Nicholas D. WeberH-Index: 10
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Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare monogenic disease caused by mutations in the ABCB4 gene, resulting in a reduction in biliary phosphatidylcholine. Reduced biliary phosphatidylcholine cannot counteract the detergent effects of bile salts, leading to cholestasis, cholangitis, cirrhosis and ultimately liver failure. Here, we report results from treating two- or five-week-old Abcb4−/− mice with an AAV vector expressing human ABCB4, resulting in significant decre...
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#1Sem J. Aronson (UvA: University of Amsterdam)H-Index: 6
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Multidrug resistance protein 3 (MDR3, ABCB4) is a hepatocellular membrane protein that mediates biliary secretion of phosphatidylcholine. Null mutations in ABCB4 gene give rise to severe early-onset cholestatic liver disease. We have previously shown that the disease-associated mutations p.G68R, p.G228R, p.D459H, and p.A934T resulted in retention of ABCB4 in the endoplasmic reticulum, thus failing to target the plasma membrane. In the present study, we tested the ability of two compounds with ch...
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Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal recessive disorder of cholestasis of hepatocellular origin, typically seen in infancy or childhood caused by a defect in the ABCB4 located on chromosome 7. Here we report on an older patient, aged 15, who presented with biochemical testing that led to an initial consideration of a diagnosis of Wilson disease (WD) resulting in a delayed diagnosis of PFIC3. Diagnosis of PFIC3 was later confirmed by molecular studies that ...
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Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a result of mutations in ABCB11 encoding bile salt export pump (BSEP), the canalicular bile salt export pump of hepatocyte. In some PFIC2 patients with missense mutations, BSEP is not detected at the canaliculus owing to mistrafficking of BSEP mutants. In vitro, chaperone drugs, such as 4-phenylbutyrate (4-PB), have been shown to partially correct mistrafficking. Four PFIC2 patients harboring at least one missense mutation (p.G982R,...
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