血管紧张素受体拮抗剂坎地沙坦对代偿性酒精性肝纤维化的有益作用：一项随机开放标签对照研究。

Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis - a randomized open-label controlled study.

机构信息

Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea.

出版信息

Liver Int. 2012 Jul;32(6):977-87. doi: 10.1111/j.1478-3231.2012.02774.x. Epub 2012 Feb 26.

DOI:10.1111/j.1478-3231.2012.02774.x

PMID:22364262

Abstract

BACKGROUND

Recent studies have shown that the renin-angiotensin system is implicated in hepatic fibrogenesis in vitro and in vivo. However, no study was done in humans with alcoholic liver disease.

AIM

To investigate the antifibrotic effect of angiotensin II type 1 receptor (AT1-R) blocking agents (ARB) in patients with alcoholic liver disease.

METHODS

The primary outcome was improvement in patients' histological features. Eighty-five patients with compensated alcoholic liver fibrosis (≥ F2) which was confirmed by baseline liver biopsy were randomized (intention-to-treat (ITT)) to receive either ARB, candesartan (8 mg/day) with ursodeoxycholic acid (UDCA) (600 mg/day) (n = 42) or UDCA alone (n = 43) as control for 6 months and follow-up liver biopsies were conducted.

RESULTS

According to the Laennec fibrosis system, candesartan showed significantly higher rates of histological improvements (ITT, 33.3% vs. 11.6%, P = 0.020). In addition, the fibrosis score was significantly reduced from 3.4 ± 1.4 to 3.1 ± 1.5 (P = 0.005) in the candesartan group. Candesartan also reduced the area of fibrosis and α-smooth muscle actin positive from 11.3 ± 6.0 to 8.3 ± 4.7 and 28.7 ± 10.5 to 23.9 ± 10.3 (%), and the hydroxyproline levels (μg/g liver tissue) from 7.8 ± 2.4 to 6.3 ± 1.7 respectively (P < 0.05). In addition, the relative expression of transforming growth factor-β1(TGF-β1), collagen-1, AT1-R, tissue inhibitor of metalloproteinase 1 (TIMP-1), metalloproteinases2 (MMP2), Rac1 and p22phox by real-time RT-PCR decreased in the candesartan group (P < 0.05). Mean arterial blood pressure in the candesartan group decreased mildly but significantly (P < 0.001). No significant complications and side effects were observed during the present study.

CONCLUSIONS

Administration of ARB in compensated alcoholic liver disease induces improvement of fibrosis in histological and quantitative measurements.

摘要

背景

最近的研究表明，肾素-血管紧张素系统在体外和体内的肝纤维化中起作用。然而，在患有酒精性肝病的患者中没有进行过这样的研究。

目的

研究血管紧张素 II 型 1 型受体（AT1-R）阻断剂（ARB）在酒精性肝病患者中的抗纤维化作用。

方法

主要结局是改善患者的组织学特征。85 例经基线肝活检证实为代偿性酒精性肝纤维化（≥F2）的患者随机（意向治疗（ITT））接受 ARB 坎地沙坦（8 毫克/天）联合熊去氧胆酸（UDCA）（600 毫克/天）（n=42）或 UDCA 单独治疗（n=43），疗程为 6 个月，并进行随访肝活检。

结果

根据 Laennec 纤维化系统，坎地沙坦的组织学改善率显著更高（ITT，33.3%比 11.6%，P=0.020）。此外，坎地沙坦组的纤维化评分从 3.4±1.4 显著降低至 3.1±1.5（P=0.005）。坎地沙坦还降低了纤维化面积和α-平滑肌肌动蛋白阳性面积，分别从 11.3±6.0 至 8.3±4.7 和 28.7±10.5 至 23.9±10.3（%），羟脯氨酸水平（μg/g 肝组织）从 7.8±2.4 至 6.3±1.7（P<0.05）。此外，坎地沙坦组实时 RT-PCR 检测的转化生长因子-β1（TGF-β1）、胶原-1、AT1-R、金属蛋白酶组织抑制剂 1（TIMP-1）、基质金属蛋白酶 2（MMP2）、Rac1 和 p22phox 的相对表达均降低（P<0.05）。坎地沙坦组平均动脉压轻度但显著下降（P<0.001）。在本研究期间，未观察到明显的并发症和副作用。