Nonalcoholic fatty liver disease (NAFLD) affects around a quarter of the global population, paralleling worldwide increases in obesity and metabolic syndrome. NAFLD arises in the context of systemic ...metabolic dysfunction that concomitantly amplifies the risk of cardiovascular disease and diabetes. These interrelated conditions have long been recognized to have a heritable component, and advances using unbiased association studies followed by functional characterization have created a paradigm for unravelling the genetic architecture of these conditions. A novel perspective is to characterize the shared genetic basis of NAFLD and other related disorders. This information on shared genetic risks and their biological overlap should in future enable the development of precision medicine approaches through better patient stratification, and enable the identification of preventive and therapeutic strategies. In this Review, we discuss current knowledge of the genetic basis of NAFLD and of possible pleiotropy between NAFLD and other liver diseases as well as other related metabolic disorders. We also discuss evidence of causality in NAFLD and other related diseases and the translational significance of such evidence, and future challenges from the study of genetic pleiotropy.
Non-alcoholic fatty liver disease (NAFLD) is now recognised as the most common liver disease worldwide. It encompasses a broad spectrum of conditions, from simple steatosis, through non-alcoholic ...steatohepatitis, to fibrosis and ultimately cirrhosis and hepatocellular carcinoma. A hallmark of NAFLD is the substantial inter-patient variation in disease progression. NAFLD is considered a complex disease trait such that interactions between the environment and a susceptible polygenic host background determine disease phenotype and influence progression. Recent years have witnessed multiple genome-wide association and large candidate gene studies, which have enriched our understanding of the genetic basis of NAFLD. Notably, the I148M PNPLA3 variant has been identified as the major common genetic determinant of NAFLD. Variants with moderate effect size in TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution. The premise for this review is to discuss the status of research into important genetic and epigenetic modifiers of NAFLD progression. The potential to translate the accumulating wealth of genetic data into the design of novel therapeutics and the clinical implementation of diagnostic/prognostic biomarkers will be explored. Finally, personalised medicine and the opportunities for future research and challenges in the immediate post genetics era will be illustrated and discussed.
Genetic Insights for Drug Development in NAFLD Eslam, Mohammed; George, Jacob
Trends in pharmacological sciences (Regular ed.),
July 2019, 2019-07-00, 20190701, Letnik:
40, Številka:
7
Journal Article
Recenzirano
Drug development is a costly, time-consuming, and challenging endeavour, with only a few agents reaching the threshold of approval for clinical use. Therefore, approaches to more efficiently identify ...targets that are likely to translate to clinical benefit are required. Interrogation of the human genome in large patient cohorts has rapidly advanced our knowledge of the genetic architecture and underlying mechanisms of many diseases, including nonalcoholic fatty liver disease (NAFLD). There are no approved pharmacotherapies for NAFLD currently. Genetic insights provide a powerful and new approach to infer and prioritise candidate drugs, with such selection avoiding myriad pitfalls, while defining likely benefits. In this review, we discuss the prospects and challenges for the optimal utilisation of genetic findings for improving and accelerating the NAFLD drug discovery pipeline.
NAFLD is the most prevalent liver disease in many countries and increases the risk of hepatic and extrahepatic adverse outcomes.There are currently no approved pharmacotherapies for NAFLD.In recent years, understanding of the genetic factors contributing to interindividual variation in NAFLD susceptibility, progression, and outcomes has expanded significantly.Genetics-based drug discovery is positioned to provide a powerful new approach to infer and prioritise candidate drugs for further development.Genetic information could predict the safety of new drugs and hint at their likely efficacy, while also suggesting opportunities for drug repurposing.
Background & Aims
Diagnostic criteria for metabolic associated fatty liver disease (MAFLD) have been proposed, but not validated. We aimed to compare the diagnostic accuracy of the MAFLD definition ...vs the existing NAFLD criteria to identify patients with significant fibrosis and to characterize the impact of mild alcohol intake.
Methods
We enrolled 765 Japanese patients with fatty liver (median age 54 years). MAFLD and NAFLD were diagnosed in 79.6% and 70.7% of patients respectively. Significant fibrosis was defined by FIB‐4 index ≥1.3 and liver stiffness ≥6.6 kPa using shear wave elastography. Mild alcohol intake was defined as <20 g/day. Factors associated with significant fibrosis were analysed by logistic regression and decision‐tree analyses.
Results
Liver stiffness was higher in MAFLD compared to NAFLD (7.7 vs 6.8 kPa, P = .0010). In logistic regression, MAFLD (OR 4.401; 95% CI 2.144‐10.629; P < .0001), alcohol intake (OR 1.761; 95% CI 1.081‐2.853; P = .0234), and NAFLD (OR 1.721; 95%CI 1.009‐2.951; P = .0463) were independently associated with significant fibrosis. By decision‐tree analysis, MAFLD, but not NAFLD or alcohol consumption was the initial classifier for significant fibrosis. The sensitivity for detecting significant fibrosis was higher for MAFLD than NAFLD (93.9% vs 73.0%). In patients with MAFLD, even mild alcohol intake was associated with an increase in the prevalence of significant fibrosis (25.0% vs 15.5%; P = .0181).
Conclusions
The MAFLD definition better identifies a group with fatty liver and significant fibrosis evaluated by non‐invasive tests. Moreover, in patients with MAFLD, even mild alcohol consumption is associated with worsening of hepatic fibrosis measures.
Construction and demolition waste treatment has become an increasingly pressing economic, social, and environmental concern across the world. This study employs a science mapping approach to provide ...a thorough and systematic examination of the literature on waste management research. This study identifies the most significant journals, authors, publications, keywords, and active countries using bibliometric and scientometric analysis. The search retrieved 895 publications from the Scopus database between 2001 and 2021. The findings reveal that the annual number of publications has risen from less than 15 in 2006 to more than 100 in 2020 and 2021. The results declare that the papers originated in 80 countries and were published in 213 journals. Review, urbanization, resource recovery, waste recycling, and environmental assessment are the top five keywords. Estimation and quantification, comprehensive analysis and assessment, environmental impacts, performance and behavior tests, management plan, diversion practices, and emerging technologies are the key emerging research topics. To identify research gaps and propose a framework for future research studies, an in-depth qualitative analysis is performed. This study serves as a multi-disciplinary reference for researchers and practitioners to relate current study areas to future trends by presenting a broad picture of the latest research in this field.
Aim
Metabolic associated fatty liver disease (MAFLD) partly overlaps with non‐alcoholic fatty liver disease (NAFLD). Thus, using a generalized estimating equation (GEE) approach, we aimed to ...investigate the difference in worsening of atherosclerotic cardiovascular disease (ASCVD) risk between patients with MAFLD and NAFLD. We also investigated factors related to the difference between the two groups.
Methods
We enrolled 2306 subjects with fatty liver (MAFLD 80.7%, NAFLD 63.4%). Subjects with MAFLD/NAFLD were sub‐classified into three groups: NAFLD with no metabolic dysfunction (non‐Met NAFLD), overlapping, and MAFLD with moderate alcohol consumption (mod‐Alc MAFLD). ASCVD risk was estimated by non‐invasive tests, including the Suita score. An event was defined as worsening of these scores from the low‐risk to the high‐risk group. Independent factors for the event were analyzed by Cox regression analysis with the GEE.
Results
In Cox regression analysis, MAFLD (HR 1.08, 95% CI 1.02–1.15, p = 0.014) and alcohol consumption (20–39 g/day; HR 1.73, 95% CI 1.26–2.36, p = 0.001) were independently associated with worsening of the Suita score. In a subanalysis, the incidence of the event was significantly lower in non‐Met NAFLD than in the overlapping group (HR 0.70, 95% CI 0.50–0.98, p = 0.042). However, no significant difference was observed in the incidence between the overlapping and mod‐Alc MAFLD group (HR 1.19, 95% CI 0.89–1.58, p = 0.235).
Conclusions
The GEE approach demonstrates that MAFLD better identifies patients with worsening of ASCVD risk than NAFLD. Moreover, the superiority of MAFLD over NAFLD was due to the presence of metabolic dysfunction rather than moderate alcohol consumption.
Metabolic associated fatty liver disease (MAFLD) is the principal worldwide cause of liver disease and affects nearly a quarter of the global population. The objective of this work was to present the ...clinical practice guidelines of the Asian Pacific Association for the Study of the Liver (APASL) on MAFLD. The guidelines cover various aspects of MAFLD including its epidemiology, diagnosis, screening, assessment, and treatment. The document is intended for practical use and for setting the stage for advancing clinical practice, knowledge, and research of MAFLD in adults, with specific reference to special groups as necessary. The guidelines also seek to improve patient care and awareness of the disease and assist stakeholders in the decision-making process by providing evidence-based data. The guidelines take into consideration the burden of clinical management for the healthcare sector.
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