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

doi:10.3969/j.issn.1001-5256.2022.01.024

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

南京中医药大学附属南京医院(南京市第二医院) 肝病科，南京 210003

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

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出版历程
- 收稿日期: 2021-07-26
- 录用日期: 2021-09-29
- 出版日期: 2022-01-20

Clinical and pathological features of progressive familial intrahepatic cholestasis type 3

Department of Hepatology, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine & Nanjing Second Hospital, Nanjing 210003, China

Research funding:

National Natural Science Foundation of China (81970454)

摘要

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。
- 胆汁淤积, 肝内 /
- P糖蛋白类 /
- 病理状态, 体征和症状
Abstract: 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.
- Cholestasis, Intrahepatic /
- P-Glycoproteins /
- Pathological Conditions, Signs and Symptoms

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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)。

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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	男	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	男	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	女	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	男	18	慢性胆汁淤积	肝内胆管扩张	杂合	软件分析可能致病
5	男	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	女	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	男	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	女	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

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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

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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	有	正常
2	胆管减少	G2、S2	无	正常
3	胆管减少	G2、S2	无	减少
4	胆管缺失	G1、S3	有	减少
6	胆管缺失	G2、S4	有	减少
7	胆管缺失	G1、S3~4	偶见	减少
8	胆管减少	G1、S2	无	正常

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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)

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