Current perspectives on the JAK/STAT signaling pathway and its activating factors in liver fibrosis

Pan Jin; Ju Jian

Issue 5

May 2013

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Article Navigation > Journal of Clinical Hepatology > 2013 > 29(5): 393-396

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Current perspectives on the JAK/STAT signaling pathway and its activating factors in liver fibrosis

Pan Jin,
Ju Jian

Published Date: 2013-05-20

Abstract

Abstract

The Janus kinase (JAK) /signal transducer and activator of transcription (STAT) signaling pathway is an important signal transduction pathway activated by a variety of cytokines and growth factors and mediates various cellular processes involved in liver fibrosis, including proliferation, differentiation, apoptosis, and inflammation.In this article, the recent findings related to the function of JAK/STAT signaling and its activating factors in liver fibrosis are reviewed.Specifically, the roles of three cytokines leptin, interferon-alpha (IFN-α) and interleukin-4 (IL-4) are detailed in regards to their activation of the intracellular JAK/STAT pathway through the hepatic stellate cell membrane to promote expression of target genes involved in the fibrotic process.
- Janus kinases,
- STAT transcription factors,
- signal transduction,
- liver cirrhosis

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原发性胆汁性胆管炎(PBC) 是一种慢性肝内胆汁淤积性、自身免疫性肝病，多见于中老年女性，其病理特点为进行性、非化脓性、破坏性肝内小胆管炎^[1]。如果不经治疗，可发展为纤维化和肝硬化，甚至发展为肝癌^[2]。组织学严重程度的评估是PBC患者预后和生存的重要决定因素^[3]。肝活检被认为是肝纤维化诊断的金标准，但肝活检为有创检查，且具有花费高、并发症多、取样体积小、主观性强等限制因素，不宜被患者接受。因此寻找有效、简单、便捷、花费低的无创诊断模型尤为重要。目前，已有很多评估肝纤维化的无创模型，如AST/PLT比值指数(ARRI)、肝纤维化4因子指数(FIB-4)、FibroScan等。Jiang等^[4]研究发现PLT是鉴别早期和晚期肝纤维化的预测因子。Takaki等^[5]研究显示国际标准化比值(INR)与慢性丙型肝炎患者的肝纤维化呈显著正相关(r=0.545，P＜0.05)。Ding等^[6]则利用INR、PLT等临床常规指标建立了国际标准化比值/PLT比值指数(INPR)模型，用以评价慢性HBV感染者的肝纤维化程度，该模型计算公式简单，临床易于实施。但INPR对PBC患者肝纤维化的诊断价值未见相关报道。本研究拟评价INPR对PBC患者肝纤维化程度的诊断价值，并与传统无创肝纤维化诊断模型APRI、FIB-4进行比较。

1. 资料与方法

1.1 研究对象

选取2013年10月—2021年3月在郑州大学第一附属医院就诊并行肝穿刺活检的PBC患者。纳入标准：(1)符合《原发性胆汁性肝硬化(又名原发性胆汁性胆管炎)诊断和治疗共识(2015)》^[1]的诊断标准；(2)在肝活检1周内行血清学指标检测。排除标准：(1)合并病毒性肝炎、酒精性肝病、非酒精性脂肪性肝病、自身免疫性肝炎、原发性硬化性胆管炎、IgG4相关胆管炎、重叠综合征及药物性肝损伤者；(2)合并肝遗传性、代谢性疾病者；(3)肝癌、肝移植者；(4)有恶性肿瘤史或其他终末期疾病者；(5)孕产妇；(6)患有影响血INR、PLT水平的相关疾病。

1.2 研究方法

1.2.1 观察指标

收集患者性别、年龄等一般资料以及PLT、INR、红细胞分布宽度(RDW)、ALT、AST、ALP、GGT、TBil、DBil、IBil、Alb等实验室指标。

1.2.2 肝活检

所有肝活检均在超声引导下进行，标本长度为1.0~2.0 cm，用甲醛固定，石蜡包埋、切片，进行HE染色、网状纤维染色、Masson染色、铁染色、铜染色、糖原染色。由两名病理科医师独立阅片诊断，采用Scheuer评分系统评估肝纤维化程度，其中S2~S4定义为显著肝纤维化(即≥S2)；S3~S4定义为进展期肝纤维化(即≥S3)；S4定义为肝硬化(即S4)。

1.3 血清学诊断模型计算公式

INPR=INR/PLT(×10⁹/L) ×100；APRI=AST(U/L)/AST正常值上限(U/L)×100/PLT(×10⁹/L)；FIB-4=年龄(岁)×AST(U/L)/ [PLT(×10⁹/L)×ALT(U/L)^1/2]。AST正常值上限为40 U/L。

1.4 统计学方法

采用SPSS 26.0统计软件及MedCalc软件进行数据分析。非正态分布的计量资料以M(P₂₅~P₇₅)表示，多组间比较采用Kruskal-Wallis H秩和检验，进一步两两比较采用Bonferroni法。计数资料组间比较采用χ²检验。通过绘制受试者工作特征曲线(ROC曲线)评估各无创血清学模型对PBC患者肝纤维化的诊断效能，ROC曲线下面积(AUC)的比较采用DeLong法。采用Spearman相关分析评估各无创模型与肝纤维化分期的相关性。P＜0.05为差异有统计学意义。

2. 结果

2.1 一般资料

共纳入PBC患者143例，平均年龄(54.4±11.3) 岁，肝纤维化分期例数分别为S0期4例(2.8%)，S1期50例(35.0%)，S2期46例(32.2%)，S3期26例(18.2%)，S4期17例(11.9%)。不同肝纤维化分期患者INPR、APRI、FIB-4、INR、PLT、AST、Alb、RDW、TBil、DBil比较，差异均有统计学意义(P值均＜0.05)；进一步两两比较结果显示，INPR、APRI、FIB-4在S4和S0、S1之间差异均有统计学意义(P值均＜0.05)，INPR、FIB-4在S1和S3及S2和S4之间差异均有统计学意义(P值均＜0.05)(表 1)。

表 1 不同肝纤维化分期患者的临床资料比较

指标	S0(n=4)	S1(n=50)	S2(n=46)	S3(n=26)	S4(n=17)	χ²值	P值
男/女(例)	0/4	6/44	7/39	1/25	1/16	2.485	0.640
年龄(岁)	54.0(49.3~64.8)	55.0(44.8~62.0)	52.0(47.0~63.0)	60.5(50.3~65.0)	54.0(49.5~65.5)	4.761	0.313
INPR	0.39(0.33~1.02)	0.52(0.43~0.69)	0.64(0.46~1.02)	0.81(0.63~1.18)²⁾	1.39(0.81~1.78)¹⁾²⁾³⁾	27.347	＜0.001
APRI	0.34(0.20~0.71)	0.64(0.37~1.32)	1.06(0.69~2.50)	1.30(0.72~1.71)	2.19(1.28~3.81)¹⁾²⁾	23.942	＜0.001
FIB-4	1.40(1.02~2.36)	2.02(1.19~3.76)	3.09(1.88~5.19)	5.00(2.48~6.01)²⁾	7.89(4.98~10.30)¹⁾²⁾³⁾	34.211	＜0.001
INR	0.96(0.90~1.02)	0.95(0.90~1.00)	0.99(0.94~1.04)	0.96(0.91~1.04)	1.11(0.96~1.22)	15.843	0.003
PLT(×10⁹/L)	248.0(121.3~289.3)	172.0(145.3~225.0)	158.0(102.5~223.0)	116.0(85.8~156.5)	88.0(67.5~107.5)	24.518	＜0.001
ALT(U/L)	29.0(21.3~38.3)	46.5(24.0~91.0)	59.0(35.8~101.2)	39.5(23.2~62.0)	63.0(29.5~96.0)	7.308	0.120
AST(U/L)	24.0(23.0~40.0)	45.5(24.0~70.5)	61.5(34.5~114.2)	55.5(33.0~70.2)	69.0(38.0~110.5)	13.626	0.009
GGT(U/L)	102.5(46.8~418.5)	140.5(47.5~311.5)	163.5(76.5~379.3)	243.0(115.5~386.8)	178.0(78.0~261.5)	4.826	0.306
ALP(U/L)	151.5(77.0~229.0)	151.0(97.5~232.8)	223.0(121.8~359.5)	229.0(103.0~315.3)	202.0(152.0~371.0)	7.420	0.115
Alb(g/L)	43.6(40.5~46.7)	39.8(38.5~42.3)	38.5(34.6~41.3)	38.4(34.3~42.4)	34.6(29.5~38.7)	21.543	＜0.001
RDW(%)	13.5(12.8~14.7)	13.5(12.7~15.0)	14.5(13.3~16.1)	14.2(13.6~16.8)	16.5(14.9~16.8)	20.972	＜0.001
TBil(μmol/L)	12.4(10.6~13.7)	10.7(7.7~18.0)	12.9(9.1~34.2)	15.3(12.3~19.2)	25.0(12.9~70.1)	13.120	0.011
DBil(μmol/L)	5.5(4.2~7.7)	5.0(3.5~9.0)	7.0(4.8~29.9)	9.1(5.9~13.2)	14.4(7.2~50.1)	14.498	0.006
IBil(μmol/L)	6.4(5.7~7.2)	4.9(3.5~8.0)	5.4(4.1~7.0)	5.6(4.2~7.0)	6.2(4.8~9.0)	5.126	0.275
注：与S0分期比较，1)P＜0.05；与S1分期比较，2)P＜0.05；与S2分期比较，3)P＜0.05。

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2.2 各指标与肝纤维化分期的相关性分析

Spearman相关分析结果显示，INR、RDW、INPR、APRI及FIB- 4均与肝纤维化分期呈正相关(r值分别为0.249、0.362、0.419、0.381、0.483，P值均＜0.01)；PLT与肝纤维化分期呈负相关(r＝-0.395，P＜0.01)。

2.3 INPR、APRI及FIB-4对PBC不同肝纤维化分期的诊断效能

INPR、APRI及FIB- 4诊断显著肝纤维化的AUC分别为0.691、0.706、0.742，最佳cut-off值分别为0.63、0.59、2.68，INPR诊断显著肝纤维化的AUC与APRI和FIB-4相比，差异均无统计学意义(Z值分别为0.354、1.773，P值均＞0.05)。INPR、APRI及FIB-4诊断进展期肝纤维化的AUC分别为0.731、0.675、0.756，最佳cut-off值分别为0.64、1.23、4.63，INPR诊断进展期肝纤维化的AUC与APRI和FIB-4相比，差异均无统计学意义(Z值分别为1.464、1.012，P值均＞0.05)。INPR、APRI及FIB-4诊断肝硬化的AUC分别为0.820、0.786、0.818，最佳cut-off值分别为0.95、1.26、4.63，INPR诊断肝硬化的AUC与APRI和FIB-4相比，差异均无统计学意义(Z值分别为0.985、0.0674，P值均＞0.05)(表 2~4，图 1)。

表 2 INPR、APRI及FIB-4对PBC显著肝纤维化的诊断价值

指标	AUC	P值	95%CI	cut-off值	敏感度(%)	特异度(%)	准确度(%)
INPR	0.691	＜0.001	0.609~0.766	0.63	67.42	68.52	67.80
APRI	0.706	＜0.001	0.625~0.780	0.59	82.02	51.85	70.60
FIB-4	0.742	＜0.001	0.662~0.811	2.68	69.66	70.37	69.20

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表 3 INPR、APRI及FIB-4对PBC进展期肝纤维化的诊断价值

指标	AUC	P值	95%CI	cut-off值	敏感度(%)	特异度(%)	准确度(%)
INPR	0.731	＜0.001	0.650~0.801	0.64	84.09	62.63	69.90
APRI	0.675	0.0003	0.591~0.751	1.23	65.91	67.68	66.40
FIB-4	0.756	＜0.001	0.677~0.824	4.63	68.18	81.82	76.90

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表 4 INPR、APRI及FIB-4对PBC肝硬化的诊断价值

指标	AUC	P值	95%CI	cut-off值	敏感度(%)	特异度(%)	准确度(%)
INPR	0.820	＜0.001	0.747~0.879	0.95	77.78	77.60	77.60
APRI	0.786	＜0.001	0.709~0.850	1.26	88.89	64.80	66.40
FIB-4	0.818	＜0.001	0.745~0.878	4.63	88.89	68.80	74.80

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图 1 INPR、APRI、FIB-4诊断不同肝纤维化分期的ROC曲线

注：a，显著肝纤维化；b，进展期肝纤维化；c，肝硬化。

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3. 讨论

不同PBC患者病程进展速度差异较大^[7]，患者的肝纤维化分期有助于指导治疗，对一些PBC早期肝纤维化患者，及时给予治疗可延缓其进展。已有研究^[8-9]发现组织学分期可以预测PBC患者存活率。PBC早期预后良好，然而，在疾病的晚期，可能会出现肝硬化相关的并发症^[10]。因此，组织学评估在PBC的病理评估和预后预测中非常重要。目前，肝活检仍是肝纤维化诊断的金标准，但活检受到取样误差、侵袭性、费用高、依从性差和禁忌证的限制，不宜被患者接受^{[3, 11-12]}。近年来，出现了大量的非侵袭性肝纤维化模型，包括APRI、FIB-4、FibroScan等，但大部分是关于乙型肝炎和丙型肝炎的研究^[13-14]，PBC的非侵入性肝纤维化诊断模型较少。INPR模型是由Ding等^[6]基于慢性乙型肝炎创立的肝纤维化无创诊断模型，该研究多因素分析结果显示，INR和PLT是显著肝纤维化和肝硬化的独立预测因子(P值均＜0.05)；相关性分析显示INPR与肝纤维化分期呈显著正相关(r=0.494)，相关系数高于APRI(r=0.453)和FIB-4(r=0.428)；ROC曲线分析显示，在评估显著肝纤维化方面，INPR表现出与APRI和FIB-4相当的表现(AUC分别为0.74、0.77、0.72)，在预测肝硬化方面优于APRI和FIB-4(AUC分别为0.86、0.74、0.80)。INPR模型计算公式简单，其包含的指标INR和PLT是常规检测指标，且不包含受测量者主观影响较大的指标。基于此，本研究探讨INPR模型对PBC患者肝纤维化程度的诊断价值。

研究^[15-16]发现，随着肝纤维化的进展，INR升高，PLT降低，这种异常情况在肝硬化患者中尤为明显。Liang等^[17]研究显示INR和PLT是慢性乙型肝炎患者肝硬化的独立预测因子。外周PLT降低在进展性肝病中较为常见，可能与脾功能亢进、骨髓抑制、PLT寿命缩短、促血小板生成素减少等因素有关。本研究分析显示，随着肝纤维化程度的加重，INPR、APRI、FIB-4评分逐渐增加，PLT水平逐渐下降。相关性分析显示INPR、APRI、FIB-4、INR、RDW与PBC患者肝纤维化分期呈显著正相关，PLT与肝纤维化分期呈显著负相关，与既往研究^[18-20]的结果相一致。ROC曲线分析显示，INPR、APRI、FIB-4诊断不同肝纤维化分期的AUC差异均无统计学意义，提示INPR在诊断PBC患者肝纤维化程度时，具有与APRI、FIB-4相当的临床价值，可准确评估患者肝纤维化程度。

综上所述，INPR作为一种新的肝纤维化无创诊断模型，在诊断PBC患者肝纤维化方面具有与传统诊断模型APRI和FIB-4相当的临床诊断价值。考虑到临床中部分PBC患者确诊前已行药物治疗，而AST和ALT易受用药等因素影响，且AST和ALT水平随着炎症的激活和缓解波动较大，因此可能会影响APRI和FIB-4，故INPR更适于在一定程度上替代肝活检评估肝纤维化进展程度并用于指导治疗。本研究亦有一些不足，如研究属于单中心、回顾性分析，样本量小，各纤维化分期病例数分布不均衡，在纳排标准的制订上不及前瞻性研究，因此在诸如影响因素及诊断界值等问题上存在偏差。未来应开展多中心、前瞻性和大样本的临床研究，减少上述偏倚及混杂因素的影响，进一步验证INPR的诊断价值。此外，临床应用INPR模型时应注意，若患者合并其他类型肝病、免疫性血小板减少症、特发性血小板减少性紫癜等影响血清INR、PLT水平的疾病，可能会导致INPR模型评分与事实存在偏差。同时，INPR是否能够预测PBC患者的预后，评估治疗效果，或是否适用于其他类型的肝病，还有待进一步研究。

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Current perspectives on the JAK/STAT signaling pathway and its activating factors in liver fibrosis