Search

Your search keyword '"NAS, NAFLD activity score"' showing total 21 results
Start Over Descriptor "NAS, NAFLD activity score" Publisher elsevier
21 results on '"NAS, NAFLD activity score"'

1. S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling

Author

Pingping Luo, Rui Zhang, Qian Yu, George L. Tipoe, Ming Zheng, Xiaoming Sun, Yingxia Liu, Jia Xiao, Wei Li, and Hong Zhang

Subjects
Alcoholic liver disease, INSR, insulin receptor, TCF/LEF, T-cell factor/lymphoid enhancer factor, AST, aspartate aminotransferase, Pharmacology, TSA, thermal shift assay, 0302 clinical medicine, WAT, white adipose tissues, HSL, hormone sensitive lipase, FFA, free fatty acids, MTT, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide, General Pharmacology, Toxicology and Pharmaceutics, NF-κB, nuclear factor kappa B, RER, respiratory exchange ratio, 0303 health sciences, LRP6, low-density lipoprotein receptor related protein 6, TNF, tumor necrosis factor, NAS, NAFLD activity score, biology, TG, triglyceride, Chemistry, NIAAA, National Institute on Alcohol Abuse and Alcoholism, Liver cell, CYP2E1, cytochrome P450 2E1, 030220 oncology & carcinogenesis, LDLR, low-density lipoprotein receptor, NRF2, nuclear factor erythroid 2-related factor 2, IRS, insulin receptor substrate, GTT, glucose tolerance test, Original Article, medicine.symptom, Safety, IRTK, insulin receptor tyrosine kinase, GSK3β, glycogen synthase kinase 3 beta, NAFLD, non-alcoholic fatty liver disease, ALD, alcoholic liver disease, SREBP-1c, sterol regulatory element-binding protein 1c, Inflammation, SPR, surface plasmon resonance, AMPK, adenosine 5′-monophosphate (AMP)-activated protein kinase, SAMC, S-allylmercaptocysteine, 03 medical and health sciences, ADIPOQ, adiponectin, Insulin resistance, ORF, open reading frame, PA, palmitate acid, ALT, alanine aminotransferase, medicine, CPT1, carnitine palmitoyltransferase I, IRS-1, GRB14, growth factor receptor-bound protein 14, Protein kinase B, 030304 developmental biology, ATGL, adipose triglyceride lipase, PPARα, peroxisome proliferator-activated receptor alpha, AKT, lcsh:RM1-950, ALDH2, aldehyde dehydrogenase 2, GSK3β, Lipid metabolism, medicine.disease, S-Allylmercaptocysteine, WT, wild-type, IL, interleukin, TC, total cholesterol, Insulin receptor, FDA, U.S. Food and Drug Administration, lcsh:Therapeutics. Pharmacology, biology.protein, NAC, N-acetyl-cysteine, Steatosis, IGF-1, insulin-like growth factors-1
Abstract

Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC (300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis, insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor (INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3β signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC (250 μmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC's beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model. Long-term (90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3β pathway., Graphical abstract S-Allylmercaptocysteine, a water-soluble component extracted from aged garlic, is an effective and safe hepato-protective complimentary agent against alcoholic liver disease partly through a direct modulation of insulin receptor signaling.Image 1

Published
2020

2. Liver Pyruvate Kinase Promotes NAFLD/NASH in Both Mice and Humans in a Sex-Specific Manner

Author

Aldons J. Lusis, Raquel Floyd, Simon Sabir, Miklós Péterfy, Paola León-Mimila, Anthony E. Jones, Linsey Stiles, Dulshan W. Jayasekera, Samuel Canizales-Quinteros, Adriana Huertas-Vazquez, Varun Shravah, Angel A. Cortez, Karthickeyan Chella Krishnan, and Ajit S. Divakaruni

Subjects
0301 basic medicine, HMDP, Hybrid Mouse Diversity Panel, Male, OXPHOS, oxidative phosphorylation, Mitochondrion, HF/HS diet, diet rich in fat and sucrose, CDAHFD, choline-deficient, L-amino acid-defined, high-fat diet with 0.1% methionine, Oral and gastrointestinal, Hepatitis, LPK, liver pyruvate kinase, Mice, 0302 clinical medicine, GGT, gamma-glutamyl transpeptidase, Fibrosis, Loss of Function Mutation, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, 2.1 Biological and endogenous factors, Aetiology, scrRNA, scrambled RNA, Original Research, CE, cholesteryl ester, TG, triglyceride, Liver Disease, NAS, NAFLD Activity Score, Gastroenterology, Middle Aged, Up-Regulation, Liver, Gain of Function Mutation, Lipogenesis, Mitochondrial Dysfunction, shRNA, short hairpin RNA, Liver Fibrosis, qPCR, quantitative polymerase chain reaction, 030211 gastroenterology & hepatology, Female, NASH, nonalcoholic steatohepatitis, ITT, insulin tolerance tests, L/PTT, lactate/pyruvate tolerance tests, Adult, medicine.medical_specialty, DEGs, differentially expressed genes, Chronic Liver Disease and Cirrhosis, ETC, electron transport chain, HDL, high-density lipoprotein, Pyruvate Kinase, DNL, de novo lipogenesis, SEM, standard error of the mean, 03 medical and health sciences, Insulin resistance, ROS, reactive oxygen species, Sex Factors, Liver Pyruvate Kinase, Internal medicine, NAFLD, AAV8, adeno-associated virus serotype 8, FFA, free fatty acid, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, Obesity, Gene Silencing, Sex Differences, Metabolic and endocrine, TBG, thyroxine binding globulin, Nutrition, Hepatology, Animal, business.industry, Gene Expression Profiling, medicine.disease, TC, total cholesterol, Disease Models, Animal, 030104 developmental biology, Endocrinology, siRNA, small interfering RNA, Disease Models, NAFLD, nonalcoholic fatty liver disease, Steatosis, Digestive Diseases, business, Dyslipidemia, Pyruvate kinase, GTT, glucose tolerance tests
Abstract

Background & Aims The etiology of nonalcoholic fatty liver disease (NAFLD) is poorly understood, with males and certain populations exhibiting markedly increased susceptibility. Using a systems genetics approach involving multi-omic analysis of ∼100 diverse inbred strains of mice, we recently identified several candidate genes driving NAFLD. We investigated the role of one of these, liver pyruvate kinase (L-PK or Pklr), in NAFLD by using patient samples and mouse models. Methods We examined L-PK expression in mice of both sexes and in a cohort of bariatric surgery patients. We used liver-specific loss- and gain-of-function strategies in independent animal models of diet-induced steatosis and fibrosis. After treatment, we measured several metabolic phenotypes including obesity, insulin resistance, dyslipidemia, liver steatosis, and fibrosis. Liver tissues were used for gene expression and immunoblotting, and liver mitochondria bioenergetics was characterized. Results In both mice and humans, L-PK expression is up-regulated in males via testosterone and is strongly associated with NAFLD severity. In a steatosis model, L-PK silencing in male mice improved glucose tolerance, insulin sensitivity, and lactate/pyruvate tolerance compared with controls. Furthermore, these animals had reduced plasma cholesterol levels and intrahepatic triglyceride accumulation. Conversely, L-PK overexpression in male mice resulted in augmented disease phenotypes. In contrast, female mice overexpressing L-PK were unaffected. Mechanistically, L-PK altered mitochondrial pyruvate flux and its incorporation into citrate, and this, in turn, increased liver triglycerides via up-regulated de novo lipogenesis and increased PNPLA3 levels accompanied by mitochondrial dysfunction. Also, L-PK increased plasma cholesterol levels via increased PCSK9 levels. On the other hand, L-PK silencing reduced de novo lipogenesis and PNPLA3 and PCSK9 levels and improved mitochondrial function. Finally, in fibrosis model, we demonstrate that L-PK silencing in male mice reduced both liver steatosis and fibrosis, accompanied by reduced de novo lipogenesis and improved mitochondrial function. Conclusions L-PK acts in a male-specific manner in the development of liver steatosis and fibrosis. Because NAFLD/nonalcoholic steatohepatitis exhibit sexual dimorphism, our results have important implications for the development of personalized therapeutics., Graphical abstract

Published
2020

3. Metabolic dysfunction-associated fatty liver disease increases risk of adverse outcomes in patients with chronic hepatitis B

Author

Harry L.A. Janssen, Laurens A. van Kleef, Bettina E. Hansen, Keyur Patel, Willem P. Brouwer, Robert A. de Man, Hannah S.J. Choi, Robert J. de Knegt, Milan J. Sonneveld, and Gastroenterology & Hepatology

Subjects
medicine.medical_specialty, NAFLD, non-alcoholic fatty liver disease, Metabolic dysfunction-associated fatty liver disease, Survival, Hepatocellular carcinoma, medicine.medical_treatment, NASH, non-alcoholic steatohepatitis, MAFLD, RC799-869, Liver transplantation, Gastroenterology, Chronic hepatitis B, FLD, fatty liver disease, ULN, upper limit of normal, SDG 3 - Good Health and Well-being, Diabetes mellitus, Internal medicine, ALT, alanine aminotransferase, Internal Medicine, medicine, HBV, Immunology and Allergy, MAFLD, metabolic dysfunction-associated fatty liver disease, HCC, NHANES, National Health and Nutrition Examination Survey, Steatohepatitis, NAS, NAFLD activity score, Hepatology, medicine.diagnostic_test, business.industry, Fatty liver, Hepatitis B, Diseases of the digestive system. Gastroenterology, medicine.disease, CHB, Liver biopsy, Adverse clinical outcomes, CHB, chronic hepatitis B, Steatosis, business, HCC, hepatocellular carcinoma, P25–P75, 25th–75th percentile, HR, hazard rate, Research Article, aHR, adjusted hazard rate
Abstract

Background & Aims A recent consensus document has defined metabolic dysfunction-associated fatty liver disease (MAFLD) as hepatic steatosis together with overweight, diabetes, and/or a combination of other metabolic risk factors. The clinical relevance of this novel diagnosis is unknown among patients with chronic hepatitis B (CHB). We studied the association between MAFLD (with or without steatohepatitis) and adverse clinical outcomes in patients with CHB. Methods We performed a retrospective long-term follow-up cohort study at 2 tertiary hospitals in patients with CHB who underwent liver biopsy. Biopsies were reassessed for steatosis, degree of fibrosis, and presence of steatohepatitis. Associations with event-free hepatocellular carcinoma (HCC)-free and transplant-free survival were explored. Results In our cohort, 1076 patients were included, median follow-up was 9.8 years (25th–75th percentile: 6.6−14.0), and 107 events occurred in 78 patients, comprising death (n = 43), HCC (n = 36), liver decompensation (n = 21), and/or liver transplantation (n = 7). MAFLD was present in 296 (27.5%) patients and was associated with reduced event-free (adjusted hazard ratio [aHR] 2.00, 95% CI 1.26–3.19), HCC-free (aHR 1.93, 95% CI 1.17–3.21), and transplant-free survival (aHR 1.80, 95% CI 0.98–3.29) in multivariable analysis. Among patients with MAFLD, the presence of steatohepatitis (p = 0.95, log-rank test) was not associated with adverse outcomes. Conclusions The presence of MAFLD in patients with CHB was associated with an increased risk for liver-related clinical events and death. Among patients with MAFLD, steatohepatitis did not increase the risk of adverse outcomes. Our findings highlight the importance of metabolic dysfunction in patients with CHB. Lay summary Recently, metabolic dysfunction-associated fatty liver disease (MAFLD) has been defined as fatty liver disease with signs of metabolic dysfunction. Among patients with chronic hepatitis B, MAFLD was associated with liver-related events and death. Metabolic health assessment should be encouraged among patients with chronic hepatitis B, especially in those with fatty liver disease., Graphical abstract, Highlights • Recently, MAFLD was defined as hepatic steatosis in the presence of metabolic dysfunction (e.g. overweight, diabetes). • In patients with chronic hepatitis, MAFLD was associated with reduced event-free (p

Published
2021

4. Prospective comparison of transient elastography, MRI and serum scores for grading steatosis and detecting non-alcoholic steatohepatitis in bariatric surgery candidates

Author

Philippe Garteiser, Pauline Jouet, Marco Dioguardi Burgio, Bernard E. Van Beers, Pierre Bedossa, Daniela Calabrese, Séverine Ledoux, Laurent Castera, Muriel Coupaye, Marina Esposito-Farèse, Sabrina Doblas, and Simon Msika

Subjects
medicine.medical_specialty, NAFLD, non-alcoholic fatty liver disease, bariatric surgery, NASH, non-alcoholic steatohepatitis, LSM, liver stiffness measurement, RC799-869, NAFLD, Nonalcoholic fatty liver disease, Non-invasive diagnosis, Internal Medicine, steatosis, AUROC, area under the receiver operating characteristic curve, Immunology and Allergy, Medicine, ST, SteatoTest, Grading (tumors), NAS, NAFLD activity score, Se, sensitivity, Hepatology, medicine.diagnostic_test, business.industry, Fatty liver, Gastroenterology, NASH, Diseases of the digestive system. Gastroenterology, medicine.disease, MRI-PDFF, MRI-proton density fat fraction, transient elastography, CAP, PPV, positive predictive value, Surgery, TE, transient elastography, FLIP, fatty liver inhibition of progression, HSI, hepatic steatosis index, NPV, negative predictive value, Liver biopsy, Sp, specificity, Steatosis, Steatohepatitis, CAP, controlled attenuation parameter, business, Transient elastography, Body mass index, MRI-PDFF, FLI, fatty liver index, Research Article
Abstract

Background & Aims Tools for the non-invasive diagnosis of non-alcoholic steatohepatitis (NASH) in morbidly obese patients with suspected non-alcoholic fatty liver disease (NAFLD) are an unmet clinical need. We prospectively compared the performance of transient elastography, MRI, and 3 serum scores for the diagnosis of NAFLD, grading of steatosis and detection of NASH in bariatric surgery candidates. Methods Of 186 patients screened, 152 underwent liver biopsy, which was used as a reference for NAFLD (steatosis [S]>5%), steatosis grading and NASH diagnosis. Biopsies were read by a single expert pathologist. MRI-based proton density fat fraction (MRI-PDFF) was measured in an open-bore, vertical field 1.0T scanner and controlled attenuation parameter (CAP) was measured by transient elastography, using the XL probe. Serum scores (SteatoTest, hepatic steatosis index and fatty liver index) were also calculated. Results The applicability of MRI was better than that of FibroScan (98% vs. 79%; p 5%, S>33%, S>66% and NASH, respectively. Transient elastography had an AUROC of 0.80 for significant fibrosis (F0-F1 vs. F2-F3). MRI-PDFF had AUROCs of 0.97, 0.95, 0.92 and 0.84 for S>5%, S>33%, S>66% and NASH, respectively. When compared head-to-head in the 97 patients with all valid tests available, MRI-PDFF outperformed CAP for grading steatosis (S>33%, AUROC 0.97 vs. 0.78; p 66%, AUROC 0.93 vs. 0.75; p = 0.0015) and diagnosing NASH (AUROC 0.82 vs. 0.68; p = 0.0056). When compared in “intention to diagnose” analysis, MRI-PDFF outperformed CAP, hepatic steatosis index and fatty liver index for grading steatosis (S>5%, S>33% and S>66%). Conclusion MRI-PDFF outperforms CAP for diagnosing NAFLD, grading steatosis and excluding NASH in morbidly obese patients undergoing bariatric surgery. Lay summary Non-invasive tests for detecting fatty liver and steatohepatitis, the active form of the disease, have not been well studied in obese patients who are candidates for bariatric surgery. The most popular tests for this purpose are Fibroscan, which can be used to measure the controlled attenuation parameter (CAP), and magnetic resonance imaging, which can be used to measure the proton density fat fraction (MRI-PDFF). We found that, when taking liver biopsy as a reference, MRI-PDFF performed better than CAP for detecting and grading fatty liver as well as excluding steatohepatitis in morbidly obese patients undergoing bariatric surgery., Graphical abstract, Highlights • NAFLD/NASH is common in morbidly obese patients undergoing bariatric surgery. • Non-invasive diagnosis of NAFLD/NASH is an unmet need in this population. • We compared MRI-PDFF, CAP and serum scores for grading steatosis and diagnosing NASH, using liver biopsy as a reference. • Applicability of magnetic resonance imaging was better than that of Fibroscan. • MRI-PDFF outperformed CAP for diagnosing and grading steatosis, as well as excluding NASH.

Published
2021

5. PAR2 controls cholesterol homeostasis and lipid metabolism in nonalcoholic fatty liver disease

Author

Elizabeth K. Fletcher, Athan Kuliopulos, Nga Nguyen, Srijoy Guha, Andrew Shearer, Daniel H. Cox, James D. Baleja, Ying Wang, Manal F. Abdelmalek, Lidija Covic, and Rajashree Rana

Subjects
Liver Cirrhosis, Male, 0301 basic medicine, GTP-Binding Protein alpha Subunits, Gi-Go, Mice, chemistry.chemical_compound, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, Mice, Knockout, NAS, NAFLD activity score, medicine.diagnostic_test, Bile acid, Reverse cholesterol transport, Fatty liver, NASH, Middle Aged, 3. Good health, medicine.anatomical_structure, Cholesterol, Liver, Fib, Fibrosis, Liver biopsy, Hepatocyte, JNK, c-Jun N-terminal kinase, Disease Progression, Female, Original Article, NASH, nonalcoholic steatohepatitis, Adult, medicine.medical_specialty, lcsh:Internal medicine, medicine.drug_class, 030209 endocrinology & metabolism, Diet, High-Fat, 03 medical and health sciences, PAR2, Protease-Activated Receptor 2, Protease-activated receptor 2, Internal medicine, medicine, Animals, Humans, Mitogen-Activated Protein Kinase 9, Receptor, PAR-2, Mitogen-Activated Protein Kinase 8, lcsh:RC31-1245, Molecular Biology, Aged, business.industry, Lipid metabolism, Cell Biology, Energy metabolism, Lipid Metabolism, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, chemistry, Lipid Peroxidation, NAFLD, nonalcoholic fatty liver disease, business
Abstract

Objective Increases in hepatic and plasma cholesterol occur in patients with nonalcoholic fatty liver disease (NAFLD), although the reason for this is not well understood. We investigated whether Protease-Activated Receptor 2 (PAR2) plays a role in cholesterol and lipid homeostasis in NAFLD. Methods Human liver biopsies (n = 108) were quantified for PAR2 expression from NAFLD cases randomly selected and stratified by liver fibrosis stage, the primary predictor for clinical outcomes, while controlling for age, gender, and BMI between fibrosis groups. Demographic data and laboratory studies on plasma samples were obtained within 6 months of liver biopsy. Wild-type and PAR2-KO (C57BL/6 F2rl1−/−) mice were fed either normal or high fat diet for 16 weeks and plasma and liver assayed for lipids and soluble metabolites. Results Severity of NAFLD and plasma cholesterol levels significantly correlated with hepatocyte PAR2 expression in NAFLD patients. Conversely, PAR2 deficiency in mice resulted in reduced expression of key hepatic genes involved in cholesterol synthesis, a 50% drop in plasma and total liver cholesterol, and induced a reverse cholesterol transport system that culminated in 25% higher fecal bile acid output. PAR2-deficient mice exhibited enhanced fatty acid β-oxidation with a ketogenic shift and an unexpected increase in liver glycogenesis. Mechanistic studies identified Gi-Jnk1/2 as key downstream effectors of protease-activated PAR2 in the regulation of lipid and cholesterol homeostasis in liver. Conclusions These data indicate that PAR2 may be a new target for the suppression of plasma cholesterol and hepatic fat accumulation in NAFLD and related metabolic conditions., Highlights • Increases in cholesterol in NAFLD and NASH is a vexing problem. • PAR2 has been identified as a connecting hub between metabolism and fibrosis. • Severity of NAFLD and cholesterol correlate with hepatocyte PAR2 expression. • PAR2 suppresses reverse cholesterol transport and lipid breakdown in liver.

Published
2019

6. Indian National Association for Study of the Liver (INASL) Guidance Paper on Nomenclature, Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease (NAFLD).

Author

Duseja A, Singh SP, De A, Madan K, Rao PN, Shukla A, Choudhuri G, Saigal S, Shalimar, Arora A, Anand AC, Das A, Kumar A, Eapen CE, Devadas K, Shenoy KT, Panigrahi M, Wadhawan M, Rathi M, Kumar M, Choudhary NS, Saraf N, Nath P, Kar S, Alam S, Shah S, Nijhawan S, Acharya SK, Aggarwal V, Saraswat VA, and Chawla YK

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease globally and in India. The already high burden of NAFLD in India is expected to further increase in the future in parallel with the ongoing epidemics of obesity and type 2 diabetes mellitus. Given the high prevalence of NAFLD in the community, it is crucial to identify those at risk of progressive liver disease to streamline referral and guide proper management. Existing guidelines on NAFLD by various international societies fail to capture the entire landscape of NAFLD in India and are often difficult to incorporate in clinical practice due to fundamental differences in sociocultural aspects and health infrastructure available in India. A lot of progress has been made in the field of NAFLD in the 7 years since the initial position paper by the Indian National Association for the Study of Liver on NAFLD in 2015. Further, the ongoing debate on the nomenclature of NAFLD is creating undue confusion among clinical practitioners. The ensuing comprehensive review provides consensus-based, guidance statements on the nomenclature, diagnosis, and treatment of NAFLD that are practically implementable in the Indian setting., (© 2022 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Published
2023
Full Text
View/download PDF

7. Hepatoprotective Effects of Aureobasidium pullulans Derived β 1,3-1,6 Glucans in a Murine Model of Non-alcoholic Steatohepatitis.

Author

Ikewaki N, Levy GA, Kurosawa G, Iwasaki M, Dedeepiya VD, Vaddi S, Senthilkumar R, Preethy S, and Abraham SJK

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent conditions characterized by inflammation and fibrosis of the liver, which can progress to cirrhosis and hepatocellular carcinoma if left untreated. Conventional modalities are mainly symptomatic, with no definite solution. Beta-glucan-based biological response modifiers are a potential strategy in lieu of their beneficial metabolic effects. Aureobasidium pullulans strains AFO-202 and N-163 beta-glucans were evaluated for anti-fibrotic and anti-inflammatory hepatoprotective potentials in a NASH animal model in this study., Methods: In the STAM™ murine model of NASH, five groups were studied for 8 weeks: (1) vehicle (RO water), (2) AFO-202 beta-glucan; (3) N-163 beta-glucan, (4) AFO-202+N-163 beta-glucan, and (5) telmisartan (standard pharmacological intervention). Evaluation of biochemical parameters in plasma and hepatic histology including Sirius red staining and F4/80 immunostaining were performed., Results: AFO-202 beta-glucan significantly decreased inflammation-associated hepatic cell ballooning and steatosis. N-163 beta-glucan decreased fibrosis and inflammation significantly ( P value < 0.05). The combination of AFO-202 with N-163 significantly decreased the NAFLD Activity Score (NAS) compared with other groups., Conclusion: This preclinical study supports the potential of N-163 and AFO-202 beta-glucans alone or in combination as potential preventive and therapeutic agent(s), for NASH., (© 2022 Indian National Association for Study of the Liver.)

Published
2022
Full Text
View/download PDF

8. Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches

Author

F. Tuccillo, Joseph L. Evans, Antonella Borrelli, Franco M. Buonaguro, Ira D. Goldfine, P. Bonelli, and Aldo Mancini

Subjects
Cirrhosis, HCC, Hepatocellular carcinoma, MnSOD, Manganese superoxide dismutase, Review Article, ecSOD, Extracellular Cu/ZnSOD, Biochemistry, Antioxidants, GIT, Gastrointestinal tract, 0302 clinical medicine, Fibrosis, MS, Metabolic syndrome, GLP-1, Glucagon-like peptide-1, LPS, Lipopolysaccharide, lcsh:QH301-705.5, Interventions, DASH, Drug-associated steatohepatitis, SSAO, Semicarbazide-sensitive amine oxidase, NKT, Natural killer T, Liver Neoplasms, NAFLD, Non-alcoholic fatty liver disease, PAMPs, Pathogen-associated molecular patterns (PAMPs), LPL, Lipoprotein lipase, PNPLA3, Patatin-like phospholipase 3, 030211 gastroenterology & hepatology, SCD1, Stearoyl-coenzyme A desaturase 1, AST, Aspartate aminotransferase, PGC-1α, Coactivator peroxisome proliferator-activated receptor-γ-1α, INT-747, Obeticholic acid (OCA), lcsh:Medicine (General), NADH, Nicotinamide adenine dinucleotide, LPB, Lipopolysaccharide-binding protein, Carcinoma, Hepatocellular, FIAF, Fasting-induced adipose factor, CS + WR, Cold storage and warm reperfusion, GF, Germ-free, FADH, Flavin adenine dinucleotide, NO, Nitric oxide, digestive system, CCR2/CCR5, C-C chemokine receptor types 2 and 5, 03 medical and health sciences, Manganese superoxide dismutase, Humans, CD14, Cluster of differentiation 14, NASH, Non-alcoholic steatohepatitis, Probiotics, nutritional and metabolic diseases, medicine.disease, VLX103, Venlafaxine-103, digestive system diseases, PIVENS, Pioglitazone versus Vitamin E versus Placebo, 030104 developmental biology, chemistry, PASH, PNPLA3-associated steatohepatitis, FXR, Farnesoid X receptor, CASH, Chemotherapy-associated steatohepatitis, LOXL, Lysyl oxidase and lysyl oxidase-like, Steatohepatitis, Reactive Oxygen Species, Mkt, Market, ROS, Reactive oxygen species, TZDs, Thiazolidinediones, 0301 basic medicine, ETC, Respiratory electron transport chain, Clinical Biochemistry, VAP-1, Vascular adhesion protein-1, PXS-4728A, SSAO/VAP-1 inhibitor BI 1467335, HVPG, Hepatic venous pressure gradient, •OH, Hydroxyl free radicals, HPC, Primary hepatic carcinoma, Chronic liver disease, SOD, Superoxide dismutase, FGF21, Fibroblast growth factor 21, aa, Amino acid, chemistry.chemical_compound, BASH, Both alcoholic and non-alcoholic liver disease, Non-alcoholic Fatty Liver Disease, H2, Molecular hydrogen, lcsh:R5-920, NAS, NAFLD activity score, medicine.diagnostic_test, NN2211, Liraglutide, O2, Molecular oxygen, Fatty liver, Elafibranor, Obeticholic acid, Drugs, ER, Estrogen receptor, IL-10, Interleukin-10, Liver, Liver biopsy, JNK, c-Jun N-terminal kinase, ASK1, Apoptosis signal- regulating kinase 1, Cu/ZnSOD, Copper/zinc superoxide dismutase, RG-125 AZD4076, N-acetylgalactosamine (GalNAc)-conjugated anti-miR-103/107 oligonucleotide, TLR, Toll-like receptor, H. pilory, Helicobacter pylori, HSCs, Hepatic stellate cells, PPAR, Peroxisome proliferator-activated receptor, medicine, ATP, Adenosine 5c-triphosphate, IL-6, Interleukin-6, MDA, Malondialdehyde, γgt, Gamma-glutamyl transferase, business.industry, Organic Chemistry, ALT, Alanine aminotransferase, TNF, Tumor necrosis factor, NF-κB, Nuclear factor kappa, O2·–, Superoxide anion, FGF19, Fibroblast growth factor 19, Gastrointestinal Microbiome, DPP-4 inhibitor, Dipeptidyl peptidase 4 inhibitor, FDA, Food and drug administration, Oxidative Stress, CVC, Cenicriviroc, lcsh:Biology (General), FFA, Free fatty acids, Cancer research, NAP, H. pylori-induced neutrophil-activating protein, Saroglitazar-ZYH1, [(S)-α-ethoxy-4-{2-[2-methyl-5-(4-methylthio) phenyl)]-1H-pyrrol-1-yl]-ethoxy})-benzenepropanoic acid magnesium salt], business
Abstract

Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC). Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the "Two Hit Theory" to the "Multiple Hit Theory". However, the general consensus is that the gut microbiota, oxidative stress, and mitochondrial damage play key roles in the pathogenesis of NASH. The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of reactive oxygen species (ROS). The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis. This problem represents the first "Achilles' heel" of the new molecules being evaluated in most ongoing clinical trials. The second is the inability of these molecules to reach the mitochondria, the primary sites of energy production and ROS generation. Recently, a variety of non-pharmacological and pharmacological treatment approaches for NASH have been evaluated including vitamin E, the thiazolidinediones, and novel molecules related to NASH pathogenesis (including obeticholic acid and elafibranor). Recently, a new isoform of human manganese superoxide dismutase (MnSOD) was isolated and obtained in a synthetic recombinant form designated rMnSOD. This protein has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis. Based on these distinctive characteristics, it can be hypothesized that this novel recombinant protein (rMnSOD) potentially represents a new and highly efficient adjuvant therapy to counteract the progression from NASH to HCC.

Published
2018

9. Biopsy-proven progressive fatty liver disease nine months post mini-gastric bypass surgery: A case study

Author

Nasser Rakhshani, Alireza Khalaj, Maryam Barzin, and Mohammad Ali Kalantar Motamedi

Subjects
medicine.medical_specialty, Abdominal pain, NAFLD, non-alcoholic fatty liver disease, BMI, body mass index, Mini-gastric bypass, 030209 endocrinology & metabolism, Case Report, WL, weight loss, 03 medical and health sciences, MGB, mini-gastric bypass, 0302 clinical medicine, Weight loss, Biopsy, medicine, Hepatic insufficiency, Hypoalbuminemia, Bariatric surgery, NAS, NAFLD activity score, medicine.diagnostic_test, business.industry, RYGB, Roux-en-Y gastric bypass, Fatty liver, medicine.disease, Surgery, Parenteral nutrition, Liver biopsy, 030211 gastroenterology & hepatology, Liver function, medicine.symptom, business, Non-alcoholic fatty liver disease
Abstract

Highlights • Performance of MGB with a 200 cm bypassed limb in a morbidly obese female. • Presentation of anemia, low albumin, elevated LFT at 8th month despite good intake. • NAFLD activity score progressed from 2/8 to 7/8, leading to revisional surgery. • Rapid course of weight loss after BS and/or long bypassed limb could be responsible. • Bowel length measurement is recommended to avoid a short common intestinal channel., Introduction Mini-gastric bypass (MGB) is a popular bariatric procedure. Its effect on non-alcoholic fatty liver disease (NAFLD), however, has not yet been comprehensively studied. Presentation of case A 57 year-old non-alcoholic female with a body mass index of 42.8 kg/m2 underwent MGB without any incident. A concurrent liver biopsy showed an NAFLD activity score (NAS) of 2/8 without fibrosis. She presented at postoperative month eight with edema, vague abdominal pain, nausea, and vomiting and was hospitalized. Her BMI had dropped to 25.7 kg/m2. Her blood workup revealed mild anemia, mildly elevated liver enzymes, and hypoalbuminemia (2.5 g/dL). Liver ultrasound revealed grade-2 fatty liver. She received parenteral nutrition and intensive nutrient supplementation. Nevertheless, with regard to unsuccessful supportive measures and rising liver enzymes, revisional surgery −gastrogastrostomy- was performed. Her liver biopsy demonstrated a NAS of 7/8 at the time of revisional surgery. Her postoperative course was uneventful and she was discharged after one week. Discussion Bariatric surgery has shown favorable results regarding improvement of NAFLD in morbid obesity. This beneficial effect has been linked to the amount of weight loss. However, case reports have shown deteriorating liver function and NAFLD even after significant weight loss. They all have in common significant weight loss in a relatively short period of time. There may also be a connection between specific bariatric surgery procedures and this phenomenon. Conclusion Future studies comparing the effect of various bariatric procedures, including MGB, are necessary to help clinicians decide the optimal procedure for patients with this liver condition.

Published
2017

10. A blocking monoclonal antibody to CCL24 alleviates liver fibrosis and inflammation in experimental models of liver damage

Author

Neta Barashi, Massimo Pinzani, Michal Segal-Salto, Arnon Aharon, Scott L. Friedman, Vicktoria Edelshtein, Jacob George, Dan Haberman, Andrew M. Hall, Adi Mor, Sharon Hashmueli, Avi Katav, and Yaakov Maor

Subjects
Chemokine, NAFLD, non-alcoholic fatty liver disease, MFI, median fluorescence intensity, NASH, non-alcoholic steatohepatitis, CCR3, C-C motif chemokine ligand 24, AST, aspartate aminotransferase, CCR3, C-C motif chemokine receptor 3, MCD, methionine-choline deficient, α-SMA, α-smooth muscle actin, Chemokine receptor, Fibrosis, ALT, alanine aminotransferase, Internal Medicine, medicine, Immunology and Allergy, lcsh:RC799-869, IL-6, interleukin-6, Antibody, Non-alcoholic steatohepatitis, NAS, NAFLD activity score, TAA, thioacetamide, Hepatology, biology, business.industry, CM-101, Gastroenterology, medicine.disease, WT, wild-type, PBMC, peripheral blood mononuclear cells, Knockout mouse, Cancer research, biology.protein, Hepatic stellate cell, CCL24, CCL24, C-C motif chemokine ligand 24, lcsh:Diseases of the digestive system. Gastroenterology, MMP, matrix metallopeptidase, Steatohepatitis, business, HSCs, hepatic stellate cells, Research Article, Non-alcoholic fatty liver disease
Abstract

Background & Aims C-C motif chemokine ligand 24 (CCL24) is a chemokine that regulates inflammatory and fibrotic activities through its receptor, C-C motif chemokine receptor (CCR3). The aim of the study was to evaluate the involvement of the CCL24-CCR3 axis in liver fibrosis and inflammation and to assess the potential of its blockade, by a monoclonal anti-CCL24 antibody, as a therapeutic strategy for non-alcoholic steatohepatitis (NASH) and liver fibrosis. Methods Expression of CCL24 and CCR3 was evaluated in liver biopsies and blood samples. CCL24 involvement in NAFLD/NASH pathogenesis was assessed in Ccl24 knockout mouse using the methionine-choline deficient (MCD) diet experimental model. Antifibrotic and anti-inflammatory effects of CM-101 were tested in the MCD and STAM mouse models and in the thioacetamide (TAA) model in rats. Liver enzymes, liver morphology, histology and collagen deposition, as well as fibrosis- and inflammation-related protein expression were assessed. Activation of hepatic stellate cells (HSCs) was evaluated in the human LX2 cell line. Results Patients with NASH and advanced NAFLD exhibited significant expression of both CCL24 and CCR3 in liver and blood samples. In the experimental MCD-diet model, Ccl24 knockout mice showed an attenuated liver damage response compared to wild-type mice, exhibiting reduced histological NAFLD activity scores and fibrosis, as well as lower levels of liver enzymes. Blocking CCL24 using CM-101 robustly reduced liver damage in 3 experimental animal models (MCD, STAM and TAA), as demonstrated by attenuation of liver fibrosis and NAFLD activity score. Furthermore, blocking CCL24 by CM-101 significantly inhibited CCL24-induced HSC motility, α-SMA expression and pro-collagen I secretion. Conclusion Our results reveal that blocking CCL24 significantly attenuates liver fibrosis and inflammation and may have a potential therapeutic effect in patients with NASH and/or liver fibrosis. Lay summary CCL24 is a chemokine that regulates inflammation and fibrosis. It was found to be significantly expressed in patients with non-alcoholic steatohepatitis, in whom it regulates profibrotic processes in the liver. Herein, we show that blockade of CCL24 using a monoclonal antibody robustly attenuated liver fibrosis and inflammation in animal models, thus suggesting a potential therapeutic role for an anti-CCL24 agent., Graphical abstract, Highlights • CCL24 is a chemokine that regulates inflammatory and fibrotic activities through its receptor, CCR3. • Significant expression of CCL24 and CCR3 were found in liver biopsies and blood samples from patients with NAFLD/NASH. • CM-101, a monoclonal antibody that selectively targets CCL24, significantly attenuates fibrotic and inflammatory processes. • Blocking CCL24 may have a potential therapeutic effect in NASH and liver fibrosis.

Published
2020

11. Pharmacotherapeutic Impact on Nonalcoholic Steatohepatitis Histology: A Systematic Review and Network Meta-analysis.

Author

Kovalic AJ

Abstract

Background: Due to lack of targeted treatment options and inconsistent utilization of histologic endpoints among clinical trials, identifying efficacious pharmacotherapies for nonalcoholic steatohepatitis [NASH] has proven challenging., Methods: A thorough systematic review and frequentist random-effects network meta-analysis was performed across all randomized clinical trials reporting a pharmacotherapeutic intervention on biopsy-proven NASH. Primary outcomes were based on the most current, up-to-date recommended histologic endpoints., Results: A total of 40 RCTs were identified including 6593 total patients. The most effective and statistically significant treatment interventions for minimum two-point improvement in NAFLD Activity Score were aldafermin 1 mg [RR 7.69, 95% CI 2.00; 29.57], vitamin E 800 IU in combination with pioglitazone 45 mg [RR 3.38, 95% CI 1.88; 6.07], pioglitazone 45 mg [RR 3.29, 95% CI 1.74; 6.22], vitamin E 800 IU [RR 2.06, 95% CI 1.33; 3.18], resmetirom 80 mg [RR 1.74, 95% CI 1.03; 2.94], obeticholic acid 25 mg [RR 1.63, 95% CI 1.32; 2.01], and obeticholic acid 10 mg [RR 1.31, 95% CI 1.02; 1.67]). The most robust pharmacotherapies for NASH resolution without worsening fibrosis were found to be aldafermin 1 mg [RR 5.77, 95% CI 1.48; 22.51], pioglitazone 45 mg [RR 2.65, 95% CI 1.43; 4.91], vitamin E 800 IU in combination with pioglitazone 45 mg [RR 2.64, 95% CI 1.36; 5.12], pioglitazone 30 mg [RR 2.46, 95% CI 1.56; 3.88], vitamin E 800 IU [RR 1.90, 95% CI 1.20; 3.00], and obeticholic acid 25 mg [RR 1.52, 95% CI 1.03; 2.23]). Obeticholic acid had a significant improvement on fibrosis. Multiple interventions were found to improve individual histologic scores across secondary outcome analyses and are detailed below., Conclusion: This novel systematic review and network meta-analysis represents the most comprehensive investigation to date regarding the pharmacotherapeutic options for biopsy-proven NASH using current recommended histologic endpoints., (© 2022 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Published
2022
Full Text
View/download PDF

12. FibroScan-AST (FAST) Score for Nonalcoholic Steatohepatitis - Validation in an Indian Cohort.

Author

De A, Keisham A, Mishra S, Mehta M, Verma N, Premkumar M, Taneja S, Das A, Singh V, and Duseja A

Abstract

Background: The FibroScan-AST (FAST) score was recently described to detect patients with nonalcoholic steatohepatitis (NASH) having elevated nonalcoholic fatty liver disease (NAFLD) activity score (NAS ≥ 4) and significant fibrosis (≥ F2) on liver biopsy (NASH+ NAS ≥ 4 + F ≥ 2)., Aim: The aim of this study was to validate the FAST score in Indian patients with NAFLD and to derive optimal cut-offs., Methods: Sixty patients with biopsy-proven NAFLD [men: 38 (63.3%), age 40 (32-52) years] with all parameters for assessing the FAST score within 3 months of liver histology were retrospectively analysed., Results: Histological NASH was present in 17 patients (28.3%), while 11 (18.3%) patients had NASH + NAS ≥ 4 + F ≥ 2. The area under the curve (AUROC) of the FAST score for discriminating NASH + NAS ≥ 4 + F ≥ 2 was 0.81. Using cut-offs by Newsome et al , the rule-out cut-off (FAST: ≤ 0.35) had a negative predictive value (NPV) of 0.88 [sensitivity: 0.91, specificity: 0.14, negative likelihood ratio (LR): 0.64], while the rule-in cut-off (FAST: ≥ 0.67) had a positive predictive value (PPV) of 0.33 (sensitivity: 0.73, specificity: 0.67, positive LR: 2.22). Fifteen (25%) patients were correctly classified as per histology, while 28 (46.67%) patients fell in the grey zone. On recalculating the optimal cut-offs for our patients, the rule-out cut-off (FAST: ≤ 0.55) had an NPV of 0.95 (sensitivity: 0.90, specificity: 0.45, negative LR: 0.21), while the optimal rule-in cut-off (FAST: ≥ 0.78) had a PPV of 0.70 (sensitivity: 0.64, specificity 0.94, positive LR: 10.39). With these cut-offs, 27 (45%) patients fell in the grey zone and 29 (48.3%) were correctly classified as per histology, performing better than the cut-offs by Newsome et al ( P < 0.001)., Conclusion: The FAST score demonstrates good AUROC for detecting NASH with significant fibrosis and inflammation on histology. Cut-offs should be recalibrated based on prevalence of disease., Lay Summary: India has a high burden of NAFLD with an estimated 25 million patients at potential risk for significant liver disease. Liver biopsy remains the gold standard for diagnosing NASH, although its application in routine clinical practice is limited. Noninvasive tests for the simultaneous detection of steatosis, inflammation and fibrosis are thus the need of the hour. The FAST score has been recently suggested for the noninvasive detection of NASH with significant fibrosis (≥ F2) and inflammation (NAS ≥ 4) on liver biopsy. We validated the utility of the FAST score for detecting NASH with significant fibrosis and inflammation on liver biopsy in Indian patients with NAFLD. This noninvasive, easy-to-use and nonproprietary FAST score can correctly classify disease severity in more than 50% patients. However, our results suggest that cut-offs should be recalibrated based on the anticipated prevalence of NASH + NAS ≥ 4 + F ≥ 2 in the given population., (© 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Published
2022
Full Text
View/download PDF

13. Characterization and Pharmacological Validation of a Preclinical Model of NASH in Göttingen Minipigs.

Author

Duvivier V, Creusot S, Broux O, Helbert A, Lesage L, Moreau K, Lesueur N, Gerard L, Lemaitre K, Provost N, Hubert EL, Baltauss T, Brzustowski A, De Preville N, Geronimi J, Adoux L, Letourneur F, Hammoutene A, Valla D, Paradis V, and Delerive P

Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, which is associated with features of metabolic syndrome. NAFLD may progress in a subset of patients into nonalcoholic steatohepatitis (NASH) with liver injury resulting ultimately in cirrhosis and potentially hepatocellular carcinoma. Today, there is no approved treatment for NASH due to, at least in part, the lack of preclinical models recapitulating features of human disease. Here, we report the development of a dietary model of NASH in the Göttingen minipig., Methods: First, we performed a longitudinal characterization of diet-induced NASH and fibrosis using biochemical, histological, and transcriptional analyses. We then evaluated the pharmacological response to Obeticholic acid (OCA) treatment for 8 weeks at 2.5mg/kg/d, a dose matching its active clinical exposure., Results: Serial histological examinations revealed a rapid installation of NASH driven by massive steatosis and inflammation, including evidence of ballooning. Furthermore, we found the progressive development of both perisinusoidal and portal fibrosis reaching fibrotic septa after 6 months of diet. Histological changes were mechanistically supported by well-defined gene signatures identified by RNA Seq analysis. While treatment with OCA was well tolerated throughout the study, it did not improve liver dysfunction nor NASH progression. By contrast, OCA treatment resulted in a significant reduction in diet-induced fibrosis in this model., Conclusions: These results, taken together, indicate that the diet-induced NASH in the Göttingen minipig recapitulates most of the features of human NASH and may be a model with improved translational value to prioritize drug candidates toward clinical development., (© 2021 The Authors.)

Published
2022
Full Text
View/download PDF

14. A Current Understanding of Bile Acids in Chronic Liver Disease.

Author

Farooqui N, Elhence A, and Shalimar

Abstract

Chronic liver disease (CLD) is one of the leading causes of disability-adjusted life years in many countries. A recent understanding of nuclear bile acid receptor pathways has increased focus on the impact of crosstalk between the gut, bile acids, and liver on liver pathology. While conventionally used in cholestatic disorders and to dissolve gallstones, the discovery of bile acids' influence on the gut microbiome and human metabolism offers a unique potential for their utility in early and advanced liver diseases because of diverse etiologies. Based on these findings, preclinical studies using bile acid-based molecules have shown encouraging results at addressing liver inflammation and fibrosis. Emerging data also suggest that bile acid profiles change distinctively across various causes of liver disease. We summarize the current knowledge and evidence related to bile acids in health and disease and discuss culminated and ongoing therapeutic trials of bile acid derivatives in CLD. In the near future, further evidence in this area might help clinicians better detect and manage liver diseases., (© 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Published
2022
Full Text
View/download PDF

15. Primary Versus Secondary NAFLD: Perspective on Advanced Fibrosis.

Author

Shetty D, Amarapurkar A, and Shukla A

Abstract

Background: The presence of macrovesicular steatosis on liver biopsy is the commonest histopathological finding. Nonalcoholic fatty liver disease (NAFLD) is the presence of ≥5% macrovesicular steatosis without significant alcohol use. It is subdivided into primary and secondary NAFLD; information on their differences is limited., Aim: To determine the histopathological differences between primary and secondary NAFLD and establish whether the prevalence of advanced fibrosis varies between the two types., Methodology: Three years of retrospective study of 90 liver biopsies with ≥5% macrovesicular steatosis. Age, gender, clinical history, serum transaminase levels were noted. The biopsy was reviewed for steatosis, inflammation, and fibrosis. Differences between primary and secondary NAFLD for age, gender, AST/ALT ratio, histopathological features were determined. Descriptive statistical analysis, 2-tailed Student's t test, Chi-square test, Fisher's exact test were used, where p <  0.05 was considered significant., Result: Primary and secondary NAFLD were 42 (46.7%) and 48 (53.3%), respectively. Inflammation was noted in 50 (55.5%) and fibrosis in 31 (34.4%). The prevalence of advanced fibrosis was 24.4%. Primary and secondary NAFLD differed significantly on ballooning degeneration, Mallory Denk bodies (MDBs), glycogenated nuclei, and fibrosis stage (p < 0.05). There were no significant differences among AST/ALT ratio, steatosis, and inflammation grade., Conclusion: Primary NAFLD is a more severe type of liver disease. On histopathology, ballooning degeneration, MDBs, glycogenated nuclei, and advanced fibrosis was more prevalent in primary than secondary NAFLD., (© 2020 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Published
2021
Full Text
View/download PDF

16. S -Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling.

Author

Luo P, Zheng M, Zhang R, Zhang H, Liu Y, Li W, Sun X, Yu Q, Tipoe GL, and Xiao J

Abstract

Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S -allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC (300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis, insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor (INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3 β signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC (250 μmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC's beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model. Long-term (90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3 β pathway., Competing Interests: The authors declare no conflicts of interest., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Published
2021
Full Text
View/download PDF

17. Natural History of Non-Alcoholic Fatty Liver Disease: A Study With Paired Liver Biopsies.

Author

Reddy YK, Marella HK, Jiang Y, Ganguli S, Snell P, Podila PSB, Maliakkal B, and Satapathy SK

Abstract

Background: Although there is unequivocal evidence for progression of nonalcoholic steatohepatitis (NASH) to cirrhosis, there is uncertainty with regard to the progression to nonalcoholic fatty liver (NAFL) and NASH., Aims: We investigated the rate of progression to NASH and advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) and assessed the factors associated with such progression., Methods: Histological assessment was performed in 36 patients with NAFLD with paired liver biopsies (≥1 year apart; median, 3.8 years; range, 1-10.33 years). NASH Clinical Research Network (NASH CRN) criteria were used to assess NAFLD Activity Score (NAS)., Results: At baseline, 26 (72%) patients had NAFL and 10 (28%) patients had NASH. At follow-up, 27% NAFL progressed to NASH (NAS score ≥5), and 50% of patients with NASH no longer met the criteria of NASH. Fibrosis progressed in 15 (42%), regressed in 9 (25%), and remained stable in 12 (33%) patients overall. Thirty-five percent of patients with NAFL had fibrosis progression. The incidence of type 2 diabetes mellitus (T2DM) was higher in patients with NASH versus NAFL (40% vs. 27%). Both at the time of baseline and follow-up, liver biopsies, composite models of noninvasive scores such as Fibrosis-4 (FIB-4) score and NAFLD fibrosis score, and ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) were all significantly higher in progressors than in nonprogressors., Conclusions: NAFLD is a dynamic liver disease with varying degrees of progression and regression. T2DM was strongly associated with fibrosis progression. Noninvasive fibrosis scores such as AST/ALT ratio, FIB-4 score, and NAFLD fibrosis score can identify those at risk of fibrosis progression., (© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Published
2020
Full Text
View/download PDF

18. Biopsy Proven Fibrosis in Non-Alcoholic Fatty Liver Disease: An Analysis of Risk Factors.

Author

Pattnaik K, Bhuyan P, Singh A, Singh SP, Nath P, Kar S, Misra B, and Rath J

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is emerging as an important cause of liver disease in India. NAFLD is characterized by hepatic steatosis in absence of a significant alcohol use or other known liver disease. Non-alcoholic steatohepatitis (NASH) is a progressive form of NAFLD which deserves particular attention because it is more prone for development of fibrosis. Liver biopsy is the gold standard for diagnosis of NASH by evaluating necroinflammatory activity and stages of fibrosis. The aim of the study was to analyze liver biopsy specimens and identify risk factors associated with fibrosis in patients of NAFLD in eastern coastal India., Methods: A total of 216 subjects with fatty liver in ultrasonography (USG) were selected for needle biopsy. Those NAFLD cases showing fibrosis in biopsy were analyzed for risk factors association., Results: Definite NASH was diagnosed in 50 (23.14%), borderline NASH in 66 (30.55%) and not NASH in 100 (46.39%) of cases. Those patients with fibrosis (22%) were taken as cases and those without fibrosis (78%) were taken as controls for risk factor analysis. Age > 40 [odds ratio (OR) 2.01 (1.09-4.04)], female gender [OR 2.74 (1.24-6.05)], body mass index (BMI) > 23 [OR 15.36 (4.59-51.37)] and moderate fatty change in USG [OR 1.89 (1.01-3.62)] were observed as risk factors for progression to fibrosis in NAFLD cases., Conclusion: Older age, females, obesity and moderate fatty liver on USG are risk factors for development of fibrosis in patients with NAFLD. Patients with these risk factors should be selected for liver biopsy and to be kept for close follow-up.

Published
2018
Full Text
View/download PDF

19. Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy.

Author

Nagaya T, Tanaka N, Kimura T, Kitabatake H, Fujimori N, Komatsu M, Horiuchi A, Yamaura T, Umemura T, Sano K, Gonzalez FJ, Aoyama T, and Tanaka E

Abstract

Background and Aim: It is recognized that nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), may develop after pancreaticoduodenectomy (PD). However, the mechanism of NASH development remains unclear. This study aimed to examine the changes in gene expression associated with NASH occurrence following PD., Methods: The expression of genes related to fatty acid/triglyceride (FA/TG) metabolism and inflammatory signaling was examined using liver samples obtained from 7 post-PD NASH patients and compared with 6 healthy individuals and 32 conventional NASH patients., Results: The livers of post-PD NASH patients demonstrated significant up-regulation of the genes encoding CD36, FA-binding proteins 1 and 4, acetyl-coenzyme A carboxylase α, diacylglycerol acyltransferase 2, and peroxisome proliferator-activated receptor (PPAR) γ compared with normal and conventional NASH livers. Although serum apolipoprotein B (ApoB) and TG were decreased in post-PD NASH patients, the mRNAs of ApoB and microsomal TG transfer protein were robustly increased, indicating impaired TG export from the liver as very-low-density lipoprotein (VLDL). Additionally, elevated mRNA levels of myeloid differentiation primary response 88 and superoxide dismutases in post-PD NASH livers suggested significant activation of innate immune response and augmentation of oxidative stress generation., Conclusions: Enhanced FA uptake into hepatocytes and lipogenesis, up-regulation of PPARγ, and disruption of VLDL excretion into the circulation are possible mechanisms of steatogenesis after PD., General Significance: These results provide a basis for understanding the pathogenesis of NAFLD/NASH following PD.

Published
2015
Full Text
View/download PDF

20. Clinical spectrum of non-alcoholic fatty liver disease in diabetic and non-diabetic patients.

Author

Goh GB, Pagadala MR, Dasarathy J, Unalp-Arida A, Sargent R, Hawkins C, Sourianarayanane A, Khiyami A, Yerian L, Pai RK, Dasarathy S, and McCullough AJ

Abstract

Background: While non-alcoholic fatty liver disease (NAFLD) has been well characterised in patients with diabetes mellitus (DM), less is known about NAFLD in non-DM patients. We investigated the clinical characteristics of NAFLD patients with and without DM and accuracy of the NAFLD fibrosis score (NFS) in these two NAFLD groups., Methods: Clinical, biochemical and histological variables were evaluated in this prospective cross-sectional study of 503 patients with biopsy proven NAFLD. Comparisons between patients with and without DM were analysed. NFS was correlated with liver histology to assess its robustness in patients with and without DM., Results: There were 503 biopsy proven NAFLD patients with 48% of the cohort being diabetic. Relative to patients without DM, patients with DM were older (52 vs. 46 years, p < 0.001), with higher proportion of females (70% vs. 54%, p < 0.001), higher BMI (37 vs. 35, p = 0.009), higher prevalence of hypertension (73% vs. 44%, p < 0.001), higher prevalence of NASH (80.2% vs. 64.4%; p < 0.001) and advanced fibrosis (40.3% vs. 17.0%; p < 0.001). A considerable amount of patients without DM still had NASH (64%) and advanced fibrosis (17%). The clinical utility of the NFS differed between NAFLD patients with and without DM, with sensitivity to exclude advanced fibrosis being 90% of NAFLD patients with DM but only 58% of patients without DM., Conclusion: Patients with DM have more severe NAFLD based on histology. However, NASH and advanced fibrosis also occur in a considerable proportion of NAFLD patients without DM. The lower utility of the NFS in NAFLD patients without DM emphasises the heterogeneous nature of the NAFLD phenotype.

Published
2014
Full Text
View/download PDF

21. Management of Non-alcoholic Fatty Liver Disease and Steatohepatitis.

Author

Le TA and Loomba R

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver enzymes and chronic liver disease in the US with expected rise in incidence paralleling the epidemic of obesity. A subset of patients with NAFLD have the progressive form of NAFLD that is termed non-alcoholic steatohepatitis (NASH), which is characterized by specific features on liver histology including hepatocellular ballooning degeneration, lobular inflammation, and zone-3 steatosis with or without peri-sinusoidal fibrosis. Non-alcoholic steatohepatitis can progress to cirrhosis and result in liver-related death. Insulin resistance is commonly seen in patients with NASH and often co-exists with other features of the metabolic syndrome including hypertension, hyperlipidemia, and obesity. Although weight loss through lifestyle modifications including dietary changes and increased physical exercise remains the backbone of management of NASH, it has proved challenging for patients to achieve and maintain weight loss goals. Thus, it is often necessary to couple lifestyle changes with another pharmacologic treatment for NASH. Insulin sensitizers including the biguanides (metformin), thiazolidinediones (pioglitazone and rosiglitazone), and glucagon-like peptide-1 receptor agonists (exenatide) are large groups of medications that have been studied for the treatment of NASH. Other agents with anti-inflammatory, anti-apoptotic, or anti-fibrotic properties which have been studied in NASH include vitamin E, pentoxifylline, betaine, and ursodeoxycholic acid. This review will provide a detailed summary on the clinical data behind the full spectrum of treatments that exist for NASH and suggest management recommendations.

Published
2012
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results