Sinha Amil, Bhuva Meha, Grant Claire, Gimson Alexander E, Thompson Edward, Duckworth Adam, Davies Susan E, Aithal Guruprasad, Griffiths William J
University of Cambridge School of Clinical Medicine, Cambridge University Hospitals, Cambridge, UK.
Cambridge Liver Unit, Addenbrooke's Hospital, Cambridge University Hospitals, Hills Road, Box 210, Cambridge, CB20QQ, UK.
Dig Dis Sci. 2022 Dec;67(12):5551-5561. doi: 10.1007/s10620-022-07416-9. Epub 2022 Mar 14.
Mutations in the ABCB4 gene are associated with failure of bile acid emulsification leading to cholestatic liver disease. Presentations range from progressive familial intrahepatic cholestasis type 3 (PFIC3) in childhood, to milder forms seen in adulthood.
We sought to characterize adult disease with particular reference to histology which has been hitherto poorly defined.
Four unrelated adults (three female, mean age 39 years) and three sisters presenting with cholestatic liver disease in adulthood, associated with variants in the ABCB4 gene, were identified. Clinical review and detailed blinded histopathological analysis were performed.
Two novel pathogenic ABCB4 variants were identified: c.620 T > G, p.(Ile207Arg) and c.2301dupT, p.(Thr768TyrfsTer26). Sub-phenotypes observed included low-phospholipid-associated cholelithiasis syndrome (LPAC), intrahepatic cholestasis of pregnancy (ICP), drug-induced cholestasis, idiopathic adulthood ductopenia, and adult PFIC3. Of note, 5/7 had presented with gallstone complications (4 meeting LPAC definition) and 4/6 females had a history of ICP. Considerable overlap was observed phenotypically and liver transplantation was required in 3/7 of patients. Histologically, cases generally demonstrated ductopenia of the smaller tracts, mild non-ductocentric portal inflammation, bilirubinostasis, significant copper-associated protein deposition, and varying degrees of fibrosis.
Adults with ABCB4 mutations may harbor a spectrum of cholestatic disease phenotypes and can progress to liver transplantation. We observed a distinct histological pattern which differs from classical biliary disease and describe two novel pathogenic ABCB4 variants. ABCB4 sequencing should be considered in patients with relevant cholestatic phenotypes and/or suggestive histology; accurate diagnosis can guide potential interventions to delay progression and inform family screening.
ABCB4基因的突变与胆汁酸乳化功能障碍相关，进而导致胆汁淤积性肝病。其临床表现多样，从儿童期的进行性家族性肝内胆汁淤积症3型（PFIC3）到成年期出现的较轻形式。
我们试图对成年期疾病进行特征描述，尤其关注迄今为止定义尚不明确的组织学特征。
确定了4名无血缘关系的成年人（3名女性，平均年龄39岁）和3名成年期出现胆汁淤积性肝病且与ABCB4基因变异相关的姐妹。进行了临床评估和详细的盲法组织病理学分析。
鉴定出两个新的致病性ABCB4变异：c.620 T＞G，p.(Ile207Arg)和c.2301dupT，p.(Thr768TyrfsTer26)。观察到的亚表型包括低磷脂相关胆石症综合征（LPAC）、妊娠期肝内胆汁淤积症（ICP）、药物性胆汁淤积、特发性成年期胆管减少症和成年期PFIC3。值得注意的是，7例中有5例出现胆结石并发症（4例符合LPAC定义），6例女性中有4例有ICP病史。在表型上观察到相当大的重叠，7例患者中有3例需要进行肝移植。组织学上，病例通常表现为较小胆管的减少、轻度非胆管中心性门脉炎症、胆红素淤积、显著的铜相关蛋白沉积以及不同程度的纤维化。
携带ABCB4突变的成年人可能具有一系列胆汁淤积性疾病表型，并可能进展至肝移植。我们观察到一种与经典胆汁疾病不同的独特组织学模式，并描述了两个新的致病性ABCB4变异。对于具有相关胆汁淤积表型和/或提示性组织学表现的患者，应考虑进行ABCB4基因测序；准确的诊断可指导潜在干预措施以延缓疾病进展并为家族筛查提供依据。
