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Scott B Reeder - One of the best experts on this subject based on the ideXlab platform.
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t 1 independent t 2 corrected chemical shift based fat water separation with multi peak fat spectral modeling is an accurate and precise measure of hepatic steatosis
Journal of Magnetic Resonance Imaging, 2011Co-Authors: Catherine D G Hines, Alex Frydrychowicz, Gavin Hamilton, Dana L Tudorascu, Karl K Vigen, Charles A Mckenzie, Claude B Sirlin, Jean H Brittain, Scott B ReederAbstract:Nonalcoholic Fatty Liver disease (NAFLD) is the most common cause of chronic liver disease in Western societies with an increasing prevalence that parallels current epidemics of obesity and diabetes (1,2). NAFLD is considered by many to be the hepatic manifestation of the metabolic syndrome, a constellation of diseases including adult-onset diabetes (type II), hyperlipidemia, and obesity (3,4). Individuals with NAFLD can progress to a more aggressive form of NAFLD known as nonalcoholic steatohepatitis (NASH), which is characterized by inflammation, Ballooning Degeneration and fibrosis, in addition to steatosis (5,6). Many patients with steatohepatitis progress to end-stage fibrosis (cirrhosis), which predisposes patients to hepatocellular carcinoma (HCC) and liver failure (7,8). Intracellular accumulation of triglycerides and fatty acids (steatosis) is the earliest and hallmark histological feature of NAFLD. Definitive diagnosis of NAFLD and grading of steatosis requires biopsy, which is regarded as the clinical gold standard test and is the current standard of care. Biopsy, however, is limited by cost, high sampling variability (9), and other significant risks that limit its utility for repeated evaluation of liver disease. For these reasons, a noninvasive, cost-effective, and quantitative alternative to biopsy is needed for accurate quantification of hepatic steatosis. MRI is highly sensitive to the presence of fat due to differences in chemical shift between water and fat. MR spectroscopy (MRS) is considered by many to be the noninvasive reference standard for quantification of hepatic fat content (10,11). MRS has both higher sensitivity and specificity for hepatic fat quantification compared with ultrasound and computed tomography (12), indicating that an MR-based technique would be advantageous for hepatic fat quantification. However, like biopsy, MRS is prone to sampling error due to the heterogeneity of steatosis because typically only a single voxel is used to assess the entire liver. Alternatively, chemical shift based water–fat separation methods have demonstrated accurate quantification of hepatic steatosis by several groups (11,13–17). Several confounding factors have been identified that corrupt the ability of MRI to accurately quantify fat using fat–water separation techniques (18). These factors must be addressed before the measured fat-fraction accurately reflects the underlying concentration of triglycerides. Specific confounding factors include T1 bias (13, 19–21), noise bias (19), the complex NMR spectrum of fat (13,14,22), T2∗ decay (13,23), and phase errors caused by eddy currents (24). To perform the correction for eddy currents, a complex image-based fat-water separation including spectral modeling and T2∗ correction is performed first. Then, a second fit to a magnitude signal model is performed, using the complex estimates of water, fat and T2∗ as the starting conditions. This provides estimates of water and fat that are free from the effects of phase shifts from eddy currents. After correction for all confounding factors, the measured fat-fraction is equivalent to the proton density fat-fraction (PDFF). PDFF is an inherent property of the tissue, and is platform and protocol independent, making it a potentially useful biomarker of liver fat content. A recently described complex chemical shift-based fat-water separation method, based on IDEAL (Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation) has been described for fat quantification in the liver (14,19,22,23,25). Using a low flip angle to minimize T1 bias (19), magnitude discrimination to minimize noise bias (19), T2∗ correction (22,23), multi-peak fat spectral modeling (14,22) including six spectral peaks of fat, and eddy current correction (24), accurate quantification has been validated in phantom experiments (26), animal experiments (17) and more recently in in vivo studies (25), over a wide range of fat-fractions (17,26). These studies collectively provide validation on the accuracy of this method. However, rigorous validation of a biomarker also requires an understanding of the precision (repeatability) of a method to assess longitudinal changes in the biomarker. Therefore the primary purpose of this work is to determine the precision of clinical MRI hepatic fat quantification when correction for all known confounding factors has been performed. A secondary purpose is to reproduce accuracy measurements reported in previous validation studies (25), using MRS as the reference standard for hepatic fat-fraction.
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t1 independent t2 corrected chemical shift based fat water separation with multi peak fat spectral modeling is an accurate and precise measure of hepatic steatosis
Journal of Magnetic Resonance Imaging, 2011Co-Authors: Catherine D G Hines, Alex Frydrychowicz, Gavin Hamilton, Dana L Tudorascu, Karl K Vigen, Charles A Mckenzie, Claude B Sirlin, Jean H Brittain, Huanzhou Yu, Scott B ReederAbstract:Nonalcoholic Fatty Liver disease (NAFLD) is the most common cause of chronic liver disease in Western societies with an increasing prevalence that parallels current epidemics of obesity and diabetes (1,2). NAFLD is considered by many to be the hepatic manifestation of the metabolic syndrome, a constellation of diseases including adult-onset diabetes (type II), hyperlipidemia, and obesity (3,4). Individuals with NAFLD can progress to a more aggressive form of NAFLD known as nonalcoholic steatohepatitis (NASH), which is characterized by inflammation, Ballooning Degeneration and fibrosis, in addition to steatosis (5,6). Many patients with steatohepatitis progress to end-stage fibrosis (cirrhosis), which predisposes patients to hepatocellular carcinoma (HCC) and liver failure (7,8). Intracellular accumulation of triglycerides and fatty acids (steatosis) is the earliest and hallmark histological feature of NAFLD. Definitive diagnosis of NAFLD and grading of steatosis requires biopsy, which is regarded as the clinical gold standard test and is the current standard of care. Biopsy, however, is limited by cost, high sampling variability (9), and other significant risks that limit its utility for repeated evaluation of liver disease. For these reasons, a noninvasive, cost-effective, and quantitative alternative to biopsy is needed for accurate quantification of hepatic steatosis. MRI is highly sensitive to the presence of fat due to differences in chemical shift between water and fat. MR spectroscopy (MRS) is considered by many to be the noninvasive reference standard for quantification of hepatic fat content (10,11). MRS has both higher sensitivity and specificity for hepatic fat quantification compared with ultrasound and computed tomography (12), indicating that an MR-based technique would be advantageous for hepatic fat quantification. However, like biopsy, MRS is prone to sampling error due to the heterogeneity of steatosis because typically only a single voxel is used to assess the entire liver. Alternatively, chemical shift based water–fat separation methods have demonstrated accurate quantification of hepatic steatosis by several groups (11,13–17). Several confounding factors have been identified that corrupt the ability of MRI to accurately quantify fat using fat–water separation techniques (18). These factors must be addressed before the measured fat-fraction accurately reflects the underlying concentration of triglycerides. Specific confounding factors include T1 bias (13, 19–21), noise bias (19), the complex NMR spectrum of fat (13,14,22), T2∗ decay (13,23), and phase errors caused by eddy currents (24). To perform the correction for eddy currents, a complex image-based fat-water separation including spectral modeling and T2∗ correction is performed first. Then, a second fit to a magnitude signal model is performed, using the complex estimates of water, fat and T2∗ as the starting conditions. This provides estimates of water and fat that are free from the effects of phase shifts from eddy currents. After correction for all confounding factors, the measured fat-fraction is equivalent to the proton density fat-fraction (PDFF). PDFF is an inherent property of the tissue, and is platform and protocol independent, making it a potentially useful biomarker of liver fat content. A recently described complex chemical shift-based fat-water separation method, based on IDEAL (Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation) has been described for fat quantification in the liver (14,19,22,23,25). Using a low flip angle to minimize T1 bias (19), magnitude discrimination to minimize noise bias (19), T2∗ correction (22,23), multi-peak fat spectral modeling (14,22) including six spectral peaks of fat, and eddy current correction (24), accurate quantification has been validated in phantom experiments (26), animal experiments (17) and more recently in in vivo studies (25), over a wide range of fat-fractions (17,26). These studies collectively provide validation on the accuracy of this method. However, rigorous validation of a biomarker also requires an understanding of the precision (repeatability) of a method to assess longitudinal changes in the biomarker. Therefore the primary purpose of this work is to determine the precision of clinical MRI hepatic fat quantification when correction for all known confounding factors has been performed. A secondary purpose is to reproduce accuracy measurements reported in previous validation studies (25), using MRS as the reference standard for hepatic fat-fraction.
Joel E Lavine - One of the best experts on this subject based on the ideXlab platform.
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correlation of vitamin e uric acid and diet composition with histologic features of pediatric nafld
Journal of Pediatric Gastroenterology and Nutrition, 2012Co-Authors: Ryan Colvin, Philip Rosenthal, Jeffrey B Schwimmer, Patricia Belt, Jean P Molleston, Karen F Murray, James Tonascia, Aynur Unalp, Joel E LavineAbstract:OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children in the United States. Although changes in diet are often recommended to improve NAFLD, little is known regarding the influence of diet on histologic features of the disease. SUBJECTS AND METHODS: This was a prospective, cross-sectional registry-based study. Children (n = 149) enrolled in the multicenter nonalcoholic steatohepatitis (NASH) Clinical Research Network had demographic, anthropometric, clinical, laboratory, and histology data obtained, including the Block Brief Food Questionnaire. Subjects were grouped by presence or absence of steatohepatitis and grades of histologic features according to NASH Clinical Research Network criteria. RESULTS: No significant differences were found between children with steatosis compared with steatohepatitis for fraction of energy from fat, carbohydrates, and protein. Sugar-sweetened beverage consumption was low and did not correlate with histologic features, although uric acid, a surrogate marker for fructose intake, was significantly increased in those with definite NASH (P = 0.008). For all groups, vitamin E consumption was insufficient compared with the recommended daily allowance. Median consumption of vitamin E was lower in children with higher grade of steatosis (8.4 vs 6.1 vs 6.9 for grades I, II, and III, respectively, P = 0.05). Those consuming less vitamin C had increased Ballooning Degeneration (P = 0.05). CONCLUSIONS: Children with NAFLD have a diet that is insufficient in vitamin E and this may contribute to the pathophysiology of NAFLD. In children with NAFLD, reported sugar-sweetened beverage consumption is low; however, uric acid, which may reflect total fructose consumption, was significantly associated with NASH and should be further evaluated.
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histopathology of pediatric nonalcoholic fatty liver disease
Hepatology, 2005Co-Authors: Jeffrey B Schwimmer, Cynthia Behling, Robert O Newbury, Reena Deutsch, Caroline M Nievergelt, Nicholas J Schork, Joel E LavineAbstract:Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common in children and adolescents. However, standard histological criteria for pediatric NAFLD and NASH are undeveloped. We reviewed consecutive patients ages 2 to 18 years with biopsy-proven NAFLD diagnosed between 1997 and 2003. Biopsies were evaluated by two pathologists for individual features of steatohepatitis. Agglomerative hierarchical cluster analysis demonstrated two different forms of steatohepatitis. Type 1 was characterized by steatosis, Ballooning Degeneration, and perisinusoidal fibrosis; type 2 was characterized by steatosis, portal inflammation, and portal fibrosis. The study included 100 children with NAFLD. Simple steatosis was present in 16% of subjects, and advanced fibrosis was present in 8%. Type 1 NASH was present in 17% of subjects, and type 2 NASH was present in 51%. Boys were significantly (P < .01) more likely to have type 2 NASH and less likely to have type 1 NASH than girls. The NASH type differed significantly (P < .001) by race and ethnicity. Type 1 NASH was more common in white children, whereas type 2 NASH was more common in children of Asian, Native American, and Hispanic ethnicity. In cases of advanced fibrosis, the pattern was generally that of type 2 NASH. In conclusion, type 1 and type 2 NASH are distinct subtypes of pediatric NAFLD, and type 2 is the most common pattern in children. NASH subtypes should be considered when interpreting liver biopsies and planning studies of the pathophysiology, genetics, natural history, or response to treatment in pediatric NAFLD.
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histopathology of pediatric nonalcoholic fatty liver disease
Hepatology, 2005Co-Authors: Jeffrey B Schwimmer, Cynthia Behling, Robert O Newbury, Reena Deutsch, Caroline M Nievergelt, Nicholas J Schork, Joel E LavineAbstract:Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common in children and adolescents. However, standard histological criteria for pediatric NAFLD and NASH are undeveloped. We reviewed consecutive patients ages 2 to 18 years with biopsy-proven NAFLD diagnosed between 1997 and 2003. Biopsies were evaluated by two pathologists for individual features of steatohepatitis. Agglomerative hierarchical cluster analysis demonstrated two different forms of steatohepatitis. Type 1 was characterized by steatosis, Ballooning Degeneration, and perisinusoidal fibrosis; type 2 was characterized by steatosis, portal inflammation, and portal fibrosis. The study included 100 children with NAFLD. Simple steatosis was present in 16% of subjects, and advanced fibrosis was present in 8%. Type 1 NASH was present in 17% of subjects, and type 2 NASH was present in 51%. Boys were significantly (P < .01) more likely to have type 2 NASH and less likely to have type 1 NASH than girls. The NASH type differed significantly (P < .001) by race and ethnicity. Type 1 NASH was more common in white children, whereas type 2 NASH was more common in children of Asian, Native American, and Hispanic ethnicity. In cases of advanced fibrosis, the pattern was generally that of type 2 NASH. In conclusion, type 1 and type 2 NASH are distinct subtypes of pediatric NAFLD, and type 2 is the most common pattern in children. NASH subtypes should be considered when interpreting liver biopsies and planning studies of the pathophysiology, genetics, natural history, or response to treatment in pediatric NAFLD. (HEPATOLOGY 2005;42:641–649.)
Catherine D G Hines - One of the best experts on this subject based on the ideXlab platform.
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t 1 independent t 2 corrected chemical shift based fat water separation with multi peak fat spectral modeling is an accurate and precise measure of hepatic steatosis
Journal of Magnetic Resonance Imaging, 2011Co-Authors: Catherine D G Hines, Alex Frydrychowicz, Gavin Hamilton, Dana L Tudorascu, Karl K Vigen, Charles A Mckenzie, Claude B Sirlin, Jean H Brittain, Scott B ReederAbstract:Nonalcoholic Fatty Liver disease (NAFLD) is the most common cause of chronic liver disease in Western societies with an increasing prevalence that parallels current epidemics of obesity and diabetes (1,2). NAFLD is considered by many to be the hepatic manifestation of the metabolic syndrome, a constellation of diseases including adult-onset diabetes (type II), hyperlipidemia, and obesity (3,4). Individuals with NAFLD can progress to a more aggressive form of NAFLD known as nonalcoholic steatohepatitis (NASH), which is characterized by inflammation, Ballooning Degeneration and fibrosis, in addition to steatosis (5,6). Many patients with steatohepatitis progress to end-stage fibrosis (cirrhosis), which predisposes patients to hepatocellular carcinoma (HCC) and liver failure (7,8). Intracellular accumulation of triglycerides and fatty acids (steatosis) is the earliest and hallmark histological feature of NAFLD. Definitive diagnosis of NAFLD and grading of steatosis requires biopsy, which is regarded as the clinical gold standard test and is the current standard of care. Biopsy, however, is limited by cost, high sampling variability (9), and other significant risks that limit its utility for repeated evaluation of liver disease. For these reasons, a noninvasive, cost-effective, and quantitative alternative to biopsy is needed for accurate quantification of hepatic steatosis. MRI is highly sensitive to the presence of fat due to differences in chemical shift between water and fat. MR spectroscopy (MRS) is considered by many to be the noninvasive reference standard for quantification of hepatic fat content (10,11). MRS has both higher sensitivity and specificity for hepatic fat quantification compared with ultrasound and computed tomography (12), indicating that an MR-based technique would be advantageous for hepatic fat quantification. However, like biopsy, MRS is prone to sampling error due to the heterogeneity of steatosis because typically only a single voxel is used to assess the entire liver. Alternatively, chemical shift based water–fat separation methods have demonstrated accurate quantification of hepatic steatosis by several groups (11,13–17). Several confounding factors have been identified that corrupt the ability of MRI to accurately quantify fat using fat–water separation techniques (18). These factors must be addressed before the measured fat-fraction accurately reflects the underlying concentration of triglycerides. Specific confounding factors include T1 bias (13, 19–21), noise bias (19), the complex NMR spectrum of fat (13,14,22), T2∗ decay (13,23), and phase errors caused by eddy currents (24). To perform the correction for eddy currents, a complex image-based fat-water separation including spectral modeling and T2∗ correction is performed first. Then, a second fit to a magnitude signal model is performed, using the complex estimates of water, fat and T2∗ as the starting conditions. This provides estimates of water and fat that are free from the effects of phase shifts from eddy currents. After correction for all confounding factors, the measured fat-fraction is equivalent to the proton density fat-fraction (PDFF). PDFF is an inherent property of the tissue, and is platform and protocol independent, making it a potentially useful biomarker of liver fat content. A recently described complex chemical shift-based fat-water separation method, based on IDEAL (Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation) has been described for fat quantification in the liver (14,19,22,23,25). Using a low flip angle to minimize T1 bias (19), magnitude discrimination to minimize noise bias (19), T2∗ correction (22,23), multi-peak fat spectral modeling (14,22) including six spectral peaks of fat, and eddy current correction (24), accurate quantification has been validated in phantom experiments (26), animal experiments (17) and more recently in in vivo studies (25), over a wide range of fat-fractions (17,26). These studies collectively provide validation on the accuracy of this method. However, rigorous validation of a biomarker also requires an understanding of the precision (repeatability) of a method to assess longitudinal changes in the biomarker. Therefore the primary purpose of this work is to determine the precision of clinical MRI hepatic fat quantification when correction for all known confounding factors has been performed. A secondary purpose is to reproduce accuracy measurements reported in previous validation studies (25), using MRS as the reference standard for hepatic fat-fraction.
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t1 independent t2 corrected chemical shift based fat water separation with multi peak fat spectral modeling is an accurate and precise measure of hepatic steatosis
Journal of Magnetic Resonance Imaging, 2011Co-Authors: Catherine D G Hines, Alex Frydrychowicz, Gavin Hamilton, Dana L Tudorascu, Karl K Vigen, Charles A Mckenzie, Claude B Sirlin, Jean H Brittain, Huanzhou Yu, Scott B ReederAbstract:Nonalcoholic Fatty Liver disease (NAFLD) is the most common cause of chronic liver disease in Western societies with an increasing prevalence that parallels current epidemics of obesity and diabetes (1,2). NAFLD is considered by many to be the hepatic manifestation of the metabolic syndrome, a constellation of diseases including adult-onset diabetes (type II), hyperlipidemia, and obesity (3,4). Individuals with NAFLD can progress to a more aggressive form of NAFLD known as nonalcoholic steatohepatitis (NASH), which is characterized by inflammation, Ballooning Degeneration and fibrosis, in addition to steatosis (5,6). Many patients with steatohepatitis progress to end-stage fibrosis (cirrhosis), which predisposes patients to hepatocellular carcinoma (HCC) and liver failure (7,8). Intracellular accumulation of triglycerides and fatty acids (steatosis) is the earliest and hallmark histological feature of NAFLD. Definitive diagnosis of NAFLD and grading of steatosis requires biopsy, which is regarded as the clinical gold standard test and is the current standard of care. Biopsy, however, is limited by cost, high sampling variability (9), and other significant risks that limit its utility for repeated evaluation of liver disease. For these reasons, a noninvasive, cost-effective, and quantitative alternative to biopsy is needed for accurate quantification of hepatic steatosis. MRI is highly sensitive to the presence of fat due to differences in chemical shift between water and fat. MR spectroscopy (MRS) is considered by many to be the noninvasive reference standard for quantification of hepatic fat content (10,11). MRS has both higher sensitivity and specificity for hepatic fat quantification compared with ultrasound and computed tomography (12), indicating that an MR-based technique would be advantageous for hepatic fat quantification. However, like biopsy, MRS is prone to sampling error due to the heterogeneity of steatosis because typically only a single voxel is used to assess the entire liver. Alternatively, chemical shift based water–fat separation methods have demonstrated accurate quantification of hepatic steatosis by several groups (11,13–17). Several confounding factors have been identified that corrupt the ability of MRI to accurately quantify fat using fat–water separation techniques (18). These factors must be addressed before the measured fat-fraction accurately reflects the underlying concentration of triglycerides. Specific confounding factors include T1 bias (13, 19–21), noise bias (19), the complex NMR spectrum of fat (13,14,22), T2∗ decay (13,23), and phase errors caused by eddy currents (24). To perform the correction for eddy currents, a complex image-based fat-water separation including spectral modeling and T2∗ correction is performed first. Then, a second fit to a magnitude signal model is performed, using the complex estimates of water, fat and T2∗ as the starting conditions. This provides estimates of water and fat that are free from the effects of phase shifts from eddy currents. After correction for all confounding factors, the measured fat-fraction is equivalent to the proton density fat-fraction (PDFF). PDFF is an inherent property of the tissue, and is platform and protocol independent, making it a potentially useful biomarker of liver fat content. A recently described complex chemical shift-based fat-water separation method, based on IDEAL (Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation) has been described for fat quantification in the liver (14,19,22,23,25). Using a low flip angle to minimize T1 bias (19), magnitude discrimination to minimize noise bias (19), T2∗ correction (22,23), multi-peak fat spectral modeling (14,22) including six spectral peaks of fat, and eddy current correction (24), accurate quantification has been validated in phantom experiments (26), animal experiments (17) and more recently in in vivo studies (25), over a wide range of fat-fractions (17,26). These studies collectively provide validation on the accuracy of this method. However, rigorous validation of a biomarker also requires an understanding of the precision (repeatability) of a method to assess longitudinal changes in the biomarker. Therefore the primary purpose of this work is to determine the precision of clinical MRI hepatic fat quantification when correction for all known confounding factors has been performed. A secondary purpose is to reproduce accuracy measurements reported in previous validation studies (25), using MRS as the reference standard for hepatic fat-fraction.
Jeffrey B Schwimmer - One of the best experts on this subject based on the ideXlab platform.
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correlation of vitamin e uric acid and diet composition with histologic features of pediatric nafld
Journal of Pediatric Gastroenterology and Nutrition, 2012Co-Authors: Ryan Colvin, Philip Rosenthal, Jeffrey B Schwimmer, Patricia Belt, Jean P Molleston, Karen F Murray, James Tonascia, Aynur Unalp, Joel E LavineAbstract:OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children in the United States. Although changes in diet are often recommended to improve NAFLD, little is known regarding the influence of diet on histologic features of the disease. SUBJECTS AND METHODS: This was a prospective, cross-sectional registry-based study. Children (n = 149) enrolled in the multicenter nonalcoholic steatohepatitis (NASH) Clinical Research Network had demographic, anthropometric, clinical, laboratory, and histology data obtained, including the Block Brief Food Questionnaire. Subjects were grouped by presence or absence of steatohepatitis and grades of histologic features according to NASH Clinical Research Network criteria. RESULTS: No significant differences were found between children with steatosis compared with steatohepatitis for fraction of energy from fat, carbohydrates, and protein. Sugar-sweetened beverage consumption was low and did not correlate with histologic features, although uric acid, a surrogate marker for fructose intake, was significantly increased in those with definite NASH (P = 0.008). For all groups, vitamin E consumption was insufficient compared with the recommended daily allowance. Median consumption of vitamin E was lower in children with higher grade of steatosis (8.4 vs 6.1 vs 6.9 for grades I, II, and III, respectively, P = 0.05). Those consuming less vitamin C had increased Ballooning Degeneration (P = 0.05). CONCLUSIONS: Children with NAFLD have a diet that is insufficient in vitamin E and this may contribute to the pathophysiology of NAFLD. In children with NAFLD, reported sugar-sweetened beverage consumption is low; however, uric acid, which may reflect total fructose consumption, was significantly associated with NASH and should be further evaluated.
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histopathology of pediatric nonalcoholic fatty liver disease
Hepatology, 2005Co-Authors: Jeffrey B Schwimmer, Cynthia Behling, Robert O Newbury, Reena Deutsch, Caroline M Nievergelt, Nicholas J Schork, Joel E LavineAbstract:Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common in children and adolescents. However, standard histological criteria for pediatric NAFLD and NASH are undeveloped. We reviewed consecutive patients ages 2 to 18 years with biopsy-proven NAFLD diagnosed between 1997 and 2003. Biopsies were evaluated by two pathologists for individual features of steatohepatitis. Agglomerative hierarchical cluster analysis demonstrated two different forms of steatohepatitis. Type 1 was characterized by steatosis, Ballooning Degeneration, and perisinusoidal fibrosis; type 2 was characterized by steatosis, portal inflammation, and portal fibrosis. The study included 100 children with NAFLD. Simple steatosis was present in 16% of subjects, and advanced fibrosis was present in 8%. Type 1 NASH was present in 17% of subjects, and type 2 NASH was present in 51%. Boys were significantly (P < .01) more likely to have type 2 NASH and less likely to have type 1 NASH than girls. The NASH type differed significantly (P < .001) by race and ethnicity. Type 1 NASH was more common in white children, whereas type 2 NASH was more common in children of Asian, Native American, and Hispanic ethnicity. In cases of advanced fibrosis, the pattern was generally that of type 2 NASH. In conclusion, type 1 and type 2 NASH are distinct subtypes of pediatric NAFLD, and type 2 is the most common pattern in children. NASH subtypes should be considered when interpreting liver biopsies and planning studies of the pathophysiology, genetics, natural history, or response to treatment in pediatric NAFLD.
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histopathology of pediatric nonalcoholic fatty liver disease
Hepatology, 2005Co-Authors: Jeffrey B Schwimmer, Cynthia Behling, Robert O Newbury, Reena Deutsch, Caroline M Nievergelt, Nicholas J Schork, Joel E LavineAbstract:Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common in children and adolescents. However, standard histological criteria for pediatric NAFLD and NASH are undeveloped. We reviewed consecutive patients ages 2 to 18 years with biopsy-proven NAFLD diagnosed between 1997 and 2003. Biopsies were evaluated by two pathologists for individual features of steatohepatitis. Agglomerative hierarchical cluster analysis demonstrated two different forms of steatohepatitis. Type 1 was characterized by steatosis, Ballooning Degeneration, and perisinusoidal fibrosis; type 2 was characterized by steatosis, portal inflammation, and portal fibrosis. The study included 100 children with NAFLD. Simple steatosis was present in 16% of subjects, and advanced fibrosis was present in 8%. Type 1 NASH was present in 17% of subjects, and type 2 NASH was present in 51%. Boys were significantly (P < .01) more likely to have type 2 NASH and less likely to have type 1 NASH than girls. The NASH type differed significantly (P < .001) by race and ethnicity. Type 1 NASH was more common in white children, whereas type 2 NASH was more common in children of Asian, Native American, and Hispanic ethnicity. In cases of advanced fibrosis, the pattern was generally that of type 2 NASH. In conclusion, type 1 and type 2 NASH are distinct subtypes of pediatric NAFLD, and type 2 is the most common pattern in children. NASH subtypes should be considered when interpreting liver biopsies and planning studies of the pathophysiology, genetics, natural history, or response to treatment in pediatric NAFLD. (HEPATOLOGY 2005;42:641–649.)
Varda Shoshanbarmatz - One of the best experts on this subject based on the ideXlab platform.
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a mitochondrial vdac1 based peptide greatly suppresses steatosis and nash associated pathologies in a mouse model
Molecular Therapy, 2019Co-Authors: Srinivas Pittala, Yakov Krelin, Yael Kuperman, Varda ShoshanbarmatzAbstract:Non-alcoholic steatosis and non-alcoholic steatohepatitis (NASH) are liver pathologies characterized by severe metabolic alterations due to fat accumulation that lead to liver damage, inflammation, and fibrosis. We demonstrate that the voltage-dependent anion channel 1 (VDAC1)-based peptide R-Tf-D-LP4 arrested steatosis and NASH progression, as produced by a high-fat diet (HFD-32) in a mouse model, and reversed liver pathology to a normal-like state. VDAC1, a multi-functional mitochondrial protein, regulates cellular metabolic and energetic functions and apoptosis and interacts with many proteins. R-Tf-D-LP4 treatment eliminated hepatocyte Ballooning Degeneration, inflammation, and liver fibrosis associated with steatosis, NASH, and hepatocarcinoma, and it restored liver pathology-associated enzyme and glucose levels. Peptide treatment affected carbohydrate and lipid metabolism, increasing the expression of enzymes and factors associated with fatty acid transport to mitochondria, enhancing β-oxidation and thermogenic processes, yet decreasing the expression of enzymes and regulators of fatty acid synthesis. The VDAC1-based peptide thus offers a promising therapeutic approach for steatosis and NASH.
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targeting liver cancer and associated pathologies in mice with a mitochondrial vdac1 based peptide
Neoplasia, 2018Co-Authors: Srinivas Pittala, Yakov Krelin, Varda ShoshanbarmatzAbstract:Abstract Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide. Despite progress in identifying risk factors, the incidence of HCC is increasing. Moreover, therapeutic options are limited and survival is poor. Therefore, alternative and innovative therapeutic strategies are urgently required. R-Tf-D-LP4, a cell-penetrating peptide derived from the mitochondrial multifunctional protein the voltage-dependent anion channel (VDAC1), is identified here as a highly effective liver cancer treatment. Recently, we demonstrated that R-Tf-D-LP4 induced apoptosis and inhibited tumor growth in mouse models. We now demonstrate that R-Tf-D-LP4 induced apoptosis in cancer liver-derived cell lines and inhibited tumor growth in three different liver cancer mouse models. These included diethylnitrosamine (DEN)-induced HCC, metabolically high-fat diet–induced HCC, and using a subcutaneous HepG2 cell xenograft model. Intravenous injection of the peptide into tumor-carrying DEN-treated mice resulted in dose-dependent inhibition of tumor growth up to complete tumor elimination. TUNEL staining of liver sections demonstrated peptide-induced apoptosis. Hematoxylin/eosin and Sirius red staining of liver sections showed decreased fibrotic formation. Immunohistochemical staining demonstrated reduced numbers of α-SMA–expressing cells in R-Tf-D-LP4–treated mouse livers. Additionally, macrophage presence in liver tissue was reduced in R-Tf-D-LP4–treated mice. Liver sections from DEN-treated mice showed steatohepatic pathology, reflected as fatty liver, inflammation, Ballooning Degeneration, and fibrosis; all were eliminated upon peptide treatment. Peptide treatment also inhibited tumor development in a nonalcoholic steatohepatitis–hepatocellular carcinoma mouse model induced by HFD. In HepG2 subcutaneous tumor xenografts, R-Tf-D-LP4 inhibited tumor growth. Conclusion: These results show that the VDAC1-based peptide R-Tf-D-LP4 has multiple effects on liver cancer cells, leading to impairment of cell energy and metabolism homeostasis, induction of apoptosis, and elimination of liver cancer-associated processes, and thus represents a promising therapeutic approach for liver cancer.
