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摘要：
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摘要：目的 探讨胆汁酸盐输出泵（bile salt export pump，BSEP）、多药耐药相关蛋
白2（multidrug resistant protein 2，MRP2）和多药耐药糖蛋白3（multidrug resistance
associated protein 3，MDR3）在原发性胆汁性胆管炎（primary biliary cholangitis，
PBC）患者肝组织中的表达特点。方法 收集2009年1月至2019年12月于南昌市第九
医院住院且经肝组织病理诊断为PBC的46例患者临床资料，根据PBC严重程度分为
PBC早期组（Ⅰ～Ⅱ期，31例）和PBC晚期组（Ⅲ～Ⅳ期，15例），比较两组患者
血清丙氨酸氨基转移酶（alanine aminotransferase，ALT）、天门冬氨酸氨基转移
酶（aspartate transaminase，AST）、总胆汁酸（total bile acid，TBA）、总胆红素
（total bilirubin，TBil）、直接胆红素（direct bilirubin，DBil）、碱性磷酸酶（alkaline
phosphatase，ALP）、γ-谷氨酰转移酶（gamma-glutamyltransferase，GGT）、高密度
脂蛋白（high-density lipoprotein，HDL）、总胆固醇（total cholesterol，TC）、甘油三
酯（triglyceride，TG）、低密度脂蛋白（low-density lipoprotein，LDL）等的差异。选
取10例慢性乙型肝炎病毒（hepatitis B virus，HBV）携带者作为对照组。对所有入选
病例肝组织进行BSEP、MDR3、MRP2免疫组织化学标记，观察各组肝组织病理形态
及3种转运蛋白表达差异。结果 PBC晚期组患者血清ALP（中位数：404 U/L vs 281 U/L）、
GGT（中位数：437 U/L vs 245 U/L）、TC（中位数：6.58 mg/L vs 4.50 mg/L）、TG
（中位数：1.72 mg/L vs 1.24 mg/L）、LDL（中位数：3.61 mg/L vs 2.27 mg/L）水平
均显著低于PBC早期组，差异有统计学意义（P均＜ 0.05）。两组患者年龄、性别、
血清ALT、AST、TBA、TBil、DBil、HDL水平及AMA阳性率差异均无统计学意义
（P均＞ 0.05）。与PBC早期组相比，PBC晚期组患者炎症活动度和纤维化程度均较
重，差异有统计学意义（χ
2
= 14.71，P = 0.0006；χ
2
= 20.57，P ＜ 0.001）。PBC早期
组与PBC晚期组患者肝细胞CK7和CK19染色阳性率无统计学差异 [54.84%（17/31）vs
46.67%（7/15），χ
2
= 0.271、P = 0.755；74.19%（23/31）vs 86.67%（13/15），连续校
正χ
2
= 0.337、P = 0.562]。PBC组患者肝组织中BSEP高表达率显著低于对照组 [54.76%
（23/42）vs 100.00%（10/10）；χ
2
= 5.311，P = 0.021]，MDR3和MRP2高表达率差异
无统计学意义 [91.18%（31/34）vs 100.00%（10/10），P = 1.000；69.7%（23/33）vs
100.00%（10/10）；χ
2
= 2.433，P = 0.119]。PBC晚期组患者BSEP高表达率显著低于PBC
早期组 [68.97%（20/29）vs 23.08%（3/13）；χ
2
= 7.630，P = 0.008]，MDR3和MRP2阳
性高表达率差异无统计学意义 [91.30%（21/23）vs 90.91%（10/11），P = 1.000；68.18%
（15/22）vs 72.73%（8/11），P = 1.000]。BSEP、MRP2、MDR3在胆汁淤积区阳性表达
减少越显著，肝细胞胆汁淤积肿胀及羽毛样变性越明显。结论 BSEP在PBC患者肝组织
中表达降低，且在PBC晚期组患者肝组织表达率显著降低，提示PBC胆汁淤积与毛细胆
管膜侧BSEP蛋白表达缺陷有关，并且PBC疾病进展可能与BSEP表达减少有关。
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Abstract: Objective To investigate the expression characteristics of bile salt export pump (BSEP),
multidrug resistant protein 2 (MRP2) and multidrug resistance associated protein 3 (MDR3) in
liver tissue of patients with primary biliary cholangitis (PBC). Methods The clinical data of 46
patients who were admitted to the Ninth Hospital of Nanchang from January 2009 to December
2019 and diagnosed with PBC by liver histopathology were collected. The patients were divided
into PBC early stage group (stageⅠ～Ⅱ, 31 cases) and PBC advanced stage group (stage Ⅲ～Ⅳ,
15 cases) according to the severity of PBC. The differences of serum alanine aminotransferase (ALT),
aspartate transaminase (AST), total bile acid (TBA), total bilirubin (TBil), alkaline phosphatase
(ALP), gamma-glutamyltransferase (GGT), direct bilirubin (DBil), high-density lipoprotein (HDL),
total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) of patients between
the two groups were compared. Another 10 cases of chronic hepatitis B virus (HBV) carriers were
selected as control group. Liver tissues from all patients were immunohistochemically labeled for
BSEP, MDR3, and MRP2 to observe the differences of liver histopathology and the expression
of three transporters of each group. Results The serum ALP (median: 404 U/L vs 281 U/L), GGT
(median: 437 U/L vs 245 U/L), TC (median: 6.58 mg/L vs 4.50 mg/L), TG (median: 1.72 mg/L vs
1.24 mg/L) and LDL (median: 3.61 mg/L vs 2.27 mg/L) levels of patients in PBC advanced stage
group were significantly lower than those in PBC early stage group. There were no significant
differences in age, gender, ALT, AST, TBA, TBil, TBil, DBil, HDL and AMA positivity rate of
patients between the two groups (all P ＞ 0.05). There were no statistical differences in the positive
rates of CK7 and CK19 staining in hepatocytes between PBC early stage group and PBC advanced
stage group [54.84% (17/31) vs 46.67% (7/15), χ
2
= 0.271, P = 0.755; 74.19% (23/31) vs 86.67%
(13/15), χ
2
= 0.337, P = 0.562]. The high expression rate of BSEP in liver tissues of patients in PBC
group was significantly lower than that in control group [54.76% (23/42) vs 100.00% (10/10); χ
2
=
5.311, P = 0.021], and there were no significant differences in MDR3 and MRP2 high expression
rates between the two groups [91.18% (31/34) vs 100.00% (10/10), P = 1.000; 69.7% (23/33)
vs 100.00% (10/10); χ
2
= 2.433, P = 0.119]. The high BSEP expression rate of patients in PBC
advanced stage group was significantly lower than that in PBC early stage group [68.97% (20/29)
vs 23.08% (3/13); χ2
= 7.630, P = 0.008], and there were no significant differences in MDR3 and
MRP2 high expression rates between the two groups [91.30% (21/23) vs 90.91% (10/11), P = 1.000;
68.18% (15/22) vs 72.73% (8/11), P = 1.000]. The more significant the reduction of BSEP, MRP2
and MDR3 positive expression in the cholestasis area, the more serious the swelling and feathering
degeneration of hepatocytes. Conclusions The expression of BSEP decreased in PBC liver tissue,
and significantly decreased in PBC advanced stage group, suggesting that PBC cholestasis was
related to the defect of BSEP protein expression in the capillary bile duct side, and the progression
of PBC disease may be related to the decreased expression of BSEP.
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