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

Moonyoung Kim, Meeyon Cho, Soonkoo Baik, Phil Ho Jeong, Ki Tae Suk, Yoon Ok Jang, Chang Jin Yea, Jae Woo Kim, Hyunsoo Kim, Sang Ok Kwon, Byungsu Yoo, Jang Young Kim, Min Seob Eom, Seung Hwan Cha, Sei Jin Chang

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)977-987
Number of pages11
JournalLiver International
Volume32
Issue number6
DOIs
Publication statusPublished - 2012 Jul 1

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Angiotensins
Liver Cirrhosis
Alcoholic Liver Diseases
Fibrosis
Ursodeoxycholic Acid
Angiotensin Type 1 Receptor
Liver
Arterial Pressure
Biopsy
Tissue Inhibitor of Metalloproteinase-1
Hydroxyproline
Transforming Growth Factors
Proxy
Renin-Angiotensin System
Smooth Muscle
candesartan
Actins
Real-Time Polymerase Chain Reaction
Collagen

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Kim, Moonyoung ; Cho, Meeyon ; Baik, Soonkoo ; Jeong, Phil Ho ; Suk, Ki Tae ; Jang, Yoon Ok ; Yea, Chang Jin ; Kim, Jae Woo ; Kim, Hyunsoo ; Kwon, Sang Ok ; Yoo, Byungsu ; Kim, Jang Young ; Eom, Min Seob ; Cha, Seung Hwan ; Chang, Sei Jin. / Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis - A randomized open-label controlled study. In: Liver International. 2012 ; Vol. 32, No. 6. pp. 977-987.
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title = "Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis - A randomized open-label controlled study",
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.",
author = "Moonyoung Kim and Meeyon Cho and Soonkoo Baik and Jeong, {Phil Ho} and Suk, {Ki Tae} and Jang, {Yoon Ok} and Yea, {Chang Jin} and Kim, {Jae Woo} and Hyunsoo Kim and Kwon, {Sang Ok} and Byungsu Yoo and Kim, {Jang Young} and Eom, {Min Seob} and Cha, {Seung Hwan} and Chang, {Sei Jin}",
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Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis - A randomized open-label controlled study. / Kim, Moonyoung; Cho, Meeyon; Baik, Soonkoo; Jeong, Phil Ho; Suk, Ki Tae; Jang, Yoon Ok; Yea, Chang Jin; Kim, Jae Woo; Kim, Hyunsoo; Kwon, Sang Ok; Yoo, Byungsu; Kim, Jang Young; Eom, Min Seob; Cha, Seung Hwan; Chang, Sei Jin.

In: Liver International, Vol. 32, No. 6, 01.07.2012, p. 977-987.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis - A randomized open-label controlled study

AU - Kim, Moonyoung

AU - Cho, Meeyon

AU - Baik, Soonkoo

AU - Jeong, Phil Ho

AU - Suk, Ki Tae

AU - Jang, Yoon Ok

AU - Yea, Chang Jin

AU - Kim, Jae Woo

AU - Kim, Hyunsoo

AU - Kwon, Sang Ok

AU - Yoo, Byungsu

AU - Kim, Jang Young

AU - Eom, Min Seob

AU - Cha, Seung Hwan

AU - Chang, Sei Jin

PY - 2012/7/1

Y1 - 2012/7/1

N2 - 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.

AB - 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.

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