原发性胆汁性胆管炎患者血清核因子相关因子2、血红素加氧酶1的含量与熊去氧胆酸短期应答的相关性

doi:10.3877/cma.j.issn.1674-0785.2020.05.009

目的

观察核因子相关因子2（Nrf2）、血红素加氧酶1（HO-1）在原发性胆汁性胆管炎（PBC）患者治疗前后血清中的水平变化，并探讨二者与熊去氧胆酸（UDCA）短期疗效的相关性。

方法

纳入山西医科大学第一医院PBC患者及健康对照者各80例。收集PBC患者治疗前后的临床资料及血清样本，采用ELISA法检测样本中Nrf2及HO-1的含量，硫代巴比妥酸法、黄嘌呤氧化酶法分别检测丙二醛（MDA）及超氧化物歧化酶（SOD）的含量，并进一步分析UDCA治疗前后PBC患者血清中Nrf2、HO-1的水平变化及临床意义。

结果

治疗前PBC患者血清Nrf2、HO-1含量分别为（626.07±103.95）U/L、（16.62±5.06）U/L）显著高于健康对照者［分别为164.45±35.12）U/L、（11.74±2.0）U/L］，差异均有统计学意义（P均<0.001）；与治疗前比较，UDCA治疗后1个月PBC患者血清中Nrf2［（754.30±104.36）U/L］、HO-1［（22.60±5.51）U/L］含量显著增加（P均<0.001），肝功能各项指标也得到改善（P均<0.001）。患者治疗前血清中Nrf2水平（r=0.751，P=0.012）、HO-1水平（r=0.621，P=0.038）与治疗效果均呈正相关。以治疗前Nrf2=586.17 U/L作为阈值,预测的UDCA短期疗效的敏感度为84.6%，特异度为77.5%，曲线下面积为0.824（P<0.05）；以治疗前HO-1=14.92 U/L作为阈值，预测的UDCA短期疗效的敏感度为88.5%，特异度为75.0%，曲线下面积为0.861（P<0.05）。

结论

Nrf2、HO-1在PBC患者疾病过程中发挥重要作用，二者在血清中的基线水平及动态变化同UDCA疗效相关，可以提示PBC患者对UDCA短期治疗的应答情况。

关键词: 核因子相关因子2, 血红素加氧酶1, 原发性胆汁性胆管炎, 熊去氧胆酸, 氧化应激

Objective

To observe the changes of serum levels of nuclear factor-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in patients with primary biliary cholangitis (PBC) before and after treatment, and to explore their correlation with short-term effects of ursodeoxycholic acid (UDCA).

Methods

A total of 80 patients with PBC and 80 healthy controls were enrolled at the First Hospital of Shanxi Medical University. The clinical data and serum samples of patients with PBC were collected before and after treatment. The contents of Nrf2 and HO-1 in the samples were detected by ELISA. The contents of malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by the methods of tartaric acid and xanthine oxidase. The changes in serum Nrf2 and HO-1 levels in patients with PBC before and after UDCA treatment and their clinical significance were then analyzed.

Results

The contents of serum Nrf2 and HO-1 in PBC patients before treatment were [(626.07±103.95) U/L and (16.62±5.06 U/L), respectively], significantly higher than those of healthy controls [(164.45±35.12) U/L and (11.74±2.0) U/L, respectively; P<0.001]. Compared with the values before treatment, the contents of serum Nrf2 [(754.30±104.36) U/L] and HO-1 [(22.60±5.51)U/L] in PBC patients were increased significantly, and liver function indexes were also improved significantly after treatment (P<0.001). The increase of Nrf2 and HO-1 contents in the cured group and the marked group was particularly significant (P<0.001). The contents of serum Nrf2 (r=0.751, P=0.012) and HO-1 (r=0.621, P=0.038) before treatment were positively correlated with the treatment effect. Using pretreatment Nrf2=586.17 U/L as a threshold, the sensitivity for predicting short-term efficacy of UDCA was 84.6%, the specificity was 77.5%, and the area under the curve was 0.824 (P<0.05). Using pretreatment HO-1=14.92 U/L as a threshold, the sensitivity for predicting short-term efficacy of UDCA was 88.5%, the specificity was 75.0%, and the area under the curve was 0.861 (P<0.05).

Conclusion

Nrf2/HO-1 play an important role in the disease process of PBC patients. The baseline levels and dynamic changes of Nrf2/HO-1 in serum are related to the therapeutic effect of UDCA, which can predict the response of PBC patients to short-term treatment of UDCA.

Key words: Nuclear factor related factor 2, Heme oxygenase-1, Primary biliary cholangitis, Ursodeoxycholic acid, Oxidative stress

表1 80例原发性胆汁性胆管炎患者治疗前和熊去氧胆酸治疗后1个月各指标的比较

时间	生化指标
时间	ALT（U/L）	AST（U/L）	ALP（U/L）	GGT（U/L）	TBA（μmol/L）
治疗前	86.30±55.86	90.80±48.72	369.80±150.37	311.30±128.60	33.96±21.24
治疗后1个月	26.55±10.87	40.05±20.21	168.05±46.99	150.15±109.30	15.85±9.60
t值	3.067	3.743	4.012	3.421	4.236
P值	0.001	0.001	0.001	0.001	0.001
时间	生化指标		氧化应激指标
时间	TBIL（μmol/L）	DBIL（μmol/L）	MDA（nmol/ml）	SOD（U/ml）
治疗前	29.67±7.88	12.13±5.23	8.23±1.45	77.71±6.60
治疗后1个月	17.67±9.41	8.50±4.55	6.60±0.80	89.30±4.08
t值	3.011	1.056	3.301	3.907
P值	<0.05	>0.05	<0.05	<0.05

表1 80例原发性胆汁性胆管炎患者治疗前和熊去氧胆酸治疗后1个月各指标的比较

时间	生化指标
时间	ALT（U/L）	AST（U/L）	ALP（U/L）	GGT（U/L）	TBA（μmol/L）
治疗前	86.30±55.86	90.80±48.72	369.80±150.37	311.30±128.60	33.96±21.24
治疗后1个月	26.55±10.87	40.05±20.21	168.05±46.99	150.15±109.30	15.85±9.60
t值	3.067	3.743	4.012	3.421	4.236
P值	0.001	0.001	0.001	0.001	0.001
时间	生化指标		氧化应激指标
时间	TBIL（μmol/L）	DBIL（μmol/L）	MDA（nmol/ml）	SOD（U/ml）
治疗前	29.67±7.88	12.13±5.23	8.23±1.45	77.71±6.60
治疗后1个月	17.67±9.41	8.50±4.55	6.60±0.80	89.30±4.08
t值	3.011	1.056	3.301	3.907
P值	<0.05	>0.05	<0.05	<0.05

表2 PBC组治疗前、治疗后1个月与对照组Nrf2、HO-1的比较

组别		例数	Nrf2(U/L)	HO-1(U/L)
PBC组		?	?	?
?	治疗前	80	626.07±103.95^a	16.62±5.06^a
?	治疗后1个月	80	754.30±104.36^b	22.60±5.51^b
对照组		80	164.45±35.12	11.74±2.0
F值		?	35.061	14.152
P值		?	0.000	0.001

表2 PBC组治疗前、治疗后1个月与对照组Nrf2、HO-1的比较

组别		例数	Nrf2(U/L)	HO-1(U/L)
PBC组		?	?	?
?	治疗前	80	626.07±103.95^a	16.62±5.06^a
?	治疗后1个月	80	754.30±104.36^b	22.60±5.51^b
对照组		80	164.45±35.12	11.74±2.0
F值		?	35.061	14.152
P值		?	0.000	0.001

图1 熊去氧胆酸治疗前、治疗后1个月应答佳与应答不佳患者Nrf2（a）、HO-1（b）水平的变化

图2 血清中Nrf2、HO-1预测熊去氧胆酸短期疗效的ROC曲线

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Correlation between serum nuclear factor-related factor 2 and heme oxygenase-1 levels and short-term response to ursodeoxycholic acid in patients with primary biliary cholangitis

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Correlation between serum nuclear factor-related factor 2 and heme oxygenase-1 levels and short-term response to ursodeoxycholic acid in patients with primary biliary cholangitis