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.
Over the past 2 decades, nonalcoholic fatty liver disease (NAFLD) has grown from a relatively unknown disease to the most common cause of chronic liver disease in the world. In fact, 25% of the ...world’s population is currently thought to have NAFLD. Nonalcoholic steatohepatitis (NASH) is the subtype of NAFLD that can progress to cirrhosis, hepatocellular carcinoma (HCC), and death. NAFLD and NASH are not only found in adults—there is also a high prevalence of these diseases in children and adolescents. Because of the close association of NAFLD with type 2 diabetes (T2DM) and obesity, the latest models predict that the prevalence of NAFLD and NASH will increase, causing a tremendous clinical and economic burden and poor patient‐reported outcomes. Nonetheless, there is no accurate noninvasive method to detect NASH, and treatment of this disease is limited to lifestyle modifications. To examine the state of NAFLD among different regions and understand the global trajectory of this disease, an international group of experts came together during the 2017 American Association for the Study of Liver Diseases Global NAFLD Forum. We provide a summary of this forum and an assessment of the current state of NAFLD and NASH worldwide.
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.
Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH) are becoming the leading cause of liver-related morbidity and mortality ...worldwide, and a primary indication for liver transplantation. The pathophysiology of NASH is multifactorial and not yet completely understood; however, innate immunity is a major contributing factor in which liver-resident macrophages (Kupffer cells) and recruited macrophages play a central part in disease progression. In this Review, we assess the evidence for macrophage involvement in the development of steatosis, inflammation and fibrosis in NASH. In this process, not only the polarization of liver macrophages towards a pro-inflammatory phenotype is important, but adipose tissue macrophages, especially in the visceral compartment, also contribute to disease severity and insulin resistance. Macrophage activation is mediated by factors such as endotoxins and translocated bacteria owing to increased intestinal permeability, factors released from damaged or lipoapoptotic hepatocytes, as well as alterations in gut microbiota and defined nutritional components, including certain free fatty acids, cholesterol and their metabolites. Reflecting the important role of macrophages in NASH, we also review studies investigating drugs that target macrophage recruitment to the liver, macrophage polarization and their inflammatory effects as potential treatment options for patients with NASH.
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.
Cytokines are critical mediators that oversee and regulate immune and inflammatory responses via complex networks and serve as biomarkers for many diseases. Quantification of cytokines has ...significant value in both clinical medicine and biology as the levels provide insights into physiological and pathological processes and can be used to aid diagnosis and treatment. Cytokines and their clinical significance are introduced from the perspective of their pro‐ and anti‐inflammatory effects. Factors affecting cytokines quantification in biological fluids, native levels in different body fluids, sample processing and storage conditions, sensitivity to freeze‐thaw, and soluble cytokine receptors are discussed. In addition, recent advances in in vitro and in vivo assays, biosensors based on different signal outputs and intracellular to extracellular protein expression are summarized. Various quantification platforms for high‐sensitivity and reliable measurement of cytokines in different scenarios are discussed, and commercially available cytokine assays are compared. A discussion of challenges in the development and advancement of technologies for cytokine quantification that aim to achieve real‐time multiplex cytokine analysis for point‐of‐care situations applicable for both biomedical research and clinical practice are discussed.
Cytokines are important cellular signaling molecules and immune system mediators. Abnormal cytokine levels may cause cytokine storm and diseases. Consequently, quantification of cytokines is valuable for diseases diagnosisand therapy. The clinical significance of cytokines, factors affecting cytokine quantification, and advances of cytokine detection are summarized, providing a prospective for real‐time quantification of multiplex cytokines in the clinic.
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.
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