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Mo1011 Response to Vitamin E for Non-Alcoholic Steatohepatitis (NASH): What Is the Mechanism?
were significantly lower in the patient group (4,443 [1,035-1.079] mcg/ml vs. 5.934 [3,26611,757] mcg/ml, p=0.006). Mean serum TWEAK level was also lower in subjects with fibrosis than in patients without fibrosis (p ,0.05). Logistic regression analysis revealed that TWEAK was an independent predictor in patients with NAFLD. Conclusion: Increased serum TWEAK concentration was significantly and independently associated with the development of NAFLD. TWEAK appeared to be robustly and negatively associated with fibrosis.
factors for fatty liver were the followings: obesity (odds ratio [OR], 7.03; 95% confidence interval [CI], 2.51-20.53) and dyslipidemia (OR, 5.42; 95% CI, 2.15-14.22) in the category of drinking , 20 g/day, obesity (OR, 4.81; 95% CI, 3.22-7.20), dyslipidemia (OR, 2.07; 95% CI, 1.38-3.08), and hyperuricemia (OR, 1.80; 95% CI, 1.14-2.81) in the category of drinking 20-40 g/day, and obesity (OR, 5.15; 95% CI, 3.32-8.05) and dyslipidemia (OR, 1.70; 95% CI, 1.12-2.59) in the category of drinking 40-60 g/day. Among cases without obesity or dyslipidemia, the prevalence of fatty liver in nondrinkers and in each drinking category was 15.9%, 9.0%, 11.3%, and 17.1%, respectively. Increase in amount of alcohol consumed was directly correlated to the prevalence of fatty liver among drinkers (P for trend = 0.016). Conclusions: Risk factors for NAFLD in nondrinkers or light drinkers and those for fatty liver in moderate drinkers are similar to each other. Increase in the amount of alcohol consumed seemed to attenuate the protective effect of alcohol consumption on fatty liver in daily drinking men.
Mo1009
AASLD Abstracts
Magnetic Resonance Elastography Accurately Predicts Advanced Fibrosis in NAFLD: A Pilot Study With Paired-Liver Biopsy Rohit Loomba, Jessica Lam, Tanya Wolfson, Brandon Ang, Archana Bhatt, Michael R. Peterson, David A. Brenner, Claude Sirlin Introduction: Magnetic resonance elastography (MRE) is a novel MR method to measure liver stiffness and has been shown to correlate with hepatic fibrosis in patients with chronic liver disease. There are limited data on MRE and fibrosis in a well-characterized cohort of patients with biopsy-proven NAFLD. Aim: The aim of this pilot study is to conduct a prospective assessment of diagnostic accuracy of MRE in predicting advanced fibrosis in patients with biopsy-proven NAFLD. Methods: This a prospective study including 52 consecutive patients (48% W) with biopsy-proven NAFLD who underwent a research visit: history, exam, liver biopsy and MRE from 2009-2012. Receiver operating curve (ROC) were examined to assess the diagnostic test characteristics of MRE in predicting advanced fibrosis (stage 3 and 4). The radiologist and pathologist were blinded to clinical and pathology/imaging data, respectively. NASH-CRN histologic scoring system was used to score the biopsy. We also tested whether MRI-fat fraction had any effect on the association between MRE and NAFLD fibrosis. Results: The mean (±sd) of age and BMI was 49.6 (± 13.1) yrs and 31.6 (± 4.5) Kg/m2, respectively. The median difference between biopsy and MRE was 2.6 months (IQR 1.3). The number of pts in stage 0, 1, 2, 3, and 4 were 22, 19, 5, 3 and 3 (figure) The AUROC for MRE discriminating advanced fibrosis from stage 0-2 fibrosis was 0.96 (p-value ,0.0001). A stiffness threshold of . 3.2 Kpa (figure) had raw sensitivity 1 (95% CI, 0.541), specificity 0.83 (95% CI, 0.69-0.92), PPV 0.43 (95% CI,0.18-0.71) and NPV 1.0 (95% CI, . 91-1). 8 of 46 (17%) patients with stage 0-2 fibrosis were misclassified but all the patients with advanced fibrosis were accurately classified. MRI-fat fraction had no additional effect on predicting advanced fibrosis. Limitations: This pilot study needs to be validated in a larger cohort of patients with biopsy-proven NAFLD given the wide confidence intervals. Conclusions: In this pilot study, MRE was highly sensitive in predicting stage 3 and 4 fibrosis in NAFLD. Pending confirmation in a larger cohort, MRE may be utilized to non-invasively diagnose advanced fibrosis in patients with NAFLD.
Mo1011 Response to Vitamin E for Non-Alcoholic Steatohepatitis (NASH): What Is the Mechanism? Jianfeng Cheng, Andrew Joyce, Katherine P. Yates, Arun J. Sanyal Background: The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (NASH)) trial demonstrated that Vitamin E improved NASH in 43% of the treated subjects. The mechanisms for the histological improvement are unknown. Elucidation of this mechanism will aid in understanding why only some subjects respond to vitamin E. Aim: To identify the key pathogenic target genes that are up- or down-regulated by vitamin E to improve NASH. Methods: Available excess liver tissues from baseline and end of treatment biopsies were analyzed from two sets of subjects enrolled in the PIVENS trial: (1) vitamin E responders (n=12), (2) vitamin E nonresponders (n=12). Among them, 8 subjects had paired baseline and post treatment tissue (3 vitamin E responders and 5 vitamin E non-responders). Response was defined as meeting the primary histological end-point of the trial. Pathway focused real time polymerase chain reaction (RT-PCR) arrays were used to investigate expression changes in oxidative stress and antioxidant defense and fatty acid metabolism genes. Analysis of covariance (ANCOVA) was used to identify significant differential expression between groups using p , 0.05 cutoff. Results: The two groups were comparable in terms of demographics, clinical profile and baseline histology. Analysis of the limited set of subjects with paired data samples revealed that GPX5 (glutathione peroxidase 5) expression was significantly down-regulated in vitamin E responders relative to vitamin E non-responders (Fold change (FC) =0.04, p=0.01). Analysis of post treatment data (8 vitamin E responders, 6 vitamin E non-responders), identified 7 genes from oxidative stress and antioxidant defense pathway with significant differential expression. DGKK, DUOX2, GPX6, LPO, NOS2, PRG3, and TPO were all significantly down-regulated in vitamin E responders relative to vitamin E non-responders. Neither set of analyses revealed significant changes in the fatty acid metabolism genes that were investigated. Conclusions: Down regulation of a select number of oxidative stress and antioxidant defense genes is associated with histologic improvement following vitamin E treatment for NASH in PIVENS subjects. Interestingly, none of the investigated fatty acid metabolism genes appear to be associated with histologic improvement. These findings are consistent with previously conducted metabolomics profiles analysis with both analyses suggesting that histologic improvement is related to decreased glutathione turnover and oxidative stress. Mo1012 Genetic Polymorphism of Cytochrome P450 4f2 (CYP4F2) and Histological Response to Vitamin E Treatment in Children and Adults With Nonalcoholic Fatty Liver Disease (NAFLD) Shaminie J. Athinarayanan, Rongrong Wei, Shaochun Bai, Maret G. Traber, Katherine P. Yates, Oscar W. Cummings, Jean P. Molleston, Naga P. Chalasani, Wanqing Liu
A threshold line at 3.2 K pa provides the best descrimination for advanced fibrosis in NAFLD Mo1010 Risk Factors for Fatty Liver in Japanese Men With Light to Moderate Alcohol Consumption Akio Moriya, Yoshiaki Iwasaki, Souhei Ohguchi, Eizo Kayashima, Tadahiko Mitsumune, Hideaki Taniguchi, Fusao Ikeda, Masaharu Ando, Kazuhide Yamamoto Background: Fatty liver in nondrinkers or minimal drinkers is regarded as nonalcoholic fatty liver disease (NAFLD) and that in heavy drinkers as alcoholic fatty liver. However, the characteristics of fatty liver at the border between them remain controversial. Meanwhile, epidemiological studies have suggested that alcohol consumption possibly protect against fatty liver; we have also demonstrated an outstanding decreased risk of fatty liver in daily drinking men with light to moderate alcohol consumption. We aimed to determine the risk factors for fatty liver in light to moderate drinking men. Methods: We obtained the clinical and laboratory data from Japanese men who underwent systematic health checkups. We excluded individuals with concurrent liver disease and those with any missing components of data, then included those who reported , 60 g/day of alcohol consumption on a daily basis (n = 1357) and non drinking men (n = 1104). We stratified drinkers into 3 categories (, 20 g/day, 20-40 g/day, and 40-60 g/day) and compared the prevalence of fatty liver assessed by ultrasonography with that of nondrinkers. We performed logistic regression analysis to evaluate the influence of following factors on the presence of fatty liver: obesity (body mass index ≥ 25 kg/m2), dyslipidemia, hypertension, glucose intolerance, hyperuricemia, smoking, and habitual exercise. Results: The prevalence of fatty liver in each drinking category was 21.1% (, 20 g/day), 23.3% (20-40 g/day), and 29.2% (40-60 g/day) and was significantly lower than that in nondrinkers (37%; P , 0.001, P , 0.001, and P = 0.002, respectively). In the analyses stratified by amount of alcohol consumed, significant risk
AASLD Abstracts
S-1012
Background: Alpha-tocopherol (Vit E) treatment improved liver histology in children and adults with NAFLD who participated in TONIC and PIVENS clinical trials, but there was significant inter-individual variability in the response to Vit E in these two trials. Cytochrome P450 4F2 (CYP4F2) is the major enzyme that metabolizes Vit E into polar metabolites which are subsequently excreted in urine. Two common variants in the CYP4F2 gene (V433M and W12G) are known to exist and it is possible that such variants may explain the variability in the response to Vit E among individuals participating in NAFLD trials. Aim: To test the hypothesis that CYP4F2 genetic polymorphism is associated with histological response to Vit E among adults and children who participated in PIVENS and TONIC clinical trials. Additionally, we examined the relationship between CYP4F2 genotype and baseline alphatocopherol levels. Methods: CYP4F2 V433M and W12G variants were genotyped in TONIC (n=155) and PIVENS (n=212) DNA samples. Histological end points of interest were (a) overall improvement in liver histology defined as ≥ 2 point improvement in NAFLD activity score with no worsening of fibrosis and (b) resolution of NASH. Analyses were conducted on those who received Vit E and the entire study population for both trials separately. Additionally we examined the relationship between CYP4F2 genotype and baseline alphatocopherol. Results: Among all genotyped samples, the frequency of V433M and W12G alleles was 0.25 and 0.14 respectively. Baseline alpha-tocopherol after adjusting for serum cholesterol among PIVENS and TONIC participants was 0.062 (0.03-0.125) and 0.046 (0.021-0.152), respectively. There was no significant relationship between CYP4F2 genotype (either V433M or W12G) and the histological response to Vit E either in children who received Vit E in the TONIC trial or in adults who received Vit E in the PIVENS trial. Similarly, CYP4F2 genotype was not associated with overall improvement in liver histology or resolution of NASH irrespective of treatment assignment either in adult PIVENS or pediatric TONIC participants. Baseline serum alpha-tocopherol levels were not different among adults in the PIVENS trial with different V433M or W12G genotypes. However, interestingly, children in the TONIC trial with CYP4F2 MM genotype had significantly higher baseline alpha-tocopherol levels compared to either VM or VV genotype (0.074 ± 0.043 vs. 0.051 ± 0.014 or 0.049 ± 0.016, p=0.0002), but W12G genotype had no relationship with baseline alpha-tocopherol levels in the TONIC trial. Conclusion: CYP4F2 genetic polymorphism had no significant impact on the response to Vit E in adults and children
factors for fatty liver were the followings: obesity (odds ratio [OR], 7.03; 95% confidence interval [CI], 2.51-20.53) and dyslipidemia (OR, 5.42; 95% CI, 2.15-14.22) in the category of drinking , 20 g/day, obesity (OR, 4.81; 95% CI, 3.22-7.20), dyslipidemia (OR, 2.07; 95% CI, 1.38-3.08), and hyperuricemia (OR, 1.80; 95% CI, 1.14-2.81) in the category of drinking 20-40 g/day, and obesity (OR, 5.15; 95% CI, 3.32-8.05) and dyslipidemia (OR, 1.70; 95% CI, 1.12-2.59) in the category of drinking 40-60 g/day. Among cases without obesity or dyslipidemia, the prevalence of fatty liver in nondrinkers and in each drinking category was 15.9%, 9.0%, 11.3%, and 17.1%, respectively. Increase in amount of alcohol consumed was directly correlated to the prevalence of fatty liver among drinkers (P for trend = 0.016). Conclusions: Risk factors for NAFLD in nondrinkers or light drinkers and those for fatty liver in moderate drinkers are similar to each other. Increase in the amount of alcohol consumed seemed to attenuate the protective effect of alcohol consumption on fatty liver in daily drinking men.
Mo1009
AASLD Abstracts
Magnetic Resonance Elastography Accurately Predicts Advanced Fibrosis in NAFLD: A Pilot Study With Paired-Liver Biopsy Rohit Loomba, Jessica Lam, Tanya Wolfson, Brandon Ang, Archana Bhatt, Michael R. Peterson, David A. Brenner, Claude Sirlin Introduction: Magnetic resonance elastography (MRE) is a novel MR method to measure liver stiffness and has been shown to correlate with hepatic fibrosis in patients with chronic liver disease. There are limited data on MRE and fibrosis in a well-characterized cohort of patients with biopsy-proven NAFLD. Aim: The aim of this pilot study is to conduct a prospective assessment of diagnostic accuracy of MRE in predicting advanced fibrosis in patients with biopsy-proven NAFLD. Methods: This a prospective study including 52 consecutive patients (48% W) with biopsy-proven NAFLD who underwent a research visit: history, exam, liver biopsy and MRE from 2009-2012. Receiver operating curve (ROC) were examined to assess the diagnostic test characteristics of MRE in predicting advanced fibrosis (stage 3 and 4). The radiologist and pathologist were blinded to clinical and pathology/imaging data, respectively. NASH-CRN histologic scoring system was used to score the biopsy. We also tested whether MRI-fat fraction had any effect on the association between MRE and NAFLD fibrosis. Results: The mean (±sd) of age and BMI was 49.6 (± 13.1) yrs and 31.6 (± 4.5) Kg/m2, respectively. The median difference between biopsy and MRE was 2.6 months (IQR 1.3). The number of pts in stage 0, 1, 2, 3, and 4 were 22, 19, 5, 3 and 3 (figure) The AUROC for MRE discriminating advanced fibrosis from stage 0-2 fibrosis was 0.96 (p-value ,0.0001). A stiffness threshold of . 3.2 Kpa (figure) had raw sensitivity 1 (95% CI, 0.541), specificity 0.83 (95% CI, 0.69-0.92), PPV 0.43 (95% CI,0.18-0.71) and NPV 1.0 (95% CI, . 91-1). 8 of 46 (17%) patients with stage 0-2 fibrosis were misclassified but all the patients with advanced fibrosis were accurately classified. MRI-fat fraction had no additional effect on predicting advanced fibrosis. Limitations: This pilot study needs to be validated in a larger cohort of patients with biopsy-proven NAFLD given the wide confidence intervals. Conclusions: In this pilot study, MRE was highly sensitive in predicting stage 3 and 4 fibrosis in NAFLD. Pending confirmation in a larger cohort, MRE may be utilized to non-invasively diagnose advanced fibrosis in patients with NAFLD.
Mo1011 Response to Vitamin E for Non-Alcoholic Steatohepatitis (NASH): What Is the Mechanism? Jianfeng Cheng, Andrew Joyce, Katherine P. Yates, Arun J. Sanyal Background: The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (NASH)) trial demonstrated that Vitamin E improved NASH in 43% of the treated subjects. The mechanisms for the histological improvement are unknown. Elucidation of this mechanism will aid in understanding why only some subjects respond to vitamin E. Aim: To identify the key pathogenic target genes that are up- or down-regulated by vitamin E to improve NASH. Methods: Available excess liver tissues from baseline and end of treatment biopsies were analyzed from two sets of subjects enrolled in the PIVENS trial: (1) vitamin E responders (n=12), (2) vitamin E nonresponders (n=12). Among them, 8 subjects had paired baseline and post treatment tissue (3 vitamin E responders and 5 vitamin E non-responders). Response was defined as meeting the primary histological end-point of the trial. Pathway focused real time polymerase chain reaction (RT-PCR) arrays were used to investigate expression changes in oxidative stress and antioxidant defense and fatty acid metabolism genes. Analysis of covariance (ANCOVA) was used to identify significant differential expression between groups using p , 0.05 cutoff. Results: The two groups were comparable in terms of demographics, clinical profile and baseline histology. Analysis of the limited set of subjects with paired data samples revealed that GPX5 (glutathione peroxidase 5) expression was significantly down-regulated in vitamin E responders relative to vitamin E non-responders (Fold change (FC) =0.04, p=0.01). Analysis of post treatment data (8 vitamin E responders, 6 vitamin E non-responders), identified 7 genes from oxidative stress and antioxidant defense pathway with significant differential expression. DGKK, DUOX2, GPX6, LPO, NOS2, PRG3, and TPO were all significantly down-regulated in vitamin E responders relative to vitamin E non-responders. Neither set of analyses revealed significant changes in the fatty acid metabolism genes that were investigated. Conclusions: Down regulation of a select number of oxidative stress and antioxidant defense genes is associated with histologic improvement following vitamin E treatment for NASH in PIVENS subjects. Interestingly, none of the investigated fatty acid metabolism genes appear to be associated with histologic improvement. These findings are consistent with previously conducted metabolomics profiles analysis with both analyses suggesting that histologic improvement is related to decreased glutathione turnover and oxidative stress. Mo1012 Genetic Polymorphism of Cytochrome P450 4f2 (CYP4F2) and Histological Response to Vitamin E Treatment in Children and Adults With Nonalcoholic Fatty Liver Disease (NAFLD) Shaminie J. Athinarayanan, Rongrong Wei, Shaochun Bai, Maret G. Traber, Katherine P. Yates, Oscar W. Cummings, Jean P. Molleston, Naga P. Chalasani, Wanqing Liu
A threshold line at 3.2 K pa provides the best descrimination for advanced fibrosis in NAFLD Mo1010 Risk Factors for Fatty Liver in Japanese Men With Light to Moderate Alcohol Consumption Akio Moriya, Yoshiaki Iwasaki, Souhei Ohguchi, Eizo Kayashima, Tadahiko Mitsumune, Hideaki Taniguchi, Fusao Ikeda, Masaharu Ando, Kazuhide Yamamoto Background: Fatty liver in nondrinkers or minimal drinkers is regarded as nonalcoholic fatty liver disease (NAFLD) and that in heavy drinkers as alcoholic fatty liver. However, the characteristics of fatty liver at the border between them remain controversial. Meanwhile, epidemiological studies have suggested that alcohol consumption possibly protect against fatty liver; we have also demonstrated an outstanding decreased risk of fatty liver in daily drinking men with light to moderate alcohol consumption. We aimed to determine the risk factors for fatty liver in light to moderate drinking men. Methods: We obtained the clinical and laboratory data from Japanese men who underwent systematic health checkups. We excluded individuals with concurrent liver disease and those with any missing components of data, then included those who reported , 60 g/day of alcohol consumption on a daily basis (n = 1357) and non drinking men (n = 1104). We stratified drinkers into 3 categories (, 20 g/day, 20-40 g/day, and 40-60 g/day) and compared the prevalence of fatty liver assessed by ultrasonography with that of nondrinkers. We performed logistic regression analysis to evaluate the influence of following factors on the presence of fatty liver: obesity (body mass index ≥ 25 kg/m2), dyslipidemia, hypertension, glucose intolerance, hyperuricemia, smoking, and habitual exercise. Results: The prevalence of fatty liver in each drinking category was 21.1% (, 20 g/day), 23.3% (20-40 g/day), and 29.2% (40-60 g/day) and was significantly lower than that in nondrinkers (37%; P , 0.001, P , 0.001, and P = 0.002, respectively). In the analyses stratified by amount of alcohol consumed, significant risk
AASLD Abstracts
S-1012
Background: Alpha-tocopherol (Vit E) treatment improved liver histology in children and adults with NAFLD who participated in TONIC and PIVENS clinical trials, but there was significant inter-individual variability in the response to Vit E in these two trials. Cytochrome P450 4F2 (CYP4F2) is the major enzyme that metabolizes Vit E into polar metabolites which are subsequently excreted in urine. Two common variants in the CYP4F2 gene (V433M and W12G) are known to exist and it is possible that such variants may explain the variability in the response to Vit E among individuals participating in NAFLD trials. Aim: To test the hypothesis that CYP4F2 genetic polymorphism is associated with histological response to Vit E among adults and children who participated in PIVENS and TONIC clinical trials. Additionally, we examined the relationship between CYP4F2 genotype and baseline alphatocopherol levels. Methods: CYP4F2 V433M and W12G variants were genotyped in TONIC (n=155) and PIVENS (n=212) DNA samples. Histological end points of interest were (a) overall improvement in liver histology defined as ≥ 2 point improvement in NAFLD activity score with no worsening of fibrosis and (b) resolution of NASH. Analyses were conducted on those who received Vit E and the entire study population for both trials separately. Additionally we examined the relationship between CYP4F2 genotype and baseline alphatocopherol. Results: Among all genotyped samples, the frequency of V433M and W12G alleles was 0.25 and 0.14 respectively. Baseline alpha-tocopherol after adjusting for serum cholesterol among PIVENS and TONIC participants was 0.062 (0.03-0.125) and 0.046 (0.021-0.152), respectively. There was no significant relationship between CYP4F2 genotype (either V433M or W12G) and the histological response to Vit E either in children who received Vit E in the TONIC trial or in adults who received Vit E in the PIVENS trial. Similarly, CYP4F2 genotype was not associated with overall improvement in liver histology or resolution of NASH irrespective of treatment assignment either in adult PIVENS or pediatric TONIC participants. Baseline serum alpha-tocopherol levels were not different among adults in the PIVENS trial with different V433M or W12G genotypes. However, interestingly, children in the TONIC trial with CYP4F2 MM genotype had significantly higher baseline alpha-tocopherol levels compared to either VM or VV genotype (0.074 ± 0.043 vs. 0.051 ± 0.014 or 0.049 ± 0.016, p=0.0002), but W12G genotype had no relationship with baseline alpha-tocopherol levels in the TONIC trial. Conclusion: CYP4F2 genetic polymorphism had no significant impact on the response to Vit E in adults and children