Molecular signature predictive of long-term liver fibrosis progression to inform anti-fibrotic drug development

Background:Methotrexate (MTX) is a cornerstone drug for the treatment of rheumatic disease and low doses of MTX are both tolerable and safe, with monitored toxicity, assessed via the liver function test. However, there is still controversy regarding the risk of liver fibrosis with long-term use of MTX. Transient elastography is commonly used to assess and monitor fibrosis progression in patients with chronic liver disease.Objectives:The present study aims to investigate liver fibrosis using transient elastography and related factors in patients with rheumatic disease receiving long-term MTX.Methods:The present retrospective, longitudinal, cross-sectional study included patients with an autoimmune disease who are taking cumulative MTX dosed over 7 g, and who had liver fibrosis upon examination using transient elastography. Liver fibrosis was defined as liver stiffness, valued over 7.2 kPa. Logistic regression analysis was performed to identify factors associated with liver fibrosis, and receiver operating characteristics analysis was used to determine the predictive value of each factor.Results:We included 83 patients with autoimmune disease, with a median MTX cumulative dose of 11.6 (range 7.3-16.0) g. Sixty-eight patients (81.9%) had rheumatoid arthritis (RA), and 13 patients (15.7%) had Takayasu arteritis. The median MTX exposure duration was 18 (range 9-31) years. The median liver stiffness value was 4 (range 1.8-10.2) kPa. Five patients (6%) showed liver fibrosis (3 patients; RA, 2 patients; Takayasu arteritis). In the linear regression analysis, cumulative MTX dose showed a tendency towards a positive correlation with increasing liver stiffness value (r2 =0.039, p = 0.074). In the logistic regression analysis, cumulative MTX dose was associated with a higher risk of liver fibrosis (OR: 1.734, 95% CI: 1.060–2.837, p = 0.029). In addition, cumulative MTX dose had an area under the curve (AUC) of 0.813 (95% CI 0.695-0.930) and a sensitivity of 80% and specificity of 71.8% at a cut-off value of 12.7 g.Conclusion:Liver fibrosis was observed in 6% of patients with long-term MTX use and higher cumulative MTX doses increased the risk of liver fibrosis. Thus, transient elastography should be considered in patients exposed to high cumulative doses of MTX.Disclosure of Interests:None declared

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487 LONG TERM SURVIVAL OF LIVER FIBROSIS AFTER VIROLOGICAL CURE (SVR) IN HIV–HCV COINFECTED PATIENTS: A WORRISOME LATENT DISEASE?

Journal of Hepatology ◽

10.1016/s0168-8278(13)60489-4 ◽

2013 ◽

Vol 58 ◽

pp. S199-S200

Author(s):

T. Poynard ◽

M.A. Valantin ◽

M. Munteanu ◽

J. Moussalli ◽

D. Thabut ◽

...

Keyword(s):

Liver Fibrosis ◽

Term Survival ◽

Long Term Survival ◽

Latent Disease

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FIB-4 Index is a Predictor of Background Liver Fibrosis and Long-Term Outcomes After Curative Resection of Hepatocellular Carcinoma

Annals of Surgical Oncology ◽

10.1245/s10434-016-5377-y ◽

2016 ◽

Vol 23 (S4) ◽

pp. 467-474 ◽

Cited By ~ 12

Author(s):

Yukiyasu Okamura ◽

Ryo Ashida ◽

Yusuke Yamamoto ◽

Takaaki Ito ◽

Teiichi Sugiura ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Fibrosis ◽

Curative Resection ◽

Long Term Outcomes

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Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice

Biology ◽

10.3390/biology10020082 ◽

2021 ◽

Vol 10 (2) ◽

pp. 82

Author(s):

Isabela A. Finamor ◽

Caroline A. Bressan ◽

Isabel Torres-Cuevas ◽

Sergio Rius-Pérez ◽

Marcelo da Veiga ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Damage ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Elevated Serum ◽

Inflammasome Activation ◽

Related Factor ◽

Type I ◽

Artificial Sweetener

Background: Aspartame is an artificial sweetener used in foods and beverages worldwide. However, it is linked to oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. This work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice. Methods: Mice were divided into two groups with six animals each: control and aspartame. Aspartame (80 mg/kg, via oral) or vehicle was administrated for 12 weeks. Results: Aspartame caused liver damage and elevated serum transaminase levels. Aspartame also generated liver fibrosis, as evidenced by histology analysis, and pro-fibrotic markers’ upregulation, including transforming growth factor β 1, collagen type I alpha 1, and alpha-smooth muscle actin. Furthermore, aspartame reduced nuclear factor erythroid 2-related factor 2 (Nrf2) activation and enzymatic antioxidant activity and increased lipid peroxidation, which triggered NOD-like receptor containing protein 3 (NLRP3) inflammasome activation and p53 induction. Furthermore, aspartame reduced peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) levels, possibly through p53 activation. This PGC-1α deficiency could be responsible for the changes in lipid profile in serum, total lipid accumulation, and gluconeogenesis impairment in liver, evidenced by the gluconeogenic enzymes’ downregulation, thus causing hypoglycemia. Conclusions: This work provides new insights to understand the mechanisms related to the adverse effects of aspartame on liver tissue.

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Identification of key metabolic changes during liver fibrosis progression in rats using a urine and serum metabolomics approach

Scientific Reports ◽

10.1038/s41598-017-11759-z ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 25

Author(s):

Hong Chang ◽

Hong-yu Meng ◽

Shu-min Liu ◽

Yu Wang ◽

Xiao-xu Yang ◽

...

Keyword(s):

Liver Fibrosis ◽

Metabolic Changes ◽

Fibrosis Progression ◽

Urine And Serum ◽

Serum Metabolomics

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PO-103 The mechanism of long-term regular exercise intervention on liver injury in patients with NAFLD based on miR-146a regulation of TLR4/NF-KB signaling pathway

Exercise Biochemistry Review ◽

10.14428/ebr.v1i4.8823 ◽

2018 ◽

Vol 1 (4) ◽

Author(s):

Qi Peng ◽

Jiaqin Chen ◽

Wei Chen ◽

Chang Feng Shao ◽

Afang Yuan

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Fatty Liver ◽

Signaling Pathway ◽

Exercise Intervention ◽

Exercise Group ◽

Control Group ◽

Regular Exercise ◽

Alcoholic Fatty Liver

Objective To investigate the effects of long-term regular exercise on hepatic function in patients with non-alcoholic fatty liver (NAFLD) using blood biochemistry and liver fibrosis markers, and to compare the differential expression of cytokines related to TLR4/NF-KB signaling pathway. A preliminary discussion was made on its regulation mechanism. Methods Forty patients with NAFLD diagnosed in the Hunan Normal University School of Medicine, according to the degree of steatosis and exercise intervention, the patients were divided into control group (NAFLD group) 20 cases and long-term regular exercise group 20 cases, and the same time in our hospital Twenty patients with physical examination were normal controls; general data of all subjects, ALT, AST, GGT, serum type III procollagen (PCIII), hyaluronan (HA), and type IV collagen (CIV) were examined; Fluorescent quantitative PCR was used to detect the differential expression of TLR4/NF-KB signaling pathway-related cytokines and miR-146a in the blood of each group of subjects, revealing the effects and possible mechanisms of long-term regular exercise on liver fibrosis. Results Compared with the normal group, the levels of serum ALT, AST, GGT, PCIII, HA, and CIV in the non-alcoholic fatty liver patients were significantly lower in the long-term regular exercise group than in the control group; blood TLR4, NF-KB, MY-D88 Compared with the control group, the gene expression level was significantly downregulated in the long-term regular exercise group. Conclusions Long-term regular exercise can effectively reduce nonalcoholic inflammatory liver injury and has a clear anti-fibrotic effect. Its mechanism may be related to long-term regular exercise through regulating the TLR4/NF-KB signaling pathway related factors and the regulation of molecular miR-146a, reducing inflammation and preventing the formation of fibrosis.

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