An Uncertainty Aided Framework for Learning based Liver T1ρT_1\rho Mapping and Analysis

Objective: Quantitative $T_1\rho$ imaging has potential for assessment of biochemical alterations of liver pathologies. Deep learning methods have been employed to accelerate quantitative $T_1\rho$ imaging. To employ artificial intelligence-based quantitative imaging methods in complicated clinical environment, it is valuable to estimate the uncertainty of the predicated $T_1\rho$ values to provide the confidence level of the quantification results. The uncertainty should also be utilized to aid the post-hoc quantitative analysis and model learning tasks. Approach: To address this need, we propose a parametric map refinement approach for learning-based $T_1\rho$ mapping and train the model in a probabilistic way to model the uncertainty. We also propose to utilize the uncertainty map to spatially weight the training of an improved $T_1\rho$ mapping network to further improve the mapping performance and to remove pixels with unreliable $T_1\rho$ values in the region of interest. The framework was tested on a dataset of 51 patients with different liver fibrosis stages. Main results: Our results indicate that the learning-based map refinement method leads to a relative mapping error of less than 3% and provides uncertainty estimation simultaneously. The estimated uncertainty reflects the actual error level, and it can be used to further reduce relative $T_1\rho$ mapping error to 2.60% as well as removing unreliable pixels in the region of interest effectively. Significance: Our studies demonstrate the proposed approach has potential to provide a learning-based quantitative MRI system for trustworthy $T_1\rho$ mapping of the liver

Carboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in Hepatocellular carcinoma development

Background: The biological pathways and functional properties by which misexpressed microRNAs (miRNAs) contribute to liver carcinogenesis have been intensively investigated. However, little is known about the upstream mechanisms that deregulate miRNA expressions in this process. In hepatocellular carcinoma (HCC), hepatitis B virus (HBV) X protein (HBx), a transcriptional trans-activator, is frequently expressed in truncated form without carboxyl-terminus but its role in miRNA expression and HCC development is unclear. Methods: Human non-tumorigenic hepatocytes were infected with lentivirus-expressing full-length and carboxyl-terminal truncated HBx (Ct-HBx) for cell growth assay and miRNA profiling. Chromatin immunoprecipitation microarray was performed to identify the miRNA promoters directly associated with HBx. Direct transcriptional control was verified by luciferase reporter assay. The differential miRNA expressions were further validated in a cohort of HBV-associated HCC tissues using real-time PCR. Results: Hepatocytes expressing Ct-HBx grew significantly faster than the full-length HBx counterparts. Ct-HBx decreased while full-length HBx increased the expression of a set of miRNAs with growth-suppressive functions. Interestingly, Ct-HBx bound to and inhibited the transcriptional activity of some of these miRNA promoters. Notably, some of the examined repressed-miRNAs (miR-26a, -29c, -146a and -190) were also significantly down-regulated in a subset of HCC tissues with carboxyl-terminal HBx truncation compared to their matching non-tumor tissues, highlighting the clinical relevance of our data. Conclusion: Our results suggest that Ct-HBx directly regulates miRNA transcription and in turn promotes hepatocellular proliferation, thus revealing a viral contribution of miRNA deregulation during hepatocarcinogenesis. © 2011 Yip et al.published_or_final_versio

Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study

Background & Aims Little is known about the natural course of nonalcoholic fatty liver disease (NAFLD) with advanced fibrosis. We describe long-term outcomes and evaluate the effects of clinical and histologic parameters on disease progression in patients with advanced NAFLD. Methods We conducted a multi-national study of 458 patients with biopsy-confirmed NAFLD with bridging fibrosis (F3, n = 159) or compensated cirrhosis (222 patients with Child-Turcotte-Pugh scores of A5 and 77 patients with scores of A6), evaluated from April 1995 through November 2013 and followed until December 2016, death, or liver transplantation at hepatology centers in Spain, Australia, Hong Kong, and Cuba. Biopsies were re-evaluated and scored; demographic, clinical, laboratory, and pathology data for each patient were collected from the time of liver biopsy collection. Cox proportional and competing risk models were used to estimate rates of transplantation-free survival and major clinical events and to identify factors associated with outcomes. Results During a mean follow-up time of 5.5 years (range, 2.7–8.2 years), 37 patients died, 37 received liver transplants, 88 had initial hepatic decompensation events, 41 developed hepatocellular carcinoma, 14 had vascular events, and 30 developed nonhepatic cancers. A higher proportion of patients with F3 fibrosis survived transplantation-free for 10 years (94%; 95% confidence interval [CI], 86%–99%) than of patients with cirrhosis and Child-Turcotte-Pugh A5 (74%; 95% CI, 61%–89%) or Child-Turcotte-Pugh A6 (17%; 95% CI, 6%–29%). Patients with cirrhosis were more likely than patients with F3 fibrosis to have hepatic decompensation (44%; 95% CI, 32%–60% vs 6%, 95% CI, 2%–13%) or hepatocellular carcinoma (17%; 95% CI, 8%–31% vs 2.3%, 95% CI, 1%–12%). The cumulative incidence of vascular events was higher in patients with F3 fibrosis (7%; 95% CI, 3%–18%) than cirrhosis (2%; 95% CI, 0%–6%). The cumulative incidence of nonhepatic malignancies was higher in patients with F3 fibrosis (14%; 95% CI, 7%–23%) than cirrhosis (6%; 95% CI, 2%–15%). Death or transplantation, decompensation, and hepatocellular carcinoma were independently associated with baseline cirrhosis and mild (<33%) steatosis, whereas moderate alcohol consumption was associated with these outcomes only in patients with cirrhosis. Conclusions Patients with NAFLD cirrhosis have predominantly liver-related events, whereas those with bridging fibrosis have predominantly nonhepatic cancers and vascular events

An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease

Background: With the rising global prevalence of fatty liver disease related to metabolic dysfunction, the association of this common liver condition with chronic kidney disease (CKD) has become increasingly evident. In 2020, the more inclusive term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to replace the term non-alcoholic fatty liver disease (NAFLD). The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD. However, to date, there is no appropriate guidance on CKD in individuals with MAFLD. Furthermore, there has been little attention paid to the link between MAFLD and CKD in the Nephrology community. Methods and Results: Using a Delphi-based approach, a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD. Conclusions: This Delphi-based consensus statement provided guidance on the epidemiology, mechanisms, management and treatment of MAFLD and CKD, as well as the relationship between the severity of MAFLD and risk of CKD, which establish a framework for the early prevention and management of these two common and interconnected diseases.Fil: Sun, Dan Qin. Jiangnan University Medical Center; China. Nantong University; ChinaFil: Targher, Giovanni. Azienda Ospedaliera Universitaria Integrata Verona; ItaliaFil: Byrne, Christopher D.. University of Southampton; Reino UnidoFil: Wheeler, David C.. University College London; Estados UnidosFil: Wong, Vincent Wai Sun. Chinese University of Hong Kong; ChinaFil: Fan, Jian Gao. Shanghai Jiao Tong University; ChinaFil: Tilg, Herbert. Medical University Innsbruck; AustriaFil: Yuan, Wei Jie. Shanghai Jiao Tong University; ChinaFil: Wanner, Christoph. Würzburg University Clinic; AlemaniaFil: Gao, Xin. Fudan University; ChinaFil: Long, Michelle T.. Boston University School of Medicine; Estados UnidosFil: Kanbay, Mehmet. Koc University School of Medicine; TurquíaFil: Nguyen, Mindie H.. Stanford University Medical Center; Estados UnidosFil: Navaneethan, Sankar D.. Baylor College of Medicine; Estados UnidosFil: Yilmaz, Yusuf. Marmara University; Turquía. Recep Tayyip Erdoğan University; TurquíaFil: Huang, Yuli. Southern Medical University; ChinaFil: Gani, Rino A.. Universitas Indonesia; IndonesiaFil: Marzuillo, Pierluigi. Università della Campania “Luigi Vanvitelli”; ItaliaFil: Boursier, Jérôme. Angers University; FranciaFil: Zhang, Huijie. Southern Medical University; ChinaFil: Jung, Chan Young. Yonsei University; Corea del SurFil: Chai, Jin. Army Medical University; ChinaFil: Valenti, Luca. Università degli Studi di Milano; ItaliaFil: Papatheodoridis, George. Kapodistrian University of Athens; GreciaFil: Sookoian, Silvia Cristina. Centro de Investigacion Traslacional En Salud (cenitres) ; Facultad de Cs. de la Salud ; Universidad Maimonides; . Universidad Abierta Interamericana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chunsun, Dai. Nanjing Medical University; ChinaFil: Eslam, Mohammed. University of Sydney; AustraliaFil: Wei, Lai. Tsinghua University; ChinaFil: George, Jacob. University of Sydney; AustraliaFil: Zheng, Ming Hua. Wenzhou Medical University; Chin

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease

Importance Metabolic dysfunction–associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis.Objective To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)–based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD.Design, Setting, and Participants This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE).Main Outcomes and Measures The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests.Results A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group.Conclusions and Relevance Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis