19例进行性家族性肝内胆汁淤积的临床及病理特点分析

肝脏 ›› 2022, Vol. 27 ›› Issue (5): 561-565.

19例进行性家族性肝内胆汁淤积的临床及病理特点分析

刘小菊, 武丽娜, 刘立伟, 刘金香, 朱志军, 孙丽莹, 赵新颜

535000 广西钦州市第一人民医院(广西医科大学第十附属医院)消化一区;首都医科大学附属北京友谊医院肝病研究中心(刘小菊);首都医科大学附属北京友谊医院肝移植中心,国家消化系统疾病临床医学研究中心(武丽娜,刘立伟,刘金香,赵新颜);首都医科大学儿童肝脏移植临床诊疗中心(朱志军,孙丽莹)

收稿日期:2022-03-20 出版日期:2022-05-31 发布日期:2022-07-13
基金资助:
国家自然科学基金青年基金(82000543)

Clinical and pathological characteristics of progressive familiar intrahepatic cholestasis: a report of 19 cases

LIU Xiao-ju¹, WU Li-na², LIU Li-wei², LIU Jin-xiang², ZHU Zi-jun³, SUN Li-ying³, ZHAO Xin-yan²

1. Department of Gastroenterology, Qinzhou First People's Hospital, Guangxi 535000, China;
2. Liver Research Center, Liver Transplant Center, Beijing Friendship Hospital,Capital Medical University;National Clinical Research Center for Digestive Disease, Beijing 100050,China;
3. Pediatric Liver Transρlantation Research Center,Capital Medical University, Beijing 100050, China

Received:2022-03-20 Online:2022-05-31 Published:2022-07-13

摘要/Abstract

摘要： 目的比较进行性家族性肝内胆汁淤积(Progressive familiar intrahepatic cholestasis, PFIC) 1、2、3型临床、病理特点,转运蛋白及基因分型等。方法对2014年至2018年在首都医科大学附属北京友谊医院明确诊断为PFIC患者进行回顾性分析,收集患者临床、生化、病理及基因测序结果。结果符合PFIC诊断标准患者19例,平均年龄(10.6±22.7)个月,男性占52%,1型3例(15.7%),2型13例(68.4%),3型3例(15.7%)。1岁以内发病15例(78.9%),肝移植12例(63.1%)。其中,PFIC 2型发病最早[(2.9±3.37)个月];3型发病最晚[(48±39.1)个月],肝损伤程度最轻。临床表现脾大最常见占84.2%(16/19),黄疸78.9%(15/19)、腹水52.6%(10/19)、皮肤瘙痒52.6%(10/19)、门脉高压47.3%(9/19)、肝大、门脉分流及胆囊继发性改变各占42.1%(8/19)。肝硬化8例(42.1%),以女性居多(女性5例,男性3例),非肝硬化11例(57.8%)。肝硬化患者的直接胆红素[270.6(59.9,390.3)比79.1(10.4,96.5)μmol/L,>3倍,P=0.02]、间接胆红素[236.4(54.9,319.5)比65.6(11.6,85.5)μmol/L,>4倍,P=0.041]显著升高、凝血酶原时间[(22.24±9.93)比(13.83±2.93)s,P=0.034]及国际标准化比值[1.7(1.2,2.4)比1.1(1.0,1.3),P=0.034]较非肝硬化组显著升高。与GGT升高组比较,GGT正常组的碱性磷酸酶[(417.2±240.3 )比(214.5±58.34)U/L,约等于2倍,P=0.049]及白细胞[(12.1±9.7)比(4.14±3.56)×10⁹/L,> 2倍,P=0.049]显著升高。从肝脏病理角度分析,1型肝内胆汁淤积最重,无BSEP、MDR3及MRP2蛋白缺失;2型BSEP蛋白减少或完全缺失;3型MDR3蛋白完全缺失,肝内胆汁淤积最轻。结论本研究通过对比分析发现,PFIC 3临床发病相对较晚、肝损伤程度最轻、GGT显著升高,此特点可作为区别于其他分型的重要线索。此外,基因测序、肝组织学上对应的转运蛋白缺失对PFIC分型有提示作用。

关键词: 进行性家族性肝内胆汁淤积, 胆汁转运蛋白, 基因检测, 遗传代谢性肝病

Abstract: Objective To compare the clinical features, transporters and genotypes of PFIC types 1, 2 and 3. Methods From 2014 to 2018, PFIC patients were diagnosed in Beijing Friendship Hospital, Capital Medical University. The clinical, biochemical, pathological and genetic sequencing results were collected. Results 19 patients met the diagnostic criteria for PFIC. The mean age was 10.6 ± 22.7 months, 52% were male. 3 cases were type 1 (15.7%), 13 cases were type 2 (68.4%), 3 cases were type 3 (15.7%). There were 15 cases (78.9%) with onset within 1 year, 12 cases (63.1%) received liver transplantation. The onset of PFIC type 2 was the earliest (2.9 ± 3.37 months). Type 3 had the latest onset (48 ± 39.1 months) and the least hepatic impairment. The most common clinical manifestations were splenomegaly in 84.2% (16/19), jaundice in 78.9% (15/19), ascites in 52.6% (10/19), pruritus in 52.6% (10/19), portal hypertension in 47.3% (9/19), hepatomegaly, portal systemic shunt and gallbladder secondary changes in 42.1% (8/19). As compared to non-cirrhotic patients, direct bilirubin [ 270.6 (59.9, 390.3) vs 79.1 (10.4, 96.5)μmol/L, > 3-fold, P=0.02], indirect bilirubin[236.4(54.9,319.5)vs 65.6(11.6,85.5)μmol/L,>4-fold,P=0.041]prothrombin time [ (22.24 ± 9.93) vs (13.83 ± 2.93)s, P=0.034] and international normalized ratio [ 1.7 (1.2, 2.4) vs 1.1 (1.0, 1.3), P=0.034] were significantly higher in patients with cirrhosis. Alkaline phosphatase [ (417.2 ± 240.3) vs (214.5 ± 58.34)U/L, approximately 2-fold, P=0.049] and leukocytes [(12.1 ± 9.7 ) vs(4.14 ± 3.56)×10⁹/L, > 2-fold, P=0.049] were significantly elevated in the normal GGT group compared to the elevated GGT group. From the perspective of liver pathology, type 1 the degree of cholestasis was the most severe, without BSEP, MDR3 and MRP2 protein loss. Decreased or complete loss of BSEP protein in type 2; MDR3 protein is completely absent in type 3 with minimal cholestasis. Conclusion The results of this study showed that PFIC 3 had mild clinical severity and GGT was significantly increased, which could be used as an important clue to differentiate the types of PFIC. In addition, gene sequencing and loss of the corresponding transporter in liver histology suggest their role for PFIC diagnosis and classification.

Key words: Progressive familiar intrahepatic cholestasis, Bile acid export pump, Gene test, Hereditary genetic liver disease

刘小菊, 武丽娜, 刘立伟, 刘金香, 朱志军, 孙丽莹, 赵新颜. 19例进行性家族性肝内胆汁淤积的临床及病理特点分析[J]. 肝脏, 2022, 27(5): 561-565.

LIU Xiao-ju, WU Li-na, LIU Li-wei, LIU Jin-xiang, ZHU Zi-jun, SUN Li-ying, ZHAO Xin-yan. Clinical and pathological characteristics of progressive familiar intrahepatic cholestasis: a report of 19 cases[J]. Chinese Hepatolgy, 2022, 27(5): 561-565.

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