进行性家族性肝内胆汁淤积症3型临床病理特征分析

Clinical and pathological features of progressive familial intrahepatic cholestasis type 3

目的探讨进行性家族性肝内胆汁淤积症3型(PFIC3)患者临床与病理学特征。方法回顾分析了2017年1月—2019年12月南京市第二医院就诊的1326例不明原因肝病患者临床资料,通过临床、病理表现及基因测序确诊PFIC3患者8例(其中1例因禁忌证未行肝组织穿刺)。分析患者临床、检验、影像、病理结果,并对ABCB4相关疾病的病理文献进行回顾,总结PFIC3临床及病理特征。结果8例PFIC3患者,其中男5例,女3例,中位年龄29.5岁。50%(4/8)表现为慢性胆汁淤积,50%(4/8)表现胆汁性肝硬化,肝硬化中75%(3/4)合并门静脉高压表现。生化检查中,75%(6/8)表现为ALP升高,100%(8/8)表现GGT升高。影像检查中,50%(4/8)表现为胆囊炎,25%(2/8)表现为胆囊结石,25%(2/8)患者胆管扩张,75%(6/8)患者脾脏肿大,25%(2/8)表现为肝硬化。肝穿刺病理中,所有患者均表现为胆管损伤和/或胆管减少,其中57.1%(4/7)表现为胆管缺失。多耐药蛋白3(MDR3)免疫组化染色42.9%(3/7)正常表达,57.1%(4/7)表达减少。根据文献回顾,其中包含胆管描述或MDR3免疫组化的文献17篇。7例低磷脂相关性胆石症中,胆管正常占71.4%(5/7),胆管减少占14.3%(1/7),胆管缺失占14.3%(1/7);6例妊娠期肝内胆汁淤积症中,胆管正常占16.7%(1/6),胆管减少占50%(3/6),胆管缺失占33.3%(2/6);8例PFIC3中,胆管减少占25%(2/8),胆管缺失占75%(6/8);21例PFIC3患者MDR3表达正常占9.5%(2/21),表达减少占23.8%(5/21),表达缺失占66.7%(14/21)。结论PFIC3以胆汁淤积、胆石症、肝纤维化为主要表现。病理表现为胆管损伤,严重者可伴胆管减少或缺失,且损伤程度与疾病严重程度相关。MDR3免疫组化可表现为正常、减少或表达缺失,正常表达患者仍不能排除诊断,必要时行基因检测确诊。

Objective To investigate the clinical and pathological features of progressive familial intrahepatic cholestasis type 3(PFIC3).Methods A retrospective analysis was performed for 1326 patients with unexplained liver disease who attended Nanjing Second Hospital from January 2017 to December 2019,among whom 8 patients were diagnosed with PFIC3 based on clinical/pathological manifestation and gene sequencing results(1 patient did not undergo liver biopsy due to contraindication).Clinical,laboratory,imaging,and pathological findings were analyzed and a literature review was performed for the pathology of ABCB4-related diseases to summarize the clinical and pathological features of PFIC-3.Results Among the 8 patients with PFIC3,there were 5 male patients and 3 female patients,with a median age of 29.5 years.Of all 8 patients,4(50%)manifested as chronic cholestasis and 4(50%)manifested as biliary cirrhosis,among whom 3(75%)had the manifestation of portal hypertension.As for biochemical examination,75%(6/8)had an increase in alkaline phosphatase,and 100%(8/8)had an increase in gamma-glutamyl transpeptidase.As for imaging examination,50%(4/8)had cholecystitis,25%(2/8)had gallstones,25%(2/8)had bile duct dilatation,75%(6/8)had splenomegaly,and 25%(2/8)had liver cirrhosis.As for liver biopsy,all 7 patients manifested as bile duct injury and/or reduction,and 57.1%(5/7)had absence of the bile duct.Multidrug resistance P-glycoprotein 3(MDR3)immunohistochemical staining showed normal expression in 42.9%(3/7)of the patients and reduced expression in 57.1%(4/7)of the patients.Literature review obtained 17 articles with a description of the bile duct or MDR3 immunohistochemistry.Among the 7 patients with low phospholipid-associated cholelithiasis,71.4%(5/7)had normal bile duct,14.3%(1/7)had bile duct reduction,and 14.3%(1/7)had absence of the bile duct;among the 6 patients with intrahepatic cholestasis of pregnancy,16.7%(1/6)had normal bile duct,50%(3/6)had bile duct reduction,and 33.3%(2/6)had absence of the bile duct;among the 8 patients with PFIC3,25%(2/8)had bile duct reduction and 75%(6/8)had absence of bile duct;among the 21 patients with PFIC3,9.5%(2/21)had normal expression of MDR3,23.8%(5/21)had a reduction in the expression of MDR3,and 66.7%(14/21)had absence of the expression of MDR3.Conclusion PFIC3 mainly manifests as cholestasis,cholelithiasis,and hepatic fibrosis.Pathological manifestation includes bile duct injury and bile duct reduction or absence of the bile duct in severe cases,and the degree of injury is associated with disease severity.MDR3 immunohistochemistry may show normal expression,reduced expression,or absence of expression,and diagnosis cannot be excluded in patients with normal expression.Genetic testing can be performed for diagnosis when necessary.