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进行性家族性肝内胆汁淤积症3型临床病理特征分析

翁宇航 熊清芳 刘杜先 张胥磊 杨永峰

引用本文:
Citation:

进行性家族性肝内胆汁淤积症3型临床病理特征分析

DOI: 10.3969/j.issn.1001-5256.2022.01.024
基金项目: 

国家自然科学基金 (81970454)

利益冲突声明:本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明:翁宇航负责收集数据,资料分析,撰写论文;熊清芳、刘杜先、张胥磊指导撰写文章;杨永峰负责课题设计,拟定写作思路,修改论文并最后定稿。
详细信息
    通信作者:

    杨永峰,yyf1997@163.com

Clinical and pathological features of progressive familial intrahepatic cholestasis type 3

Research funding: 

National Natural Science Foundation of China (81970454)

  • 摘要:   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。

     

  • 图  1  PFIC3患者肝组织病理表现

    注:a,病例2汇管区小叶间胆管可见上皮细胞缺失,胆管损伤(HE染色,×400);b,病例4汇管区纤维增生,未见和小叶间动脉伴行的小叶间胆管,胆管缺失(HE染色,×200);c,病例1以汇管区为中心的纤维增生形成假小叶(Masson染色,×100);d,病例7显示一个较大的汇管区胆管缺失,界面处可见细胆管,部分肝细胞CK7表达(免疫组化,×200);e,病例2 MDR3沿肝细胞毛细胆管面表达,表达量基本正常(免疫组化,×400);f,病例6约20%肝细胞毛细胆管面MDR3表达,表达明显减少,部分肝细胞浆MDR3弱表达(免疫组化,×400)。

    表  1  8例PFIC3患者临床特征

    编号 性别 年龄 临床表现 影像表现 ABCB4突变类型 突变意义
    1 25 慢性胆汁淤积、肝硬化、门静脉高压、上消化道出血 肝硬化、胆囊炎、胆囊结石、脾肿大 复合杂合 软件分析可能致病
    2 21 慢性胆汁淤积 肝右叶钙化灶、胆囊炎、脾轻度肿大 复合杂合 国内外文献均报道,软件分析可能致病
    3 54 慢性胆汁淤积 胆囊炎、胆囊结石、脾肿大、脾脏低密度结节 杂合 软件分析可能致病
    4 18 慢性胆汁淤积 肝内胆管扩张 杂合 软件分析可能致病
    5 31 慢性胆汁淤积、肝硬化 肝右叶囊肿、胆囊壁毛糙、脾脏肿大 杂合 软件分析可能致病
    6 38 慢性胆汁淤积、肝硬化、门静脉高压 肝脏形态失常、肝右叶胆管轻度扩张 复合杂合 文献报道可能影响剪切
    7 37 慢性胆汁淤积、肝硬化、门静脉高压、上消化道出血 肝硬化表现、脾肿大、门静脉增粗、门静脉高压、胆囊炎 杂合 软件分析可能影响剪切
    8 28 慢性胆汁淤积 肝内钙化灶、胆囊壁毛糙、脾轻度肿大 杂合 软件分析可能致病
    下载: 导出CSV

    表  2  8例PFIC3患者实验室检查

    指标 病例1 病例2 病例3 病例4 病例5 病例6 病例7 病例8
    RBC(×109/L) 2.74~4.23 4.52~4.77 3.69~4.06 4.01~4.84 4.27 2.81~3.01 4.07~4.27 4.42
    Hb(g/L) 79~108 132~138 116~125 120~146 138 82~84 116~119 143
    WBC(×109/L) 1.57~3.13 4.85~6.51 2.34~2.37 2.78~5.34 8.24 12.72~15.91 2.19~2.39 5.49
    PLT(×109/L) 23~54 137~189 55~65 91~158 159 367~403 42~65 278
    INR 1.23~1.25 0.91~0.99 1.06 0.97 1.14 1.14~1.20 1.10 0.96
    TBil(μmol/L) 84.70~195.30 15.80~33.40 18.10~27.60 18.60~25.90 105 72.40~108.50 19.90~25.50 9.00~15.90
    ALT(U/L) 98.3~420.1 42.9~237.1 31.6~71.0 76.0~126.6 95.7 50.0~57.4 51.5~128.3 29.4~126.1
    AST(U/L) 93.1~632.6 58.2~186.7 31.8~55.7 34.4~53.5 42.9 140.5~150.0 44.0~106.4 18.2~74.4
    Alb(g/L) 30.8~39.9 41.2~45.2 36.1~37.7 41.2~54.2 53 20.6~21.0 38.2~39.0 40.2~45.2
    ALP(U/L) 554.5~1 202.4 372.1~989.5 177.1~206.5 91~223 88.9 467.6~528.8 386.6~514.2 51~65
    GGT(U/L) 364.9~575.6 769.7~1 644.9 263.3~389.1 205.8~321.1 86.8 161.1~232.6 219.4~348.9 86~157
    LDH(U/L) 129~251 185~226 171~194 125~147 177 281~322 143~163 143~162
    下载: 导出CSV

    表  3  PFIC3患者组织病理学及免疫组化染色特征

    病例 胆管损伤程度 炎症分级(G)、纤维分期(S) 肝细胞CK7表达 MDR3表达
    1 胆管缺失 G1、S4 正常
    2 胆管减少 G2、S2 正常
    3 胆管减少 G2、S2 减少
    4 胆管缺失 G1、S3 减少
    6 胆管缺失 G2、S4 减少
    7 胆管缺失 G1、S3~4 偶见 减少
    8 胆管减少 G1、S2 正常
    下载: 导出CSV

    表  4  ABCB4突变患者病理特征文献[17-33]回顾

    临床表型 胆管特征 MDR3免疫组化特征
    LPAC 正常:71.4%(5/7) 正常:100%(1/1)
    减少:14.3%(1/7)
    缺失:14.3%(1/7)
    ICP 正常:16.7%(1/6)
    减少:50%(3/6)
    缺失:33.3%(2/6)
    PFIC3 正常:0 正常:9.5%(2/21)
    减少:25%(2/8) 减少:23.8%(5/21)
    缺失:75%(6/8) 缺失:66.7%(14/21)
    下载: 导出CSV
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