- Email: [email protected]
130 CONSTRUCTION OF A RISK INDEX FOR HEPATOCELLULAR CARCINOMA IN CHRONIC HEPATITIS C PATIENTS
Parallel Session 16: PATHOGENESIS OF STEATOHEPATITIS Results: The study population included 3,752 and 2,074 patients with chronic and cleared HCV-infection, respectively. The estimated 5-year probabilities of survival were 0.84 (95% CI: 0.83−0.86) in the chronic HCV group and 0.88 (95% CI: 0.87−0.90) in the cleared HCV group. During 26,573 person-years of observation (PYR), 822 persons died (mortality rate = 30.9/1,000 PYR, 95% CI: 28.9−33.1). Chronic HCV-infection was a predictor of increased mortality (adjusted MRR 1.37, 95% CI 1.10−1.71) and liver-related mortality (adjusted MRR 2.23, 95% CI 1.34−3.72) after excluding the initial two years of observation representing lead in mortality. Conclusions: Chronic compared to cleared HCV-infection was associated with increased overall and liver-related mortality. Overall mortality in HCV infected patients Time from HCV-RNA test
HCV infection
Deaths
Person years of observation
MR (95% CI)
Crude MRR (95% CI)
Adjusted MRR (95% CI)
Overall
Cleared
246
9662
1
N.A.
Chronic
576
16910
135
3756
1.34 (1.15−1.55) 1
N.A.
Cleared Chronic
287
6740
111
5907
1.18 (0.97−1.45) 1
1.05 (0.85−1.29)
Cleared Chronic
289
10171
25.5 (22.5−28.8) 34.1 (31.4−37.0) 35.9 (30.4−42.6) 42.6 (37.9−47.8) 18.8 (15.6−22.6) 28.4 (25.3−31.9)
1.51 (1.21−1.88)
1.37 (1.10−1.71)
0−2 years
2−10 years
applied cross-validation methods splitting the patients into two groups: training set and testing set. First we constructed 6 models in the training set, from the simplest to the most complicated, including some or all of the following factors: age, sex body mass index, history of diabetes, ALT, ALP, GGT, total bilirubin, platelet count and alpha-fetoprotein (AFP) by logistic regression using HCC development as the only event. Then we validated the models in the test set by receiver operating characteristics (ROC) curve. Results: During the follow-up period until the end of year 2007, HCC was diagnosed in 397 patients. Among 6 models evaluated, a model including age, sex, ALT, platelet count and AFP was selected that provided area under ROC curve of 0.857 (95% confidence interval, 0.828−0.882) not significantly inferior to more complicated models. Scores are assigned to each of the 5 factors according to the estimated regression coefficient in the model (Table). The risk of HCC development in 10 years in patients with 0−9, 10−15, 16−20 and 21−27 points was estimated to be 0.3%, 20.2%, 46.5% and 72.1%, respectively according to the index. Conclusion: We constructed a simple comprehensive index for the assessment of HCC development of CH-C patients useful for daily practice.
1
1
S53
Points 0 Age (yo) Gender PLT (×103 /mL) ALT (× ULN) AFP (ng/mL)
1
2
3
4
5
6
8
10
30 31−40 41−50 51−60 61−70 >70 Female Male >200 151–200 101–150 100 1 1.1−2 2.1−3 20 20.1–200 >200
Liver related mortality in HCV infected patients Time from HCV-RNA test
HCV infection
Deaths
Person years of observation
MR (95% CI)
Crude MRR (95% CI)
Adjusted MRR (95% CI)
Overall
Cleared
54
9662
1
N.A.
Chronic
162
16910
35
3756
1.71 (1.26−2.33) 1
N.A.
Cleared Chronic
84
6740
19
5907
1.34 (0.90−1.98) 1
1.11 (0.74−1.68)
Cleared Chronic
78
10171
5.6 (4.3−7.3) 9.6 (8.2−11.2) 9.3 (6.7−13.0) 12.5 (10.1−15.4) 3.2 (2.1−5.0) 7.7 (6.1−9.6)
2.38 (1.44−3.94)
2.23 (1.34−3.72)
0−2 years
2−10 years
1
1
130 CONSTRUCTION OF A RISK INDEX FOR HEPATOCELLULAR CARCINOMA IN CHRONIC HEPATITIS C PATIENTS R. Tateishi1 , Haruhiko Yoshida1 , S. Shiina1 , Y. Matsuyama2 , Hideo Yoshida1 , R. Masuzaki1 , T. Sato1 , E. Goto1 , J. Imamura1 , Y. Kondo1 , T. Goto1 , F. Kanai3 , N. Kato1 , M. Omata1 . 1 Department of Gastroenterology, The University of Tokyo Graduate School of Medicine, 2 Department of Biostatistics, The University of Tokyo Graduate School of Medicine, Tokyo, 3 Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, Chiba, Japan E-mail: [email protected] Background and Aim: In the assessment of risk for hepatocellular carcinoma (HCC) development in chronic hepatitis C (CH-C) patients, various factors should be considered such as grade of liver fibrosis and inflammation, sex, and age. We intended to construct a risk index for HCC in CH-C patients in this study. Methods: We enrolled 1459 patients with CH-C who visited our department between 1994 and 2004 excluding those who had HCC or a history of it, coinfection with hepatitis B virus, or decompensated diseases. We
Parallel Session 16: PATHOGENESIS OF STEATOHEPATITIS
131 A STUDY ON A RABBIT MODEL OF STEATOHEPATITIS WITH ADVANCED FIBROSIS N. Kawada, T. Ogawa, R. Shiga. Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan E-mail: [email protected] Background and Aims: To produce an animal model pathologically similar to human steatohepatitis with advanced fibrosis and to study the effect of ezetimibe, an inhibitor of Niemann-Pick C1-Like 1 (NPC1L1) protein, on the development of inflammation and fibrosis of this model. Methods: Japanese white rabbits were fed 0.75% cholesterol diet including 12% corn oil for 9 months. After the sacrifice, the rabbit livers and serums were obtained and used for chemical and histological evaluations. The remaining liver tissues were utilized for evaluating mRNA or protein expressions of IL-1, IL-10, TNF-alpha, TGF-beta, collagen 1A1, TIMPs, and MMPs by real-time PCR. Oxidative stress was evaluated by the level of lipid peroxide and 4-hydroxynonenal. Poteomics and cDNA microarrays were performed for the comprehensive analyses of molecules involved in this model. In another experimental setting, we tested the effect of ezetimibe (1.8 mg/body/day). Results: The livers looked whitish and the surface exhibited irregularity. Steatosis of hepatocytes was evident. Stainings showed that inflammatory cells including RAM-11-positive macrophages accumulated in the sinusoids and the formation of fibrotic septum composed of collagens and SMA-positive activated stellate cells crossed over central and portal veins, indicating the reconstruction of parenchyma. Triglyceride, lipid peroxide, and total cholesterol in sera of model rabbits were increased 1.9-, 38-, and 1,277-fold, respectively, compared to the control. Realtime PCR revealed the increase of mRNA levels of IL-1 (2.6-fold), IL-10 (9-fold), TNF-alpha (6-fold), TGF-beta (4-fold), collagen 1A1 (35-fold),
HCV infection
Deaths
Person years of observation
MR (95% CI)
Crude MRR (95% CI)
Adjusted MRR (95% CI)
Overall
Cleared
246
9662
1
N.A.
Chronic
576
16910
135
3756
1.34 (1.15−1.55) 1
N.A.
Cleared Chronic
287
6740
111
5907
1.18 (0.97−1.45) 1
1.05 (0.85−1.29)
Cleared Chronic
289
10171
25.5 (22.5−28.8) 34.1 (31.4−37.0) 35.9 (30.4−42.6) 42.6 (37.9−47.8) 18.8 (15.6−22.6) 28.4 (25.3−31.9)
1.51 (1.21−1.88)
1.37 (1.10−1.71)
0−2 years
2−10 years
applied cross-validation methods splitting the patients into two groups: training set and testing set. First we constructed 6 models in the training set, from the simplest to the most complicated, including some or all of the following factors: age, sex body mass index, history of diabetes, ALT, ALP, GGT, total bilirubin, platelet count and alpha-fetoprotein (AFP) by logistic regression using HCC development as the only event. Then we validated the models in the test set by receiver operating characteristics (ROC) curve. Results: During the follow-up period until the end of year 2007, HCC was diagnosed in 397 patients. Among 6 models evaluated, a model including age, sex, ALT, platelet count and AFP was selected that provided area under ROC curve of 0.857 (95% confidence interval, 0.828−0.882) not significantly inferior to more complicated models. Scores are assigned to each of the 5 factors according to the estimated regression coefficient in the model (Table). The risk of HCC development in 10 years in patients with 0−9, 10−15, 16−20 and 21−27 points was estimated to be 0.3%, 20.2%, 46.5% and 72.1%, respectively according to the index. Conclusion: We constructed a simple comprehensive index for the assessment of HCC development of CH-C patients useful for daily practice.
1
1
S53
Points 0 Age (yo) Gender PLT (×103 /mL) ALT (× ULN) AFP (ng/mL)
1
2
3
4
5
6
8
10
30 31−40 41−50 51−60 61−70 >70 Female Male >200 151–200 101–150 100 1 1.1−2 2.1−3 20 20.1–200 >200
Liver related mortality in HCV infected patients Time from HCV-RNA test
HCV infection
Deaths
Person years of observation
MR (95% CI)
Crude MRR (95% CI)
Adjusted MRR (95% CI)
Overall
Cleared
54
9662
1
N.A.
Chronic
162
16910
35
3756
1.71 (1.26−2.33) 1
N.A.
Cleared Chronic
84
6740
19
5907
1.34 (0.90−1.98) 1
1.11 (0.74−1.68)
Cleared Chronic
78
10171
5.6 (4.3−7.3) 9.6 (8.2−11.2) 9.3 (6.7−13.0) 12.5 (10.1−15.4) 3.2 (2.1−5.0) 7.7 (6.1−9.6)
2.38 (1.44−3.94)
2.23 (1.34−3.72)
0−2 years
2−10 years
1
1
130 CONSTRUCTION OF A RISK INDEX FOR HEPATOCELLULAR CARCINOMA IN CHRONIC HEPATITIS C PATIENTS R. Tateishi1 , Haruhiko Yoshida1 , S. Shiina1 , Y. Matsuyama2 , Hideo Yoshida1 , R. Masuzaki1 , T. Sato1 , E. Goto1 , J. Imamura1 , Y. Kondo1 , T. Goto1 , F. Kanai3 , N. Kato1 , M. Omata1 . 1 Department of Gastroenterology, The University of Tokyo Graduate School of Medicine, 2 Department of Biostatistics, The University of Tokyo Graduate School of Medicine, Tokyo, 3 Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, Chiba, Japan E-mail: [email protected] Background and Aim: In the assessment of risk for hepatocellular carcinoma (HCC) development in chronic hepatitis C (CH-C) patients, various factors should be considered such as grade of liver fibrosis and inflammation, sex, and age. We intended to construct a risk index for HCC in CH-C patients in this study. Methods: We enrolled 1459 patients with CH-C who visited our department between 1994 and 2004 excluding those who had HCC or a history of it, coinfection with hepatitis B virus, or decompensated diseases. We
Parallel Session 16: PATHOGENESIS OF STEATOHEPATITIS
131 A STUDY ON A RABBIT MODEL OF STEATOHEPATITIS WITH ADVANCED FIBROSIS N. Kawada, T. Ogawa, R. Shiga. Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan E-mail: [email protected] Background and Aims: To produce an animal model pathologically similar to human steatohepatitis with advanced fibrosis and to study the effect of ezetimibe, an inhibitor of Niemann-Pick C1-Like 1 (NPC1L1) protein, on the development of inflammation and fibrosis of this model. Methods: Japanese white rabbits were fed 0.75% cholesterol diet including 12% corn oil for 9 months. After the sacrifice, the rabbit livers and serums were obtained and used for chemical and histological evaluations. The remaining liver tissues were utilized for evaluating mRNA or protein expressions of IL-1, IL-10, TNF-alpha, TGF-beta, collagen 1A1, TIMPs, and MMPs by real-time PCR. Oxidative stress was evaluated by the level of lipid peroxide and 4-hydroxynonenal. Poteomics and cDNA microarrays were performed for the comprehensive analyses of molecules involved in this model. In another experimental setting, we tested the effect of ezetimibe (1.8 mg/body/day). Results: The livers looked whitish and the surface exhibited irregularity. Steatosis of hepatocytes was evident. Stainings showed that inflammatory cells including RAM-11-positive macrophages accumulated in the sinusoids and the formation of fibrotic septum composed of collagens and SMA-positive activated stellate cells crossed over central and portal veins, indicating the reconstruction of parenchyma. Triglyceride, lipid peroxide, and total cholesterol in sera of model rabbits were increased 1.9-, 38-, and 1,277-fold, respectively, compared to the control. Realtime PCR revealed the increase of mRNA levels of IL-1 (2.6-fold), IL-10 (9-fold), TNF-alpha (6-fold), TGF-beta (4-fold), collagen 1A1 (35-fold),