المؤلفون: Sanyal, Arun J, Williams, Stephen A, Lavine, Joel E, Neuschwander-Tetri, Brent A, Alexander, Leigh, Ostroff, Rachel, Biegel, Hannah, Kowdley, Kris V, Chalasani, Naga, Dasarathy, Srinivasan, Diehl, Anna Mae, Loomba, Rohit, Hameed, Bilal, Behling, Cynthia, Kleiner, David E, Karpen, Saul J, Williams, Jessica, Jia, Yi, Yates, Katherine P, Tonascia, James

المصدر: Journal of Hepatology. 78(4)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Hepatitis, Nutrition, Chronic Liver Disease and Cirrhosis, Liver Disease, Digestive Diseases, Clinical Research, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Humans, Biopsy, Fibrosis, Inflammation, Liver, Liver Cirrhosis, Non-alcoholic Fatty Liver Disease, Pioglitazone, Proteomics, Vitamin E, Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, NAFLD activity score, fibrosis stage, cirrhosis, stea-tohepatitis, steatosis, hepatocellular ballooning, lobular inflammation, fibrosis, proteomics, aptamers, steatohepatitis, Public Health and Health Services, Gastroenterology & Hepatology, Clinical sciences

الوصف: Background & aimsDespite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD.MethodsUsing modified-aptamer proteomics, we assayed 5,220 proteins in each of 2,852 single serum samples from 636 individuals with histologically confirmed NAFLD. We developed and validated dichotomized protein-phenotype models to identify clinically relevant severities of steatosis (grade 0 vs. 1-3), hepatocellular ballooning (0 vs. 1 or 2), lobular inflammation (0-1 vs. 2-3) and fibrosis (stages 0-1 vs. 2-4).ResultsThe AUCs of the four protein models, based on 37 analytes (18 not previously linked to NAFLD), for the diagnosis of their respective components (at a clinically relevant severity) in training/paired validation sets were: fibrosis (AUC 0.92/0.85); steatosis (AUC 0.95/0.79), inflammation (AUC 0.83/0.72), and ballooning (AUC 0.87/0.83). An additional outcome, at-risk NASH, defined as steatohepatitis with NAFLD activity score ≥4 (with a score of at least 1 for each of its components) and fibrosis stage ≥2, was predicted by multiplying the outputs of each individual component model (AUC 0.93/0.85). We further evaluated their ability to detect change in histology following treatment with placebo, pioglitazone, vitamin E or obeticholic acid. Component model scores significantly improved in the active therapies vs. placebo, and differential effects of vitamin E, pioglitazone, and obeticholic acid were identified.ConclusionsSerum protein scanning identified signatures corresponding to the key components of liver biopsy in NAFLD. The models developed were sufficiently sensitive to characterize the longitudinal change for three different drug interventions. These data support continued validation of these proteomic models to enable a "liquid biopsy"-based assessment of NAFLD.Clinical trial numberNot applicable.Impact and implicationsAn aptamer-based protein scan of serum proteins was performed to identify diagnostic signatures of the key histological features of non-alcoholic fatty liver disease (NAFLD), for which no approved non-invasive diagnostic tools are currently available. We also identified specific protein signatures related to the presence and severity of NAFLD and its histological components that were also sensitive to change over time. These are fundamental initial steps in establishing a serum proteome-based diagnostic signature of NASH and provide the rationale for using these signatures to test treatment response and to identify several novel targets for evaluation in the pathogenesis of NAFLD.

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الوصول الحر: https://escholarship.org/uc/item/0d9809npTest

المؤلفون: Vos, Miriam B, Van Natta, Mark L, Blondet, Niviann M, Dasarathy, Srinivasan, Fishbein, Mark, Hertel, Paula, Jain, Ajay K, Karpen, Saul J, Lavine, Joel E, Mohammad, Saeed, Miriel, Laura A, Molleston, Jean P, Mouzaki, Marialena, Sanyal, Arun, Sharkey, Emily P, Schwimmer, Jeffrey B, Tonascia, James, Wilson, Laura A, Xanthakos, Stavra A, Network, NASH Clinical Research

المصدر: Hepatology. 76(2)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Pediatric, Digestive Diseases, Clinical Research, Prevention, Hepatitis, Liver Disease, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adolescent, Angiotensin Receptor Antagonists, Blood Pressure, Child, Double-Blind Method, Female, Humans, Hypertension, Losartan, Male, Non-alcoholic Fatty Liver Disease, Treatment Outcome, NASH Clinical Research Network, Medical Biochemistry and Metabolomics, Immunology, Gastroenterology & Hepatology, Clinical sciences

الوصف: Background and aimsTo date, no pharmacotherapy exists for pediatric NAFLD. Losartan, an angiotensin II receptor blocker, has been proposed as a treatment due to its antifibrotic effects.Approach and resultsThe Nonalcoholic Steatohepatitis Clinical Research Network conducted a multicenter, double-masked, placebo-controlled, randomized clinical trial in children with histologically confirmed NAFLD at 10 sites (September 2018 to April 2020). Inclusion criteria were age 8-17 years, histologic NAFLD activity score ≥ 3, and serum alanine aminotransferase (ALT) ≥ 50 U/l. Children received 100 mg of losartan or placebo orally once daily for 24 weeks. The primary outcome was change in ALT levels from baseline to 24 weeks, and the preset sample size was n = 110. Treatment effects were assessed using linear regression of change in treatment group adjusted for baseline value. Eighty-three participants (81% male, 80% Hispanic) were randomized to losartan (n = 43) or placebo (n = 40). During an enrollment pause, necessitated by the 2019 coronavirus pandemic, an unplanned interim analysis showed low probability (7%) of significant group difference. The Data and Safety Monitoring Board recommended early study termination. Baseline characteristics were similar between groups. The 24-week change in ALT did not differ significantly between losartan versus placebo groups (adjusted mean difference: 1.1 U/l; 95% CI = -30.6, 32.7; p = 0.95), although alkaline phosphatase decreased significantly in the losartan group (adjusted mean difference: -23.4 U/l; 95% CI = -41.5, -5.3; p = 0.01). Systolic blood pressure decreased in the losartan group but increased in placebo (adjusted mean difference: -7.5 mm Hg; 95% CI = -12.2, -2.8; p = 0.002). Compliance by pill counts and numbers and types of adverse events did not differ by group.ConclusionsLosartan did not significantly reduce ALT in children with NAFLD when compared with placebo.

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الوصول الحر: https://escholarship.org/uc/item/4zr8572gTest

المؤلفون: Brandman, Danielle, Boyle, Marie, McPherson, Stuart, Van Natta, Mark L, Sanyal, Arun J, Kowdley, Kris, Neuschwander‐Tetri, Brent, Chalasani, Naga, Abdelmalek, Manal F, Terrault, Norah A, McCullough, Art, Bettencourt, Ricki, Caussy, Cyrielle, Kleiner, David E, Behling, Cynthia, Tonascia, James, Anstee, Quentin M, Loomba, Rohit, Network, Members of the Nonalcoholic Steatohepatitis Clinical Research

المصدر: Alimentary Pharmacology & Therapeutics. 55(11)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Digestive Diseases, Hepatitis, Liver Disease, Chronic Liver Disease and Cirrhosis, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Oral and gastrointestinal, Good Health and Well Being, Adult, Biopsy, Clinical Decision Rules, Cross-Sectional Studies, Female, Fibrosis, Humans, Liver, Liver Cirrhosis, Non-alcoholic Fatty Liver Disease, cirrhosis, nonalcoholic fatty liver disease, noninvasive assessment, Members of the Nonalcoholic Steatohepatitis Clinical Research Network, Pharmacology and Pharmaceutical Sciences, Gastroenterology & Hepatology, Clinical sciences, Pharmacology and pharmaceutical sciences

الوصف: Background and aimsPatients with nonalcoholic fatty liver disease (NAFLD) cirrhosis benefit from referral to subspecialty care. While several clinical prediction rules exist to identify advanced fibrosis, the cutoff for excluding cirrhosis due to NAFLD is unclear. This analysis compared clinical prediction rules for excluding biopsy-proven cirrhosis in NAFLD.MethodsAdult patients were enrolled in the NASH Clinical Research Network (US) and the Newcastle Cohort (UK). Clinical and laboratory data were collected at enrolment, and a liver biopsy was taken within 1 year of enrolment. Optimal cutoffs for each score (eg, FIB-4) to exclude cirrhosis were derived from the US cohort, and sensitivity, specificity, positive predictive value, negative predictive value and AUROC were calculated. The cutoffs were evaluated in the UK cohort.Results147/1483 (10%) patients in the US cohort had cirrhosis. All prediction rules had similarly high NPV (0.95-0.97). FIB-4 and NAFLD fibrosis scores were the most accurate in characterising patients as having cirrhosis (AUROC 0.84-0.86). 59/494 (12%) patients in the UK cohort had cirrhosis. Prediction rules had high NPV (0.92-0.96), and FIB-4 and NAFLD fibrosis score the most accurate in the prediction of cirrhosis in the UK cohort (AUROC 0.87-0.89).ConclusionsThis cross-sectional analysis of large, multicentre international datasets shows that current clinical prediction rules perform well in excluding cirrhosis with appropriately chosen cutoffs. These clinical prediction rules can be used in primary care to identify patients, particularly those who are white, female, and

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الوصول الحر: https://escholarship.org/uc/item/6bg9n7jgTest

المؤلفون: Woreta, Tinsay A, Van Natta, Mark L, Lazo, Mariana, Krishnan, Arunkumar, Neuschwander-Tetri, Brent A, Loomba, Rohit, Diehl, Anna Mae, Abdelmalek, Manal F, Chalasani, Naga, Gawrieh, Samer, Dasarathy, Srinivasan, Vuppalanchi, Raj, Siddiqui, Mohammad S, Kowdley, Kris V, McCullough, Arthur, Terrault, Norah A, Behling, Cynthia, Kleiner, David E, Fishbein, Mark, Hertel, Paula, Wilson, Laura A, Mitchell, Emily P, Miriel, Laura A, Clark, Jeanne M, Tonascia, James, Sanyal, Arun J

المصدر: PLOS ONE. 17(4)

مصطلحات موضوعية: Prevention, Digestive Diseases, Clinical Research, Chronic Liver Disease and Cirrhosis, Hepatitis, Liver Disease, Obesity, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Oral and gastrointestinal, Adult, Algorithms, Biopsy, Cohort Studies, Female, Fibrosis, Humans, Liver, Liver Cirrhosis, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Severity of Illness Index, NASH Clinical Research Network, General Science & Technology

الوصف: Background and aimsManagement of patients with NASH who are at elevated risk of progressing to complications of cirrhosis (at-risk NASH) would be enhanced by an accurate, noninvasive diagnostic test. The new FAST™ score, a combination of FibroScan® parameters liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) and aspartate aminotransferase (AST), has shown good diagnostic accuracy for at-risk NASH (area-under-the-Receiver-Operating-Characteristic [AUROC] = 0.80) in European cohorts. We aimed to validate the FAST™ score in a North American cohort and show how its diagnostic accuracy might vary by patient mix. We also compared the diagnostic performance of FAST™ to other non-invasive algorithms for the diagnosis of at-risk NASH.MethodsWe studied adults with biopsy-proven non-alcoholic fatty liver disease (NAFLD) from the multicenter NASH Clinical Research Network (CRN) Adult Database 2 (DB2) cohort study. At-risk-NASH was histologically defined as definite NASH with a NAFLD Activity Score (NAS) ≥ 4 with at least 1 point in each category and a fibrosis stage ≥ 2. We used the Echosens® formula for FAST™ from LSM (kPa), CAP (dB/m), and AST (U/L), and the FAST™-based Rule-Out (FAST™ ≤ 0.35, sensitivity = 90%) and Rule-In (FAST™ ≥ 0.67, specificity = 90%) zones. We determined the following diagnostic performance measures: AUROC, sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV); these were calculated for the total sample and by subgroups of patients and by FibroScan® exam features. We also compared the at-risk NASH diagnostic performance of FAST™ to other non-invasive algorithms: NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) index, and AST to platelet ratio index (APRI).ResultsThe NASH CRN population of 585 patients was 62% female, 79% white, 14% Hispanic, and 73% obese; the mean age was 51 years. The mean (SD) AST and ALT were 50 (37) U/L and 66 (45) U/L, respectively. 214 (37%) had at-risk NASH. The AUROC of FAST™ for at-risk NASH in the NASH CRN study population was 0.81 (95% CI: 0.77, 0.84. Using FAST™-based cut-offs, 35% of patients were ruled-out with corresponding NPV = 0.90 and 27% of patients were ruled-in with corresponding PPV = 0.69. The diagnostic accuracy of FAST™ was higher in non-whites vs. whites (AUROC: 0.91 vs 0.78; p = 0.001), and in patients with a normal BMI vs. BMI > 35 kg/m2 (AUROC: 0.94 vs 0.78, p = 0.008). No differences were observed by other patient characteristics or FibroScan® exam features. The FAST™ score had higher diagnostic accuracy than other non-invasive algorithms for the diagnosis of at-risk NASH (AUROC for NFS, FIB-4, and APRI 0.67, 0.73, 0.74, respectively).ConclusionWe validated the FAST™ score for the diagnosis of at-risk NASH in a large, multi-racial population in North America, with a prevalence of at-risk NASH of 37%. Diagnostic performance varies by subgroups of NASH patients defined by race and obesity. FAST™ performed better than other non-invasive algorithms for the diagnosis of at-risk NASH.

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الوصول الحر: https://escholarship.org/uc/item/30p411qnTest

المؤلفون: Sanyal, Arun J, Van Natta, Mark L, Clark, Jeanne, Neuschwander-Tetri, Brent A, Diehl, AnnaMae, Dasarathy, Srinivasan, Loomba, Rohit, Chalasani, Naga, Kowdley, Kris, Hameed, Bilal, Wilson, Laura A, Yates, Katherine P, Belt, Patricia, Lazo, Mariana, Kleiner, David E, Behling, Cynthia, Tonascia, James

المصدر: New England Journal of Medicine. 385(17)

مصطلحات موضوعية: Chronic Liver Disease and Cirrhosis, Clinical Research, Liver Disease, Digestive Diseases, Good Health and Well Being, Adult, Biopsy, Carcinoma, Hepatocellular, Female, Gastrointestinal Hemorrhage, Humans, Incidence, Liver, Liver Cirrhosis, Liver Neoplasms, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Prognosis, Prospective Studies, Severity of Illness Index, NASH Clinical Research Network, Medical and Health Sciences, General & Internal Medicine

الوصف: BackgroundThe prognoses with respect to mortality and hepatic and nonhepatic outcomes across the histologic spectrum of nonalcoholic fatty liver disease (NAFLD) are not well defined.MethodsWe prospectively followed a multicenter patient population that included the full histologic spectrum of NAFLD. The incidences of death and other outcomes were compared across baseline histologic characteristics.ResultsA total of 1773 adults with NAFLD were followed for a median of 4 years. All-cause mortality increased with increasing fibrosis stages (0.32 deaths per 100 person-years for stage F0 to F2 [no, mild, or moderate fibrosis], 0.89 deaths per 100 persons-years for stage F3 [bridging fibrosis], and 1.76 deaths per 100 person-years for stage F4 [cirrhosis]). The incidence of liver-related complications per 100 person-years increased with fibrosis stage (F0 to F2 vs. F3 vs. F4) as follows: variceal hemorrhage (0.00 vs. 0.06 vs. 0.70), ascites (0.04 vs. 0.52 vs. 1.20), encephalopathy (0.02 vs. 0.75 vs. 2.39), and hepatocellular cancer (0.04 vs. 0.34 vs. 0.14). As compared with patients with stage F0 to F2 fibrosis, patients with stage F4 fibrosis also had a higher incidence of type 2 diabetes (7.53 vs. 4.45 events per 100 person-years) and a decrease of more than 40% in the estimated glomerular filtration rate (2.98 vs. 0.97 events per 100 person-years). The incidence of cardiac events and nonhepatic cancers were similar across fibrosis stages. After adjustment for age, sex, race, diabetes status, and baseline histologic severity, the incidence of any hepatic decompensation event (variceal hemorrhage, ascites, or encephalopathy) was associated with increased all-cause mortality (adjusted hazard ratio, 6.8; 95% confidence interval, 2.2 to 21.3).ConclusionsIn this prospective study involving patients with NAFLD, fibrosis stages F3 and F4 were associated with increased risks of liver-related complications and death. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; NAFLD DB2 ClinicalTrials.gov number, NCT01030484.).

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الوصول الحر: https://escholarship.org/uc/item/9bv4k9pfTest

المؤلفون: Xanthakos, Stavra A, Lavine, Joel E, Yates, Katherine P, Schwimmer, Jeffrey B, Molleston, Jean P, Rosenthal, Philip, Murray, Karen F, Vos, Miriam B, Jain, Ajay K, Scheimann, Ann O, Miloh, Tamir, Fishbein, Mark, Behling, Cynthia A, Brunt, Elizabeth M, Sanyal, Arun J, Tonascia, James, Abrams, Stephanie, Garner, Donna, Hertel, Paula, Himes, Ryan, Lawson, Alicia, Triggs, Nicole, Bramlage, Kristin, Carr, April, Cecil, Kim, McNeill, Meghan, Mouzaki, Marialena, Trout, Andrew, Xanthakos, Stavra, Bernstein, Kimberlee, DeVore, Stephanie, Kohli, Rohit, Lake, Kathleen, Podberesky, Daniel, Towbin, Alex, Mencin, Ali, Reynoso, Elena, Alazraki, Adina, Cleeton, Rebecca, Cordero, Maria, Hernandez, Albert, Karpen, Saul, Munos, Jessica Cruz, Raviele, Nicholas, Vos, Miriam, Bozic, Molly, Carr, Laura, Cummings, Oscar W, Harlow, Kathryn, Klipsch, Ann, Ragozzino, Emily, Rao, Girish, Kafka, Kimberly, Scheimann, Ann, Fishbein, Mark H, Ito, Joy, Mohammad, Saeed, Whitington, Peter F, Barlow, Sarah, Carpenter, Danielle, Cattoor, Theresa, Derdoy, Jose, Freebersyser, Janet, Jain, Ajay, King, Debra, Lai, Jinping, Siegner, Joan, Stewart, Susan, Torretta, Susan, Wriston, Kristina, Angeles, Jorge, Arin, Jennifer, Behling, Cynthia, Bross, Craig, Carrier, Carissa, Collins, Jennifer, De La Pena, Diana, Durelle, Janis, Huckaby, Mary Catherine, Middleton, Michael S, Newton, Kimberly, Sirlin, Claude, Ugalde-Nicalo, Patricia, Courtier, Jesse, Gill, Ryan, Langlois, Camille, Perito, Emily Rothbaum, Tsai, Patrika, Blondet, Niviann, Cooper, Kara, Murray, Karen, Otto, Randolph, Yeh, Matthew

المصدر: Gastroenterology. 159(5)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Obesity, Clinical Trials and Supportive Activities, Clinical Research, Digestive Diseases, Liver Disease, Chronic Liver Disease and Cirrhosis, Pediatric, Diabetes, Hepatitis, Oral and gastrointestinal, Adolescent, Age Factors, Alanine Transaminase, Aspartate Aminotransferases, Biomarkers, Biopsy, Blood Glucose, Child, Diabetes Mellitus, Type 2, Disease Progression, Female, Healthy Lifestyle, Humans, Male, Non-alcoholic Fatty Liver Disease, Pediatric Obesity, Prospective Studies, Randomized Controlled Trials as Topic, Risk Assessment, Risk Factors, Risk Reduction Behavior, Severity of Illness Index, Time Factors, Treatment Outcome, ALT, Cirrhosis, Histology, Natural History, NASH Clinical Research Network, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics

الوصف: Background & aimsNonalcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease. Little is known about outcomes in recognized youth.MethodsWe compared paired liver biopsies from 122 of 139 children with NAFLD (74% male; 64% white; 71% Hispanic; mean age, 13 ± 3 years; age range, 8-17 years) who received placebo and standard of care lifestyle advice in 2 double-blind, randomized clinical trials within the nonalcoholic steatohepatitis (NASH) clinical research network from 2005 through 2015. We analyzed histologic changes with respect to baseline and longitudinal change in clinical variables using regression analysis.ResultsAt enrollment, 31% of the children had definite NASH, 34% had borderline zone 1 NASH, 13% had borderline zone 3 NASH, and 21% had fatty liver but not NASH. Over a mean period of 1.6 ± 0.4 years, borderline or definite NASH resolved in 29% of the children, whereas 18% of the children with fatty liver or borderline NASH developed definite NASH. Fibrosis improved in 34% of the children but worsened in 23%. Any progression to definite NASH and/or in fibrosis was associated with adolescent age, and higher waist circumference, levels of alanine or aspartate aminotransferase, total and low-density lipoprotein cholesterol at baseline (

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الوصول الحر: https://escholarship.org/uc/item/5vk079t9Test
https://escholarship.org/content/qt5vk079t9/qt5vk079t9.pdfTest

المؤلفون: Loomba, Rohit, Neuschwander‐Tetri, Brent A, Sanyal, Arun, Chalasani, Naga, Diehl, Anna Mae, Terrault, Norah, Kowdley, Kris, Dasarathy, Srinivasan, Kleiner, David, Behling, Cynthia, Lavine, Joel, Van Natta, Mark, Middleton, Michael, Tonascia, James, Sirlin, Claude, Network, for the NASH Clinical Research

المصدر: Hepatology. 72(4)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Digestive Diseases, Clinical Research, Clinical Trials and Supportive Activities, Liver Disease, Hepatitis, Chronic Liver Disease and Cirrhosis, Biomedical Imaging, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Oral and gastrointestinal, Adipose Tissue, Adult, Aged, Chenodeoxycholic Acid, Double-Blind Method, Female, Humans, Liver, Magnetic Resonance Imaging, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Protons, Weight Loss, NASH Clinical Research Network, Medical Biochemistry and Metabolomics, Immunology, Gastroenterology & Hepatology, Clinical sciences

الوصف: Background and aimsEmerging data from a single-center study suggests that a 30% relative reduction in liver fat content as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) from baseline may be associated with histologic improvement in nonalcoholic steatohepatitis (NASH). There are limited multicenter data comparing an active drug versus placebo on the association between the quantity of liver fat reduction assessed by MRI-PDFF and histologic response in NASH. This study aims to examine the association between 30% relative reduction in MRI-PDFF and histologic response in obeticholic acid (OCA) versus placebo-treated patients in the FLINT (farnesoid X receptor ligand obeticholic acid in NASH trial).Approach and resultsThis is a secondary analysis of the FLINT trial including 78 patients with MRI-PDFF measured before and after treatment along with paired liver histology assessment. Histologic response was defined as a 2-point improvement in nonalcoholic fatty liver disease activity score without worsening of fibrosis. OCA (25 mg orally once daily) was better than placebo in improving MRI-PDFF by an absolute difference of -3.4% (95% confidence interval [CI], -6.5 to -0.2%, P value = 0.04) and relative difference of -17% (95% CI, -34 to 0%, P value = 0.05). The optimal cutoff point for relative decline in MRI-PDFF for histologic response was 30% (using Youden's index). The rate of histologic response in those who achieved less than 30% decline in MRI-PDFF versus those who achieved a 30% or greater decline in MRI-PDFF (MRI-PDFF responders) relative to baseline was 19% versus 50%, respectively. Compared with MRI-PDFF nonresponders, MRI-PDFF responders demonstrated both a statistically and clinically significant higher odds 4.86 (95% CI, 1.4-12.8, P value

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الوصول الحر: https://escholarship.org/uc/item/57t3875sTest

المؤلفون: Siddiqui, Mohammad Shadab, Van Natta, Mark L, Connelly, Margery A, Vuppalanchi, Raj, Neuschwander-Tetri, Brent A, Tonascia, James, Guy, Cynthia, Loomba, Rohit, Dasarathy, Srinivasan, Wattacheril, Julia, Chalasani, Naga, Sanyal, Arun J, CRN, for the NASH

المصدر: Journal of Hepatology. 72(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Atherosclerosis, Hepatitis, Clinical Trials and Supportive Activities, Cardiovascular, Chronic Liver Disease and Cirrhosis, Liver Disease, Clinical Research, Digestive Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being, Adult, Biopsy, Chenodeoxycholic Acid, Drug Therapy, Combination, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoproteins, HDL, Lipoproteins, LDL, Lipoproteins, VLDL, Liver, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Receptors, Cytoplasmic and Nuclear, Treatment Outcome, Nonalcoholic steatohepatitis, NASH, Very low-density lipoprotein, Low-density lipoprotein, High-density lipoprotein, Lipoproteins, Cholesterol, OCA, NASH CRN, Public Health and Health Services, Gastroenterology & Hepatology, Clinical sciences

الوصف: Background & aimsObeticholic acid (OCA), a farnesoid X receptor agonist, increases total and low-density lipoprotein cholesterol (LDL-C) in patients with non-alcoholic steatohepatitis. In the present study, we aimed to evaluate the impact of OCA therapy on lipoprotein sub-particles.MethodThis study included 196 patients (99 OCA group and 97 placebo group) who were enrolled in the FLINT trial and had samples available for lipid analysis and liver biopsies at enrollment and end-of-treatment (EOT) at 72 weeks. Very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particles were evaluated at baseline, 12 and 72 weeks after randomization, and 24 weeks following EOT.ResultsBaseline lipoprotein profiles were similar among OCA and placebo groups. OCA did not affect total VLDL particle concentrations, but OCA vs. placebo treatment was associated with decreased large VLDL particle concentration at 12 weeks (baseline-adjusted mean: 6.8 vs. 8.9 nmol/L; p = 0.002), mirrored by an increase in less atherogenic, small VLDL particle concentration (33.9 vs. 28.0 nmol/L; p = 0.02). After 12 weeks, total LDL particle concentration was higher in the OCA group than the placebo group (1,667 vs. 1,329 nmol/L; p

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الوصول الحر: https://escholarship.org/uc/item/3t35g6bhTest

المؤلفون: Banini, Bubu A, Cazanave, Sophie C, Yates, Katherine P, Asgharpour, Amon, Vincent, Robert, Mirshahi, Faridoddin, Le, Peter, Contos, Melissa J, Tonascia, James, Chalasani, Naga P, Kowdley, Kris V, McCullough, Arthur J, Behling, Cynthia A, Schwimmer, Jeffrey B, Lavine, Joel E, Sanyal, Arun J

المصدر: Journal of Clinical Gastroenterology. 53(10)

مصطلحات موضوعية: Hepatitis, Clinical Trials and Supportive Activities, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Clinical Research, Complementary and Integrative Health, Liver Disease, Oral and gastrointestinal, Adult, Alleles, Female, Genotype, Haptoglobins, Humans, Male, Non-alcoholic Fatty Liver Disease, Randomized Controlled Trials as Topic, Treatment Outcome, Vitamin E, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, vitamin E, haptoglobin genotype, oxidative stress, Nonalcoholic Steatohepatitis Clinical Research Network, Clinical Sciences, Gastroenterology & Hepatology

الوصف: BackgroundHaptoglobin (Hp) genotype has been linked to oxidative stress and cardiovascular outcomes in response to vitamin E (VitE) among patients with diabetes mellitus. Its effect on histologic response to VitE in nonalcoholic steatohepatitis (NASH) is unknown.GoalsOur objective was to determine if Hp genotype associates with response to VitE in patients with NASH.StudyA post hoc analysis of 228 patients receiving VitE or placebo in 2 clinical trials was performed. Regression analysis was used to assess the effect of VitE versus placebo, by Hp genotype (1-1, 2-1, or 2-2), on histologic features and laboratory markers of nonalcoholic fatty liver disease, comparing baseline to end of treatment values. An interaction term was included in the regression models to assess differential treatment effect across Hp genotype.ResultsHp 2-2 patients treated with VitE versus placebo showed significant histologic improvement (51% vs. 20%; OR=4.2; P=0.006), resolution of steatohepatitis (44% vs. 12%; OR=6.2; P=0.009), decrease in nonalcoholic fatty liver disease Activity Score (NAS) (-2.2 vs. -0.6; P=0.001), and decrease in liver enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase. Hp 2-1 patients on VitE versus placebo showed improved resolution of steatohepatitis, NAS and liver enzymes. Hp 1-1 patients showed no significant improvement in histology or liver enzymes. VitE had no effect on fibrosis stage in any group. Regression analysis showed incremental benefit of having Hp 2-2 or 2-1 versus 1-1 for all liver enzyme.ConclusionsHp 2 allele is associated with greater histologic and biological improvement in NASH with VitE treatment compared with the Hp 1 allele.

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الوصول الحر: https://escholarship.org/uc/item/4vw0k1srTest

المؤلفون: Gawrieh, Samer, Wilson, Laura A, Cummings, Oscar W, Clark, Jeanne M, Loomba, Rohit, Hameed, Bilal, Abdelmalek, Manal F, Dasarathy, Srinivasan, Neuschwander-Tetri, Brent A, Kowdley, Kris, Kleiner, David, Doo, Edward, Tonascia, James, Sanyal, Arun, Chalasani, Naga

المصدر: The American Journal of Gastroenterology. 114(10)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Liver Disease, Chronic Liver Disease and Cirrhosis, Clinical Research, Digestive Diseases, Hepatitis, Oral and gastrointestinal, Aged, Alanine Transaminase, Aspartate Aminotransferases, Biopsy, Disease Progression, Female, Humans, Liver, Liver Cirrhosis, Liver Function Tests, Logistic Models, Male, Middle Aged, Models, Biological, Non-alcoholic Fatty Liver Disease, Predictive Value of Tests, Prevalence, Prospective Studies, Risk Assessment, Risk Factors, NASH Clinical Research Network, Gastroenterology & Hepatology, Clinical sciences

الوصف: ObjectivesPatients with nonalcoholic fatty liver disease (NAFLD) and normal aminotransferase levels may have advanced liver histology. We conducted a study to characterize the prevalence of and factors associated with advanced liver histology in patients with histologically characterized NAFLD and normal aminotransferase levels.MethodsWe evaluated 534 adults with biopsy-proven NAFLD and alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6cg272q7Test