Natural History of Nonalcoholic Fatty Liver Disease: Implications for Clinical Practice and an Individualized Approach

Nonalcoholic fatty liver disease (NAFLD) is becoming the most prevalent liver disease worldwide, associated with epidemics of overweight and resulting metabolic syndrome (MetS). Around 20–30% of patients with NAFLD develop progressive liver fibrosis, which is the most important predictor of liver-related and overall morbidity and mortality. In contrast to classical understanding, no significant association has been demonstrated between the inflammatory component of NAFLD, i.e., nonalcoholic steatohepatitis (NASH), and the adverse clinical outcomes. Older age (>50 years) and presence of type 2 diabetes mellitus, in addition to some genetic variants, are most consistently reported indicators of increased risk of having liver fibrosis. However, critical driving force for the progression of fibrosis and risk factors for this have still not been fully elucidated. Apart from the genetic profile, gut dysbiosis, weight gain, worsening of insulin resistance, and worsening of liver steatosis represent candidate factors associated with unfavourable development of liver disease. Cardiovascular events, extrahepatic malignancies, and liver-related deaths are the leading causes of mortality in NAFLD. As patients with advanced fibrosis are under highest risk of adverse clinical outcomes, efforts should be made to recognize individuals under risk and rule out the presence of this stage of fibrosis, preferably by using simple noninvasive tools. This process should start at the primary care level by using validated biochemical tests, followed by direct serum tests for fibrosis or elastography in the remaining patients. Patients with advanced fibrosis should be referred to hepatologists for aggressive lifestyle modification and correction of the components of MetS, and cirrhotic patients should be screened for hepatocellular carcinoma and oesophageal varices

Multiparametric ultrasound in liver diseases: an overview for the practising clinician

Ultrasound (US) is usually the first and most commonly used tool in the diagnostic algorithm for liver disease. It is widely available, non-invasive and offers a real-time assessment of the liver in several anatomic planes, using different US modalities such as greyscale imaging, Doppler, elastography and contrast-enhanced US. This multiparametric ultrasound (MPUS) provides more information of the examined structures and allows for a faster and more accurate diagnosis, usually at the point of care, thus reducing the requirement for some invasive and more expensive methods. Current data on the MPUS in hepatology are summarised in this review, mostly focused on its use for non-invasive staging of liver fibrosis, detection and classification of portal hypertension and oesophageal varices, prognosis in chronic liver diseases and characterisation of focal liver lesions (FLLs). Based on the available data, we propose practical algorithms for clinical use of MPUS in chronic liver disease and FLL

Non-Invasive Assesment of Chronic Liver Disease by Two Dimensional Shear Wave Elastography: An Overview

Background: Liver Stiffness (LS) assessed by Sonoelastography (SE), has been demonstrated as reliable non-invasive indicator of liver fibrosis stage in patients with Chronic Liver Diseases (CLD). Sonoelastography performs best in ruling-out cirrhosis (F=4) and ruling-in signifficant fibrosis (F≥2). However, it is insufficiently accurate to replace endoscopy for detection of Esophageal Varices (EV), being able to only ruling-out large EV. LS ≥ 25 kPa by Transient Elastography (TE) is considered highly suggestive for the presence of Clinically Significant Portal Hypertension (CSPH). Higher liver and spleen stiffness have been asociated with adverse clinical outcomes in CLD. Two-dimensional shear wave elastography (2D-SWE), the latest developed SE method, allows both visualisation and quantification of liver elasticity in real time superimposed over B-mode ultrasound image. Discussion: Meta-analysis of studies with Supersonic Shear Imaging (SSI) revealed comparable performance of this 2D-SWE to TE in fibrosis staging, with AUROCs 0.85 for F≥2 (LS cut-off 8.04 kPa) and 0.93 for F=4 (LS cut-off 11.12 kPa). Few studies reported very good performance of 2DSWE (SSI) to rule-in CSPH (AUROCs 0.79-0.95; LS cut-offs 15-25 kPa). While conflicting data exist with respect to its performance in predicting the presence of EV, prognostic utility of 2D-SWE (SSI) was demonstrated in a single study that reported 3.4-fold (P=0.026) higher risk of adverse outcome in patients with baseline LS≥21.5 kPa followed over 28 months. Conclusion: 2D-SWE (SSI) might be used to stage liver fibrosis in CLD, identify patients with compensated cirrhosis under risk of adverse outcomes and potentially stratify risk of having CSPH and EV

Population screening for liver fibrosis: towards early diagnosis and intervention for chronic liver diseases

Cirrhosis, highly prevalent worldwide, develops after years of hepatic inflammation triggering progressive fibrosis. Currently, the main etiologies of cirrhosis are non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), although chronic hepatitis B and C infections are still major etiological factors in some areas of the world. Recent studies have shown that liver fibrosis can be assessed with relatively high accuracy non-invasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at-risk populations. Thus far, a limited number of population-based studies using non-invasive tests in different areas of the world indicate that a significant percentage of subjects without known liver disease (around 5% in general populations and a higher rate -18 to 27%- in populations with risk factors for liver disease) have significant undetected liver fibrosis or established cirrhosis. Larger international studies are required to show the harms and benefits before concluding that screening for liver fibrosis should be applied to populations at risk for chronic liver diseases. Screening for liver fibrosis has the potential for changing the current approach from diagnosing chronic liver diseases late when patients have already developed complications of cirrhosis to diagnosing liver fibrosis in asymptomatic subjects providing the opportunity of preventing disease progression

Prox1 Regulates the Notch1-Mediated Inhibition of Neurogenesis

During development of the spinal cord, Prox1 controls the balance between proliferation and differentiation of neural progenitor cells via suppression of Notch1 gene expression

Gene Expression Profiles in Human and Mouse Primary Cells Provide New Insights into the Differential Actions of Vitamin D-3 Metabolites

1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3) had earlier been regarded as the only active hormone. The newly identified actions of 25-hydroxyvitamin D3 (25(OH)D3) and 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) broadened the vitamin D3 endocrine system, however, the current data are fragmented and a systematic understanding is lacking. Here we performed the first systematic study of global gene expression to clarify their similarities and differences. Three metabolites at physiologically comparable levels were utilized to treat human and mouse fibroblasts prior to DNA microarray analyses. Human primary prostate stromal P29SN cells (hP29SN), which convert 25(OH)D3 into 1α,25(OH)2D3 by 1α-hydroxylase (encoded by the gene CYP27B1), displayed regulation of 164, 171, and 175 genes by treatment with 1α,25(OH)2D3, 25(OH)D3, and 24R,25(OH)2D3, respectively. Mouse primary Cyp27b1 knockout fibroblasts (mCyp27b1−/−), which lack 1α-hydroxylation, displayed regulation of 619, 469, and 66 genes using the same respective treatments. The number of shared genes regulated by two metabolites is much lower in hP29SN than in mCyp27b1−/−. By using DAVID Functional Annotation Bioinformatics Microarray Analysis tools and Ingenuity Pathways Analysis, we identified the agonistic regulation of calcium homeostasis and bone remodeling between 1α,25(OH)2D3 and 25(OH)D3 and unique non-classical actions of each metabolite in physiological and pathological processes, including cell cycle, keratinocyte differentiation, amyotrophic lateral sclerosis signaling, gene transcription, immunomodulation, epigenetics, cell differentiation, and membrane protein expression. In conclusion, there are three distinct vitamin D3 hormones with clearly different biological activities. This study presents a new conceptual insight into the vitamin D3 endocrine system, which may guide the strategic use of vitamin D3 in disease prevention and treatment.Peer reviewe