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( Rohit Loomba ),( Naim Alkhouri ),( Mazen Noureddin ),( Jie Zhang ),( Bryan J. Mccolgan ),( C. Stephen Djedjos ),( Robert P. Myers ),( Michael Middleton ),( Zachary Goodman ),( Kris Kowdley ),( Atsus 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1
Aims: Magnetic resonance elastography(MRE) is a quantitative imaging biomarker for the detection of advanced fibrosis due to NASH. Our aim was to validate the performance of MRE for detection of advanced fibrosis using data from multiple clinical trials. Methods: Baseline data were pooled on 296 subjects with NASH from seven randomized, phase 2 and 3 trials including ATLAS and STELLAR-3/-4 trials. All subjects underwent 2D MRE and liver biopsy with staging of fibrosis according to NASH CRN classification. Associations between MRE-stiffness, fibrosis stage, noninvasive tests (NITs) of fibrosis (ELF, FibroTest, FIB-4, NAFLD Fibrosis Score [NFS]), and NASH activity (NAFLD Activity Score ≥5 vs <5) were determined. The discrimination of MRE for advanced fibrosis (F3-F4 vs F0-F2) and cirrhosis (F4 vs F0- F3) was evaluated using areas under receiver operating characteristic (AUROC) curves, and cutoffs from literature-based MRE thresholds (3.64 and 4.67 kPa, respectively) and optimal thresholds(defined by the maximal sum of sensitivity and specificity) were determined. Results: Among 296 subjects, fibrosis stages were F0-1(6%), F2(11%), F3(44%), and F4(40%); median MRE-stiffness was 4.71 kPa(IQR 3.52, 6.35). MRE-stiffness was correlated with fibrosis stage(Spearman ρ=0.60), and other NITs of fibrosis(ρ =0.47-0.52; all P<0.05). The AUROCs(95% CI) of MRE-stiffness for detecting advanced fibrosis and cirrhosis were 0.85(0.80, 0.90) and 0.81(0.76, 0.86), respectively. In general, cutoffs from the literature and optimal cutoffs derived from this dataset had similar performance for classification of fibrosis by 2D MRE. Among subjects with F0-F2 fibrosis on biopsy, those with MRE-stiffness ≥3.64 kPa (potential misclassification) had higher ELF and FibroSure than those with MRE-stiffness <3.64 kPa (both P<0.05). Conversely, among subjects with F3-F4 fibrosis on biopsy, those with MRE-stiffness <3.64 kPa had lower ELF, FibroSure, FIB-4, and NFS compared with those with MRE-stiffness ≥3.64 kPa(all P<0.05). Conclusions: This multi-center, multi-study validation demonstrates the clinical utility of 2D MRE for the detection of advanced fibrosis due to NASH.
Hyaluronan synthase 2–mediated hyaluronan production mediates Notch1 activation and liver fibrosis
Yang, Yoon Mee,Noureddin, Mazen,Liu, Cheng,Ohashi, Koichiro,Kim, So Yeon,Ramnath, Divya,Powell, Elizabeth E.,Sweet, Matthew J.,Roh, Yoon Seok,Hsin, I-Fang,Deng, Nan,Liu, Zhenqiu,Liang, Jiurong,Mena, E American Association for the Advancement of Scienc 2019 Science Translational Medicine Vol.11 No.496
<P>Hyaluronan (HA), a major extracellular matrix glycosaminoglycan, is a biomarker for cirrhosis. However, little is known about the regulatory and downstream mechanisms of HA overproduction in liver fibrosis. Hepatic HA and HA synthase 2 (HAS2) expression was elevated in both human and murine liver fibrosis. HA production and liver fibrosis were reduced in mice lacking HAS2 in hepatic stellate cells (HSCs), whereas mice overexpressing HAS2 had exacerbated liver fibrosis. HAS2 was transcriptionally up-regulated by transforming growth factor–β through Wilms tumor 1 to promote fibrogenic, proliferative, and invasive properties of HSCs via CD44, Toll-like receptor 4 (TLR4), and newly identified downstream effector Notch1. Inhibition of HA synthesis by 4-methylumbelliferone reduced HSC activation and liver fibrosis in mice. Our study provides evidence that HAS2 actively synthesizes HA in HSCs and that it promotes HSC activation and liver fibrosis through Notch1. Targeted HA inhibition may have potential to be an effective therapy for liver fibrosis.</P>
Teng Pai-Chi,Huang Daniel Q.,Lin Ting-Yi,Noureddin Mazen,Yang Ju Dong 거트앤리버 소화기연관학회협의회 2023 Gut and Liver Vol.17 No.1
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world. NAFLD is a hepatic manifestation of insulin resistance, the core pathophysiology of diabetes. Multiple clinical studies show that diabetes increases the risk of liver disease progression and cirrhosis development in patients with NAFLD. Diabetes has causal associations with many different cancers, including hepatocellular carcinoma (HCC). More recent studies demonstrate that diabetes increases the risk of HCC in patients with underlying NAFLD cirrhosis, confirming the direct hepatocarcinogenic effect of diabetes among cirrhosis patients. Diabetes promotes hepatocarcinogenesis via the activation of inflammatory cascades producing reactive oxygen species and proinflammatory cytokines, leading to genomic instability, cellular proliferation, and inhibition of apoptosis. Given the global increase in the burden of NAFLD and HCC, high-risk patients such as older diabetic individuals should be carefully monitored for HCC development. Future larger studies should explore whether the effect of diabetes on HCC risk in NAFLD cirrhosis is modifiable by the type of antidiabetic medication and the effectiveness of diabetes control.
Factors associated with unrecognized cirrhosis in patients with hepatocellular carcinoma
Yi-Te Lee,Mohammad A. Karim,Hye Chung Kum,Sulki Park,Nicole E. Rich,Mazen Noureddin,Amit G. Singal,Ju Dong Yang 대한간학회 2023 Clinical and Molecular Hepatology(대한간학회지) Vol.29 No.2
Background/Aims: Cirrhosis is the most important risk factor of hepatocellular carcinoma (HCC), and patients with cirrhosis are recommended to receive semiannual surveillance for early HCC detection. However, early cirrhosis is often asymptomatic and can go undiagnosed for years, leading to underuse of HCC surveillance in clinical practice. We characterized the frequency and associated factors of unrecognized cirrhosis in a national sample of patients with HCC from the United States. Methods: HCC patients aged 68 years and older, diagnosed during 2011 to 2015 were included from the SEERMedicare Linked Database. If cirrhosis was diagnosed within 6 months immediately preceding HCC diagnosis or after HCC diagnosis, cases were categorized as unrecognized cirrhosis. Factors associated with unrecognized cirrhosis were identified using logistic regression analyses. Factors associated with overall survival were evaluated using Cox regression analyses. Results: Among 5,098 HCC patients, 74.8% patients had cirrhosis. Among those with cirrhosis, 57.4% had unrecognized cirrhosis, with the highest proportion (76.3%) among those with NAFLD-related HCC. Male sex (aOR: 2.12, 95% CI: 1.83–2.46), non-Hispanic Black race (aOR: 1.93, 95% CI: 1.45–2.57), and NAFLD etiology (aOR: 4.46, 95% CI: 3.68–5.41) were associated with having unrecognized cirrhosis. Among NAFLD-related HCC patients, male sex (aOR: 2.32, 95% CI: 1.71–3.14) was associated with unrecognized cirrhosis. Unrecognized cirrhosis was independently associated with worse overall survival (aHR: 1.17, 95% CI: 1.08–1.27) compared to recognized cirrhosis. Conclusions: Unrecognized cirrhosis is common in NAFLD-related HCC, particularly among male and Black patients, highlighting these groups as important intervention targets to improve HCC surveillance uptake and outcomes.
Kim, Tae Hyun,Yang, Yoon Mee,Han, Chang Yeob,Koo, Ja Hyun,Oh, Hyunhee,Kim, Su Sung,You, Byoung Hoon,Choi, Young Hee,Park, Tae-Sik,Lee, Chang Ho,Kurose, Hitoshi,Noureddin, Mazen,Seki, Ekihiro,Wan, Yu-J American Society for Clinical Investigation 2018 The Journal of clinical investigation Vol.128 No.12