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Mo1542 Effect of Weight Loss on MRE Estimated Stiffness in Patients With Nonalcoholic Fatty Liver Disease
24 weeks was associated with a decrease in ALT in the wt. loss group of -20.4% compared to a slight increase in ALT in no-wt. loss group of +3.8% (p-value < 0.02 between groups). Conclusions: Weight loss by ‡5% reduction in BMI in patients with NAFLD led to a significant decrease in MRE-estimated liver stiffness. A 14% mean reduction in MRE-estimated liver stiffness is the minimal threshold that may be associated with weight loss-induced benefits in NAFLD. These data help clarify the utility of MRI-biomarkers of fibrosis in future clinical trials.
Adding EFT on top of HF risk factors model improved pediction of NAFLD fibrosis (AUC from 0.76 to 0.80, p = 0.09)
AASLD Abstracts
Mo1541 A Non-Invasive Pre-Screen Diagnostic Algorithm to Differentiate Between Genetic Hereditary Hemochromatosis and the Dysmetabolic Iron Overload Syndrome Frederik C. Kruger, Hilmar K. Lückhoff, Maritha Kotze, Susan J. van Rensburg BACKGROUND: Impaired iron homeostasis and chronic inflammation are implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) as the hepatic expression of the metabolic syndrome. The dysmetabolic iron overload syndrome (DIOS) associated with NAFLD is the most common differential diagnosis for genetic hereditary hemochromatosis (HH) in obese patients presenting with hyperferritinemia accompanied by low/normal transferrin saturation (TS). AIM: In this study, we investigated the relationship between ironrelated as well as inflammatory biomarkers and the metabolic syndrome in relation to HFE C282Y/H63D genotype. METHODS: Data of 500 South African participants enrolled in a chronic disease screening program with a genetic component (2009-2014) were selected from a secure research database. Biochemical assessment was performed according to standard laboratory protocols. All patients were genotyped for the HFE C282Y/H63D mutations using allele-specific TaqMan real-time polymerase chain reaction technology. RESULTS: Body mass index (BMI) was positively correlated with ferritin (p=0.013) and negatively correlated with TS (p<0.001) independent of HFE genotype. Mean high-sensitivity C-reactive protein (hsCRP) levels increased (p<0.010) and TS decreased (p=0.010) in parallel with an increasing number of metabolic syndrome features. Ferritin was positively correlated with diastolic blood pressure (p=0.002) as well as fasting glucose (p=0.031) and negatively correlated with HDL cholesterol levels (p=0.003). TS was negatively correlated with triglycerides (p=0.022) as well as hs-CRP levels (p=0.002). hs-CRP accurately predicted the presentation of the metabolic syndrome in obese patients (AUC=0.84) with high sensitivity (81%) and specificity (79%). CONCLUSION: Our findings support the assessment of inflammatory biomarkers in relation to BMI as part of a pre-screen algorithm for HFE genotyping used to differentiate between genetic HH and DIOS in obese patients. The clinical application of this algorithm could assist clinicians in identifying a subgroup of obese patients who should be screened for NAFLD commonly associated with impaired iron homeostasis.
Figure 1: Change in MRE with Weight Loss. Footnote: Data expressed as mean. Wt loss group represents pts with >5% decrease in BMI at 24 weeks; No-wt. loss group represents pts with <5% decrease in BMI or gain in BMI at 24 weeks. Abbreviations: MRE, magnetic resonance elastography; kPa, kilopascal.
Mo1543 Inhibition of MPST Prevents Hepatic Steatosis Through Hydrogen SulfideDependent Mechanism Meng Li, Chengfu Xu, Xingyong Wan, Jianguo Gao, Chaohui Yu, Youming Li Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver injury and fibrosis worldwide, but the pathogenesis remains largely obscure. The cystathionine-b-synthase (CBS) and cystathionine-g-lyase (CSE) system, which contributes to endogenous hydrogen sulfide (H2S) biosynthesis, has been proposed to be a potential therapeutic target for NAFLD. 3-mercaptopyruvate sulfurtransferase (MPST) is another enzyme that also contributes to H2S biosynthesis, which is expected to prevent NAFD development. We aimed to investigate the role of MPST in the development of NAFLD. Methods: A variety of cellular and molecular approaches were used to study the effects of MPST on hepatic steatosis and oxidative stress involved in NAFLD both in vitro and in vivo. Results: IHC staining demonstrated that MPST expression was significantly up-regulated in NAFLD patients. Despite of elevated hepatic MPST expression in high-fat diet (HFD)-fed mice and in free fatty acid (FFA)-stimulated L02 cells, hepatic H2S biosynthesis was impaired in these in vivo and in vitro NAFLD models. Knockdown of MPST significantly enhanced rather than decreased H2S production, ameliorating hepatocyte steatosis in HFD-induced mice and in FFA-stimulated L02 cells. Moreover, knockdown of MPST markedly upregulated CBS and CSE with elevation of H2S production in HFD-fed mice and FFA-treated L02 cells; whereas overexpression of MPST suppressed these effects. Finally, mechanistic studies indicated that endogenous H2S mediated the regulatory effect of MPST on hepatocyte steatosis by suppressing SREBP-1 pathway, weakening JNK-1 phosphorylation and ameliorating hepatic oxidative stress. Conclusions: Our findings suggested that MPST is implicated in NAFLD via H2S dependent mechanism. MPST inhibits rather than enhances H2S production in NAFLD via the downregulation of CBS and CSE system, thereby exacerbating NAFLD. Anti-MPST rather than activation of MPST should be used for the treatment of NAFLD.
Mo1542 Effect of Weight Loss on MRE Estimated Stiffness in Patients With Nonalcoholic Fatty Liver Disease Niraj S. Patel, Jonathan Hooker, Monica Gonzalez, Archana Bhatt, Phirum Nguyen, Kimberly Ramirez, Lisa Richards, Emily Rizo, Carolyn Hernandez, Tatiana Kisseleva, Bernd Schnabl, David A. Brenner, Claude B. Sirlin, Rohit Loomba Background: Weight loss has been associated with improvement in liver histology in nonalcoholic steatohepatitis (NASH). Prior studies show that a minimum threshold of 5% weight loss is required to show an improvement in liver histology in NASH. Magnetic resonance elastography (MRE) is an advanced magnetic resonance imaging-based technique that measures liver stiffness as a non-invasive quantitative imaging biomarker of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). However, there are no data on the effect of 5% weight loss on MRE-estimated liver stiffness. Aim: The aim of this study is to determine the effect of 5% weight loss on MRE-estimated liver stiffness in patients with NAFLD. Methods: This is a secondary analysis of the placebo arms of two randomized controlled trials assessing the effect of ezetimibe and sitagliptin on biochemical and imaging outcomes in NAFLD. We included 39 patients with NAFLD who were treated with placebo and had MRE at baseline and at 24 weeks. Changes in MRE-estimated liver stiffness and biochemical markers were assessed separately for patients in the weight loss group (defined as >5% decline in BMI) versus no-weight loss (<5% decline in BMI) group. Results: Among the 39 patients with NAFLD, 5 patients achieved >5% weight loss (wt. loss group) and 34 patients did not have significant weight loss (no-wt. loss group). At baseline, there were no differences in the demographics, laboratory data and MRE values between the two groups. At week 24, the average BMI change in the wt. loss group was -7.2% vs. -0.1% in the no-wt. loss group. At week 24, in the wt. loss group, there was a decrease in MRE-estimated liver stiffness of -14.0% from 2.79 (±0.74)kPa to 2.35 (±0.39)kPa (p < 0.05), while there was a slight increase in MRE-estimated liver stiffness in the no-wt. loss group of +3.1% from 3.10 (±1.08)kPa to 3.18 (±1.32 )kPa (Figure 1), (p-value < 0.05 between groups). The change in MRE over
AASLD Abstracts
Mo1544 Nonalcoholic Steatohepatitis Is Associated With a State of BetaineInsufficiency Silvia Sookoian, Puneet Puri, Gustavo O. Castaño, Romina Scian, Faridoddin Mirshahi, Arun J. Sanyal, Carlos Pirola Background: Nonalcoholic fatty liver disease (NAFLD) develops from a complex process, including changes in the liver methylome. S-adenosylmethionine (SAM) is the major methyl donor in the cell, and the liver is the major site for SAM- synthesis and degradation; SAM is involved in the regulation of the methylome-dynamics during DNA methylation. Methyl groups are usually delivered by dietary methyl donors, which include methionine, choline and betaine. Betaine (N,N,N-trimethylglicine) is a critical player in the pathway of methylogenesis. Results from a recent genome-wide association study coupled with high-throughput metabolic profiling showed variants in the gene DMGDH, which encodes for the mitochondrial dimethylglycine dehydrogenase, significantly associated with circulating levels of betaine and betaine-related metabolites. Methods: We performed a two-stage case-control study, including patients with biopsy proven NAFLD recruited from two-different hospital setting
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Adding EFT on top of HF risk factors model improved pediction of NAFLD fibrosis (AUC from 0.76 to 0.80, p = 0.09)
AASLD Abstracts
Mo1541 A Non-Invasive Pre-Screen Diagnostic Algorithm to Differentiate Between Genetic Hereditary Hemochromatosis and the Dysmetabolic Iron Overload Syndrome Frederik C. Kruger, Hilmar K. Lückhoff, Maritha Kotze, Susan J. van Rensburg BACKGROUND: Impaired iron homeostasis and chronic inflammation are implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) as the hepatic expression of the metabolic syndrome. The dysmetabolic iron overload syndrome (DIOS) associated with NAFLD is the most common differential diagnosis for genetic hereditary hemochromatosis (HH) in obese patients presenting with hyperferritinemia accompanied by low/normal transferrin saturation (TS). AIM: In this study, we investigated the relationship between ironrelated as well as inflammatory biomarkers and the metabolic syndrome in relation to HFE C282Y/H63D genotype. METHODS: Data of 500 South African participants enrolled in a chronic disease screening program with a genetic component (2009-2014) were selected from a secure research database. Biochemical assessment was performed according to standard laboratory protocols. All patients were genotyped for the HFE C282Y/H63D mutations using allele-specific TaqMan real-time polymerase chain reaction technology. RESULTS: Body mass index (BMI) was positively correlated with ferritin (p=0.013) and negatively correlated with TS (p<0.001) independent of HFE genotype. Mean high-sensitivity C-reactive protein (hsCRP) levels increased (p<0.010) and TS decreased (p=0.010) in parallel with an increasing number of metabolic syndrome features. Ferritin was positively correlated with diastolic blood pressure (p=0.002) as well as fasting glucose (p=0.031) and negatively correlated with HDL cholesterol levels (p=0.003). TS was negatively correlated with triglycerides (p=0.022) as well as hs-CRP levels (p=0.002). hs-CRP accurately predicted the presentation of the metabolic syndrome in obese patients (AUC=0.84) with high sensitivity (81%) and specificity (79%). CONCLUSION: Our findings support the assessment of inflammatory biomarkers in relation to BMI as part of a pre-screen algorithm for HFE genotyping used to differentiate between genetic HH and DIOS in obese patients. The clinical application of this algorithm could assist clinicians in identifying a subgroup of obese patients who should be screened for NAFLD commonly associated with impaired iron homeostasis.
Figure 1: Change in MRE with Weight Loss. Footnote: Data expressed as mean. Wt loss group represents pts with >5% decrease in BMI at 24 weeks; No-wt. loss group represents pts with <5% decrease in BMI or gain in BMI at 24 weeks. Abbreviations: MRE, magnetic resonance elastography; kPa, kilopascal.
Mo1543 Inhibition of MPST Prevents Hepatic Steatosis Through Hydrogen SulfideDependent Mechanism Meng Li, Chengfu Xu, Xingyong Wan, Jianguo Gao, Chaohui Yu, Youming Li Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver injury and fibrosis worldwide, but the pathogenesis remains largely obscure. The cystathionine-b-synthase (CBS) and cystathionine-g-lyase (CSE) system, which contributes to endogenous hydrogen sulfide (H2S) biosynthesis, has been proposed to be a potential therapeutic target for NAFLD. 3-mercaptopyruvate sulfurtransferase (MPST) is another enzyme that also contributes to H2S biosynthesis, which is expected to prevent NAFD development. We aimed to investigate the role of MPST in the development of NAFLD. Methods: A variety of cellular and molecular approaches were used to study the effects of MPST on hepatic steatosis and oxidative stress involved in NAFLD both in vitro and in vivo. Results: IHC staining demonstrated that MPST expression was significantly up-regulated in NAFLD patients. Despite of elevated hepatic MPST expression in high-fat diet (HFD)-fed mice and in free fatty acid (FFA)-stimulated L02 cells, hepatic H2S biosynthesis was impaired in these in vivo and in vitro NAFLD models. Knockdown of MPST significantly enhanced rather than decreased H2S production, ameliorating hepatocyte steatosis in HFD-induced mice and in FFA-stimulated L02 cells. Moreover, knockdown of MPST markedly upregulated CBS and CSE with elevation of H2S production in HFD-fed mice and FFA-treated L02 cells; whereas overexpression of MPST suppressed these effects. Finally, mechanistic studies indicated that endogenous H2S mediated the regulatory effect of MPST on hepatocyte steatosis by suppressing SREBP-1 pathway, weakening JNK-1 phosphorylation and ameliorating hepatic oxidative stress. Conclusions: Our findings suggested that MPST is implicated in NAFLD via H2S dependent mechanism. MPST inhibits rather than enhances H2S production in NAFLD via the downregulation of CBS and CSE system, thereby exacerbating NAFLD. Anti-MPST rather than activation of MPST should be used for the treatment of NAFLD.
Mo1542 Effect of Weight Loss on MRE Estimated Stiffness in Patients With Nonalcoholic Fatty Liver Disease Niraj S. Patel, Jonathan Hooker, Monica Gonzalez, Archana Bhatt, Phirum Nguyen, Kimberly Ramirez, Lisa Richards, Emily Rizo, Carolyn Hernandez, Tatiana Kisseleva, Bernd Schnabl, David A. Brenner, Claude B. Sirlin, Rohit Loomba Background: Weight loss has been associated with improvement in liver histology in nonalcoholic steatohepatitis (NASH). Prior studies show that a minimum threshold of 5% weight loss is required to show an improvement in liver histology in NASH. Magnetic resonance elastography (MRE) is an advanced magnetic resonance imaging-based technique that measures liver stiffness as a non-invasive quantitative imaging biomarker of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). However, there are no data on the effect of 5% weight loss on MRE-estimated liver stiffness. Aim: The aim of this study is to determine the effect of 5% weight loss on MRE-estimated liver stiffness in patients with NAFLD. Methods: This is a secondary analysis of the placebo arms of two randomized controlled trials assessing the effect of ezetimibe and sitagliptin on biochemical and imaging outcomes in NAFLD. We included 39 patients with NAFLD who were treated with placebo and had MRE at baseline and at 24 weeks. Changes in MRE-estimated liver stiffness and biochemical markers were assessed separately for patients in the weight loss group (defined as >5% decline in BMI) versus no-weight loss (<5% decline in BMI) group. Results: Among the 39 patients with NAFLD, 5 patients achieved >5% weight loss (wt. loss group) and 34 patients did not have significant weight loss (no-wt. loss group). At baseline, there were no differences in the demographics, laboratory data and MRE values between the two groups. At week 24, the average BMI change in the wt. loss group was -7.2% vs. -0.1% in the no-wt. loss group. At week 24, in the wt. loss group, there was a decrease in MRE-estimated liver stiffness of -14.0% from 2.79 (±0.74)kPa to 2.35 (±0.39)kPa (p < 0.05), while there was a slight increase in MRE-estimated liver stiffness in the no-wt. loss group of +3.1% from 3.10 (±1.08)kPa to 3.18 (±1.32 )kPa (Figure 1), (p-value < 0.05 between groups). The change in MRE over
AASLD Abstracts
Mo1544 Nonalcoholic Steatohepatitis Is Associated With a State of BetaineInsufficiency Silvia Sookoian, Puneet Puri, Gustavo O. Castaño, Romina Scian, Faridoddin Mirshahi, Arun J. Sanyal, Carlos Pirola Background: Nonalcoholic fatty liver disease (NAFLD) develops from a complex process, including changes in the liver methylome. S-adenosylmethionine (SAM) is the major methyl donor in the cell, and the liver is the major site for SAM- synthesis and degradation; SAM is involved in the regulation of the methylome-dynamics during DNA methylation. Methyl groups are usually delivered by dietary methyl donors, which include methionine, choline and betaine. Betaine (N,N,N-trimethylglicine) is a critical player in the pathway of methylogenesis. Results from a recent genome-wide association study coupled with high-throughput metabolic profiling showed variants in the gene DMGDH, which encodes for the mitochondrial dimethylglycine dehydrogenase, significantly associated with circulating levels of betaine and betaine-related metabolites. Methods: We performed a two-stage case-control study, including patients with biopsy proven NAFLD recruited from two-different hospital setting
S-1140
X : 10052$CH02 03-28-16 22:36:37
Page 1140