scholarly journals Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis

2020 ◽  
Vol 12 (572) ◽  
pp. eaba4448
Author(s):  
Olivier Govaere ◽  
Simon Cockell ◽  
Dina Tiniakos ◽  
Rachel Queen ◽  
Ramy Younes ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Disease Activity ◽  
Nonalcoholic Fatty Liver Disease ◽  
Rna Sequencing ◽  
Fatty Liver Disease ◽  
Fibrosis Stage ◽  
Sequencing Data ◽  
Serum Samples ◽  
Nonalcoholic Fatty Liver

The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409, a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort (n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10, GDF15, and PDGFA, whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.

The Relationship of Serum Hemojuvelin and Hepcidin Levels with Iron Overload in Nonalcoholic Fatty Liver Disease

2015 ◽  
Vol 24 (3) ◽  
pp. 293-300 ◽  
Author(s):  
Salih Boga ◽  
Huseyin Alkim ◽  
Canan Alkim ◽  
Ali Riza Koksal ◽  
Mehmet Bayram ◽  
...  
Keyword(s):  
Liver Disease ◽  
Iron Overload ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Clinical Characteristics ◽  
Serum Levels ◽  
Fibrosis Stage ◽  
Enzyme Linked Immunosorbent Assay ◽  
Nonalcoholic Fatty Liver

Background & Aims: Mild iron overload is frequently reported in patients with nonalcoholic fatty liver disease (NAFLD). Hepcidin is the master iron-regulatory peptide and hemojuvelin (HJV) is the key regulator of iron-dependent secretion of hepcidin. The aims of this study were to evaluate serum HJV and hepcidin levels in patients with biopsy-proven NAFLD with and without hepatic iron overload, and to identify potential associations of HJV and hepcidin with the clinical characteristics of the patients enrolled. Methods: Serum levels of HJV and hepcidin were measured in 66 NAFLD patients with (n=12) and without (n=54) iron overload, and controls (n=35) by enzyme-linked immunosorbent assay. Hemojuvelin and hepcidin levels were assessed in relation to clinical characteristics and liver histologic evaluation of the participants. Results: Significantly lower serum HJV (281.1 [239.2-353.6] vs. 584.8 [440.3-661] ng/ml, p<0.001) and similar serum hepcidin levels (60.5±31.1 vs. 55.8±11.9 ng/ml, p=0.285) were found in NAFLD patients when compared to controls. İron-overloaded NAFLD patients had significantly lower HJV (249.9 [187.6-296.3] vs. 292.9 [243-435] ng/ml, p=0.032) and significantly higher hepcidin (78.4±35.5 vs. 56.5±28.9ng/ml, p=0.027) levels than NAFLD patients without iron overload. Fibrosis stage was significantly higher in iron overloaded NAFLD group (p<0.001). Ferritin levels correlated significantly both with HOMA-IR (r=0.368, p=0.002) and fibrosis stage (r=0.571, p<0.001). Conclusions: Our findings suggest that HJV levels are low in NAFLD and even lower in iron overloaded NAFLD, while hepcidin levels are higher in NAFLD with iron overload. The gradually decreased HJV and increased hepcidin concentrations in our patients most likely reflect the physiological response to iron accumulation in the liver.

scholarly journals Nonalcoholic Fatty Liver Disease: Different Classifications Concordance and Relationship between Degrees of Morphological Features and Spectrum of the Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Juliana Maya Monteiro ◽  
Geysa Maya Monteiro ◽  
Adriana Caroli-Bottino ◽  
Vera Lucia Pannain
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Main Tool ◽  
Morphological Features ◽  
Fibrosis Stage ◽  
Nonalcoholic Fatty Liver ◽  
Stage 1 ◽  
Lobular Inflammation

The morphological features of nonalcoholic fatty liver disease (NAFLD) range from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Liver biopsy remains the main tool for NASH diagnosis and many histological systems to diagnose and grade NAFLD were proposed. We evaluated the relationship among NAFLD activity score (NAS), histological diagnoses (non-NASH, possible NASH, and definite NASH), and histological algorithm proposed by Bedossa et al.; additionally the degrees of morphological features were semiquantified and correlated with non-NASH and NASH. Seventy-one liver biopsies were studied. The agreement among the three systems considering NASH and non-NASH was excellent (Κ=0.96). Among the 22 biopsies with NAS 3-4, 72.7% showed to be NASH according to Bedossa’s algorithm. The degree of steatosis, ballooning, lobular inflammation, and fibrosis stage were correlated with NASH (P<0.001). Fibrosis stage 1 was also found in non-NASH. Over the spectrum of NAFLD, no association was observed between intensity of steatosis and fibrosis grade. The degrees of lobular inflammation showed association with fibrosis stage (P<0.0001). In conclusion, there is agreement among different NAFLD classifications and NAS > 4 may be a better cutoff from which to consider NASH diagnosis; besides the highest degrees of steatosis, ballooning, inflammation, and fibrosis are associated with NASH.

scholarly journals Ezetimibe decreased nonalcoholic fatty liver disease activity score but not hepatic steatosis

2019 ◽  
Vol 34 (2) ◽  
pp. 296-304 ◽  
Author(s):  
Hyo Young Lee ◽  
Dae Won Jun ◽  
Hyun Jung Kim ◽  
Hyunwoo Oh ◽  
Waqar Khalid Saeed ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Disease Activity ◽  
Nonalcoholic Fatty Liver Disease ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Disease Activity Score ◽  
Activity Score ◽  
Nonalcoholic Fatty Liver

Angiopoietin-2 levels correlates with disease activity in children with nonalcoholic fatty liver disease

2021 ◽  
Author(s):  
Melania Manco ◽  
Nadia Panera ◽  
Annalisa Crudele ◽  
Maria Rita Braghini ◽  
Marzia Bianchi ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Disease Activity ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver ◽  
Angiopoietin 2

scholarly journals Association Between Fibrosis Stage and Outcomes of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

2020 ◽  
Vol 158 (6) ◽  
pp. 1611-1625.e12 ◽  
Author(s):  
Rod S. Taylor ◽  
Rebecca J. Taylor ◽  
Sue Bayliss ◽  
Hannes Hagström ◽  
Patrik Nasr ◽  
...  
Keyword(s):  
Systematic Review ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Meta Analysis ◽  
Fibrosis Stage ◽  
Nonalcoholic Fatty Liver

scholarly journals Sex hormone-binding globulin levels are inversely associated with nonalcoholic fatty liver disease in HIV-infected and –uninfected men

2019 ◽  
Author(s):  
Jennifer C Price ◽  
Ruibin Wang ◽  
Eric C Seaberg ◽  
Todd T Brown ◽  
Matthew J Budoff ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Sex Hormone ◽  
Sex Hormone Binding Globulin ◽  
Total Testosterone ◽  
Hormone Binding ◽  
Serum Samples ◽  
Nonalcoholic Fatty Liver

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease worldwide. Elevated sex hormone-binding globulin (SHBG) levels have been observed in the setting of HIV and may protect against some metabolic disorders. We aimed to investigate whether higher SHBG levels may protect against NAFLD in men with/without HIV. Methods NAFLD was assessed using non-contrast CT in 530 men in the Multicenter AIDS Cohort Study (MACS) who drank <3 alcoholic drinks/day and were uninfected with chronic hepatitis C or B (340HIV+,190HIV-). Morning serum samples were tested for SHBG, total testosterone (TT), and adiponectin. Multivariable logistic regression was used to assess associations between HIV, SHBG, TT, adiponectin and NAFLD. Results Median SHBG was highest among HIV+/NAFLD- men and lowest among HIV-/NAFLD+ men. Adjusted for demographics, HIV, visceral adiposity, HOMA-IR, TT, and PNPLA3 genotype, higher SHBG was associated with lower odds of NAFLD [odds ratio(OR) 0.52 per doubling,95% confidence interval(CI) 0.34-0.80]. In separate multivariable models without SHBG, HIV (OR 0.46,95%CI 0.26-0.79) and higher adiponectin (OR 0.66 per doubling,95%CI 0.49-0.89) were associated with lower NAFLD odds, whereas TT was not significantly associated (OR 0.74 per doubling,95%CI 0.53-1.04). Adjusting for SHBG attenuated the associations of HIV (OR 0.61,95%CI 0.34-1.08) and adiponectin (OR 0.74,95%CI 0.54-1.02) with NAFLD. Conclusions SHBG levels were higher among HIV+ men, independently associated with lower NAFLD, and could partially explain the associations of HIV and higher adiponectin with lower NAFLD in our cohort. These findings suggest that SHBG may protect against NAFLD, supporting further prospective and mechanistic studies.

scholarly journals Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis

Hepatology ◽  
2017 ◽  
Vol 65 (5) ◽  
pp. 1557-1565 ◽  
Author(s):  
Parambir S. Dulai ◽  
Siddharth Singh ◽  
Janki Patel ◽  
Meera Soni ◽  
Larry J. Prokop ◽  
...  
Keyword(s):  
Systematic Review ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Meta Analysis ◽  
Fibrosis Stage ◽  
Nonalcoholic Fatty Liver ◽  
Risk Of Mortality ◽  
Increased Risk
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