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Introduction : Therapeutic oligonucleotides have emerged as a promising new class of drug that could silence undruggable targets; they can potentially treat metabolic liver diseases such as nonalcoholic fatty liver disease (NAFLD), hereditary hemochromatosis and alpha 1 antitrypsin deficiency. Areas covered : This article illuminates the mechanism of action of, and drug delivery approaches for therapeutic oligonucleotides such as antisense oligonucleotides (ASOs), short interfering RNAs (siRNAs), and MicroRNAs (miRs). We reveal why the liver is the ideal organ for therapeutic oligonucleotides, discuss its unique architecture, and shed light on those susceptible molecular targets that can be modulated. We also examine preclinical and clinical data on the utility of oligonucleotides in silencing the expression of genes responsible for metabolic liver diseases. Expert opinion : The liver has numerous susceptible molecular therapeutic targets; hence, metabolic liver diseases can be treated effectively by modulating these targets via novel therapeutic oligonucleotides. Undoubtedly, these exciting developments integrate well with precision medicine progress. Specific therapeutic oligonucleotides can be designed based on the exact underlying molecular mechanism of the disease. So, there is a justification for furthering the development of therapeutic oligonucleotides for metabolic liver diseases. Safety concerns such as immunogenicity and off-target effects will however require careful monitoring.

Obeticholic acid (OCA), 6α-ethyl-3α,7α-dihydroxy-5-cholan-24-oic acid, is a semisynthetic derivative of the chenodeoxycholic acid (CDCA, 3α,7α-dihydroxy-5-cholan-24-oic acid), a relatively hydrophobic primary bile acid synthesized in the liver from cholesterol. OCA, also known as 6-ethyl-CDCA or INT-747, was originally described by investigators at the Perugia University in 2002 as a selective ligand for the bile acid sensor, farnesoid-X-receptor (FXR). In addition to FXR and similarly to CDCA, OCA also activates GPBAR1/TGR5, a cell membrane G protein-coupled receptor for secondary bile acids. In 2016, based on the results of phase II studies showing efficacy in reducing the plasma levels of alkaline phosphatase, a surrogate biomarker for disease progression in primary biliary cholangitis (PBC), OCA has gained approval as a second-line treatment for PBC patients nonresponsive to UDCA. The use of OCA in PBC patients associates with several side effects, the most common of which is pruritus, whose incidence is dose-dependent and is extremely high when this agent is used as a monotherapy. Additionally, the use of OCA associates with the increased risk for the development of liver failure in cirrhotic PBC patients. Currently, OCA is investigated for its potential in the treatment of nonalcoholic steatohepatitis (NASH). Phase II and III trials have shown that OCA might attenuate the severity of liver fibrosis in patients with NASH, but it has no efficacy in reversing the steatotic component of the disease, while reduces the circulating levels of HDL-C and increases LDL-C. In summary, OCA has been the first-in-class of FXR ligands advanced to a clinical stage and is now entering its third decade of life, highlighting the potential benefits and risk linked to FXR-targeted therapies.

Alcohol consumption is often a comorbid condition in other chronic liver diseases. It has been shown to act in synergy to increase liver injury in viral hepatitis, hereditary hemochromatosis, and nonalcoholic fatty liver disease (NAFLD), leading to an increased risk of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Data suggest that modest alcohol consumption may be inversely related to the risk of developing NAFLD and lower rates of progression of NAFLD to nonalcoholic steatohepatitis (NASH). This article reviews data on the relationship between alcohol consumption and other chronic liver diseases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To assess the reproducibility of six ultrasound (US)‐determined shear wave (SW) viscoelastography parameters for assessment of mechanical properties of the liver in volunteers and patients with biopsy‐proven metabolic dysfunction‐associated steatotic liver disease (MASLD) or metabolic dysfunction‐associated steatohepatitis (MASH). Methods: This prospective, cross‐sectional, institutional review board‐approved study included 10 volunteers and 20 patients with MASLD or MASH who underwent liver US elastography twice, at least 2 weeks apart. SW speed (SWS), Young's modulus (E), shear modulus (G), SW attenuation (SWA), SW dispersion (SWD), and viscosity were computed from radiofrequency data recorded on a research US scanner. Linear mixed models were used to consider the sonographer on duty as a confounder. The reproducibility of measurements was assessed by intraclass correlation coefficient (ICC), coefficient of variation (CV), reproducibility coefficient (RDC), and Bland‐Altman analyses. Results: The sonographer performing the exam had no impact on viscoelastic parameters (P >.05). ICCs of SWS, E, G, SWA, SWD, and viscosity were, respectively, 0.89 (95% confidence intervals [CI]: 0.79‐0.95), 0.81 (95% CI: 0.79‐0.95), 0.90 (95% CI: 0.80‐0.95), 0.96 (95% CI: 0.93‐0.98), 0.78 (95% CI: 0.60‐0.89), and 0.90 (95% CI: 0.80‐0.95); CVs were 11.9, 23.3, 24.2, 10.1, 29.0, and 32.2%; RDCs were 33.0, 64.5, 66.9, 27.7, 80.3, and 89.2%, and Bland‐Altman mean biases and 95% limits of agreement were −0.05 (−0.45, 0.35) m/s, −0.61 (−5.33, 4.10) kPa, −0.25 (−2.06, 1.56) kPa, −0.01 (−0.27, 0.26) Np/m/Hz, −0.09 (−7.09, 6.91) m/s/kHz, and −0.33 (−2.60, 1.94) Pa/s, between the two visits. Conclusion: US‐determined viscoelastography parameters can be measured with high reproducibility and consistency between two visits 2 weeks apart on the same ultrasound machine. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease worldwide. There are limited biomarkers that can detect progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The purpose of our study was to utilize CT texture analysis to distinguish steatosis from NASH. 16 patients with NAFLD (38% male, median (interquartile range): age 57 (48–64) years, BMI 37.5 (35.0–46.8) kg/m2) underwent liver biopsy and abdominal non-contrast CT. CT texture analysis was performed to quantify gray-level tissue summaries (e.g., entropy, kurtosis, skewness, and attenuation) using commercially available software (TexRad, Cambridge England). Logistic regression analyses were performed to quantify the association between steatosis/NASH status and CT texture. ROC curve analysis was performed to determine sensitivity, specificity, AUC, 95% CIs, and cutoff values of texture parameters to differentiate steatosis from NASH. By histology, 6/16 (37%) of patients had simple steatosis and 10/16 (63%) had NASH. Patients with NASH had lower entropy (median, interquartile range (IQR): 4.3 (4.1, 4.8) vs. 5.0 (4.9, 5.2), P = 0.013) and lower mean value of positive pixels (MPP) (34.4 (21.8, 52.2) vs. 66.5 (57.0, 70.7), P = 0.009) than those with simple steatosis. Entropy values below 4.73 predict NASH with 100% (95%CI: 67–100%) specificity and 80% (50–100%) sensitivity, AUC: 0.88. MPP values below 54.0 predict NASH with 100% (67–100%) specificity and 100% (50–100%) sensitivity, AUC 0.90. Our study provides preliminary evidence that CT texture analysis may serve as a novel imaging biomarker for disease activity in NAFLD and the discrimination of steatosis and NASH. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent chronic liver diseases worldwide. Non-alcoholic steatohepatitis (NASH) is a progressive type of NAFLD that may cause cirrhosis, hepatocellular carcinoma, or almost mortality. Therefore, early diagnosis of the NASH is crucial. NASH is scored using the main histopathological features: ballooning, inflammation, steatosis, and fibrosis. The diagnosis of NASH by pathologists is time-consuming and can vary subjectively. On the other hand, several studies have reported deep learning approaches to enable fully automated NASH scoring. However, these studies suffer from limited labeled and imbalanced datasets. The purpose of this study to achieve fully automated NASH scoring with deep learning models that overcome data limitations. This study proposes an unsupervised transfer learning model for NASH scoring and fibrosis staging on a small-size dataset within two steps. In the first step, Convolutional Auto Encoder (CAE) is utilized as a deep feature extractor in an unsupervised manner during reconstruction. The second step is fine-tuning for classification consisting of the CAE encoder set as initial layers combined with fully connected layers and softmax. The proposed unsupervised transfer learning model is evaluated on a public NASH dataset. We compare the performance of the proposed network (CAE+classifier) with transfer learning models including Inception-v3, VGG16, ResNet-50. The proposed model has 94.87% AUC for ballooning, 89.47% AUC for inflammation, 96.15% AUC for steatosis, and 93.18% AUC for fibrosis. The proposed model is superior to transfer learning models (Inception-v3, VGG16, ResNet-50) with less parameter size and low computational complexity on a small NASH dataset. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, with a continuously growing prevalence. The pathophysiology of the disease is complex and includes several mechanisms, with metabolic syndrome and insulin resistance playing a major role. It is crucial to diagnose NAFLD before it advances to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis, presented by its complications which include ascites, portal hypertension, bleeding varices and encephalopathy. Another important complication of NAFLD and cirrhosis is hepatocellular carcinoma (HCC), a cancer with increasing incidence and poor prognosis. Even with the growing prevalence of NAFLD, diagnosis via liver biopsies is unrealistic, considering the costs and complications. Noninvasive tests, including serum biomarkers and elastography, are cost-effective and convenient, thereby replacing liver biopsies in diagnosing and excluding liver fibrosis. However, currently, these noninvasive tests have several limitations, such as variability, inadequate accuracy and risk factors for error. The limitations and variability of these tests comet the investigator to propose combining them in diagnostic algorithms to produce more accurate tools. Identifying patients with significant fibrosis is important for targeted therapies to prevent disease progression. Effective screening using noninvasive tests can be crucial for patient risk stratification and early diagnosis. [ABSTRACT FROM AUTHOR]

Background: An exploratory study was performed to determine the prevalence of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs78409 [G] allele among the Hmong as a risk factor for nonalcoholic fatty liver disease (NAFLD). NAFLD/nonalcoholic steatohepatitis is the world's most common chronic liver disease and is expected to replace viral hepatitis as the leading cause of cirrhosis and potential precursor to hepatocellular carcinoma (HCC). Of all populations in California, the Hmong experience the highest risk of death from HCC and the highest prevalence of metabolic syndrome risk factors among Asians that predispose them to NAFLD. Here a genetic explanation was sought for the high rates of chronic liver disease among the Hmong. The literature pointed to the PNPLA3 rs738409 [G] allele as a potential genetic culprit.Methods: Cell-free DNA was isolated from 26 serum samples previously collected in community settings. Quantitative polymerase chain reaction-based single-nucleotide polymorphism (SNP) genotyping was performed with a validated TaqMan SNP genotyping assay, and results were analyzed with TaqMan Genotyper software.Results: The PNPLA3 rs738409 [C>G] variant occurred at a frequency of 0.46 (12 of 26; 95% confidence interval, 0.27-0.67). This carrier rate would rank the Hmong as the third highest population in the 1000 Genomes Project.Conclusions: Although this small sample size limits the generalizability, the high frequency rates of this allele along with the presence of metabolic syndrome risk factors warrant further studies into the etiology of NAFLD among the Hmong. Cancer 2018;124:1583-9. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the hepatic metabolic alterations in nonalcoholic fatty liver disease (NAFLD) by using 1 H-MRS (proton magnetic resonance spectroscopy) with long echo time and to test the reproducibility of human study in an animal model. Liver biopsy is the gold standard for diagnosing NAFLD but with practical constraints. 1 H-MRS allows in vivo assessment of hepatocellular metabolism and has shown potential for biochemical differentiation in diffuse liver disease.Materials and Methods: In all, 32 subjects (11 patients with nonalcoholic steatohepatitis [NASH], 15 with simple steatosis [SS], and six healthy controls) were studied. For test reproducibility, 36 C57BL/6 mice, including 10 mice with streptozotocin-induced NASH, 15 with SS, and 11 high-fat diet controls, were studied. 1 H-MRS measurements at 3T and 4.7T MRI were performed on a localized voxel of the liver using PRESS sequence. Hepatic alanine (Ala), lactate+triglyceride (Lac+TG), and TG levels were compared between NASH, SS, and control groups using analysis of variance (ANOVA) tests. Diagnostic accuracy was determined by calculating the area under the receiver operating characteristics (ROC) curve. The associations between metabolite levels and pathologic grades or NAFLD activity scores (NAS) were assessed using Pearson's correlation.Results: NASH patients had higher levels of Ala (P < 0.001), Lac+TG (P < 0.001), and TG (P < 0.05) than SS patients or controls. The AUROC curve to distinguish NASH from SS was 1.00 (95% confidence interval [CI] 1.00-1.00) for Ala and 0.782 (95% CI 0.61-0.96) for Lac+TG. Ala and Lac+TG concentrations were positively correlated with steatosis grade (Ala Pearson's r = 0.723; Lac+TG r = 0.446), lobular inflammation (Ala r = 0.513), and NAS (Ala r = 0.743; Lac+TG r = 0.474).Conclusion: 1 H-MRS is potentially useful for noninvasive diagnosis of NASH and simple steatosis by hepatic metabolite quantification.Level Of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1298-1310. [ABSTRACT FROM AUTHOR]

Abstract: Transforming growth factor ? (TGF-?) belongs to a class of pleiotropic cytokines that are involved in the processes of embryonic development, wound healing, cell proliferation, and differentiation. Moreover, TGF-? is also regarded as a central regulator in the pathogenesis and development of various liver diseases because it contributes to almost all of the stages of disease progression. A range of liver cells are considered to secrete TGF-? ligands and express related receptors and, consequently, play a crucial role in the progression of liver disease via different signal pathways. In this manuscript, we review the role of the TGF-? signaling pathway in liver disease and the potential of targeting the TGF-? signaling in the pharmacological treatment of liver diseases. [Copyright &y& Elsevier]

Abstract: Cholesterol and chronic activation of hypoxia-inducible factor-1 (HIF-1) have been separately implicated in the pathogenesis and progression of liver diseases. In AML12 hepatocytes increased HIF-1α protein accumulation was evident after 2h of incubation with cholesterol, whereas enhanced HIF-1 transcriptional activity was observed after 6h. Investigations into the molecular mechanism have shown that cholesterol inhibited HIF-1α degradation. Mitochondrial dysfunction and enhanced mitochondrial reactive oxygen species (ROS) generation were observed in 2-h cholesterol-treated cells along with augmented nitric oxide (NO) levels. Further analysis indicated that HIF-1α stabilization at later time (6h), but not after 2h, of incubation with cholesterol was dependent on NO production. To elucidate the role of mitochondrial dysfunction in HIF-1α stabilization, mitochondrial DNA-depleted hepatocytes were prepared. In these cells the ability of cholesterol to activate the HIF-1 pathway was abolished. Similarly, catalase overexpression also attenuated cholesterol-induced HIF-1α accumulation. These results demonstrate that cholesterol promotes HIF-1 activation in a ROS- and NO-dependent manner. Chronic liver activation of HIF-1 by cholesterol may mediate its deleterious effects in the liver. [Copyright &y& Elsevier]

Highlights: [•] Nrf2 plays a key role in rat liver fibrosis. [•] Nrf2 may reveal gene expression changes in liver injury and fibrosis. [•] Nrf2 serve as a potential mechanism for HSC activation and liver fibrosis. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. In smaller studies, sleep apnea has been previously associated with NAFLD. The aim of this study was to assess the prevalence and independent associations of sleep disorders in patients with NAFLD using recent population-based data. Methods: Three cycles of the National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2010 were used. The diagnosis of NAFLD was established as elevated liver enzymes in the absence of all other causes of chronic liver disease. Sleep disorders were diagnosed using sleep disorder questionnaires completed by NHANES participants, and included self-reported history of sleep apnea, insomnia, and restless leg syndrome. The prevalence of sleep disorders was compared between those with and without NAFLD. Results: A total of 10,541 adult NHANES participants with complete demographic, clinical, and laboratory data were included. Of those, 15.0% had NAFLD and 7.2% reported having sleep disorders. Of those with sleep disorders, 64.7% reported history of sleep apnea, 16.0% had history of insomnia, and 4.0% had restless leg syndrome. Individuals with NAFLD were more likely to be male (53.8% vs. 45.7%, P < 0.0001), obese (50.1% vs. 33.4%, P < 0.0001) and had higher prevalence of sleep disorders (9.1% vs. 6.9%, P = 0.0118). In multivariate analysis, having any sleep disorder, sleep apnea and insomnia were all independently associated with NAFLD [OR (95% CI) = 1.40 (1.11–1.76), OR = 1.39 (0.98–1.97), and OR = 2.17 (1.19–3.95); respectively)]. Conclusions: This large population-based data suggests that NAFLD is associated with sleep disorders. Although the exact mechanism is unknown, this association is most likely through metabolic conditions associated with NAFLD. [Copyright &y& Elsevier]

Liver transplantation (LT) has evolved rapidly since the first successful liver transplant performed in1967. Despite a humble beginning, this procedure gained widespread acceptance in the western world as a suitable option for patients with end stage liver disease (ESLD) by the beginning of the 1980s. At present, approximately 25,000 liver transplants are being performed worldwide every year with approximately 90% one year survival. The techniques of living donor liver transplantation (LDLT) developed in East Asia in the 1990s to overcome the shortage of suitable grafts for children and scarcity of deceased donors. While deceased donor liver transplantation (DDLT) constitutes more than 90% of LT in the western world, in India and other Asian countries, most transplants are LDLT. Despite the initial disparity, outcomes following LDLT in eastern countries have been quite satisfactory when compared to the western programs. The etiologies of liver failure requiring LT vary in different parts of the world. The commonest etiology for acute liver failure (ALF) leading to LT is drugs in the west and acute viral hepatitis in Asia. The most common indication for LT due to ESLD in west is alcoholic cirrhosis and hepatitis C virus (HCV), while hepatitis B virus (HBV) predominates in the east. There is a variation in prognostic models for assessing candidature and prioritizing organ allocation across the world. Model for end–stage liver disease (MELD) is followed in United States and some European centers. Other European countries rely on the Child–Turcotte–Pugh (CTP) score. Some parts of Asia still follow chronological order of listing. The debate regarding the best model for organ allocation is far from over. [ABSTRACT FROM AUTHOR]

Long-chain omega-3 fatty acids belong to a family of polyunsatu- rated fatty acids that are known to have important beneficial effects on metabolism and inflammation. Such effects may confer a benefit in specific chronic noncommunicable diseases that are becoming very prevalent in Westernized societies [e.g., nonalcoholic fatty liver disease (NAFLD)]. Typically, with a Westernized diet, long-chain omega-6 fatty acid consumption is markedly greater than omega-3 fatty acid con- sumption. The potential consequences of an alteration in the ratio of omega-6 to omega-3 fatty acid consumption are increased production of proinflammatory arachidonic acid-derived eicosanoids and impaired regulation of hepatic and adipose function, predisposing to NAFLD. NAFLD represents a spectrum of liver fat-related conditions that orig- inates with ectopic fat accumulation in liver (hepatic steatosis) and progresses, with the development of hepatic inflammation and fibrosis, to nonalcoholic steatohepatitis (NASH). If the adipose tissue is inflamed with widespread macrophage infiltration, the production of adipokines may act to exacerbate liver inflammation and NASH. Omega-3 fatty acid treatment may have beneficial effects iti regulating hepatic lipid metabolism, adipose tissue function, and inflammation. Recent studies testing the effects of omega-3 fatty acids in NAFLD are showing promise and suggesting that these fatty acids may be useful in the treat- ment of NAFLD. To date, further research is needed in NAFLD to (a) establish the dose of long-chain omega-3 fatty acids as a treatment, (b) determine the duration of therapy, and (c) test whether there is benefit on the different component features of NAFLD (hepatic fat, inflammation, and fibrosis). [ABSTRACT FROM AUTHOR]

Abstract: Quantitating hepatic steatosis is important in many liver diseases and liver transplantation. Since steatosis estimation by pathologists has inherent intra- and inter-observer variability, we compared and contrasted computerized techniques with magnetic resonance imaging measurements, pathologist visual scoring, and clinical parameters. Computerized methods applied to whole slide images included a commercial positive pixel count algorithm and a custom algorithm programmed at our institution. For all liver samples (n =59), including pediatric, adult, frozen section, and permanent specimens, statistically significant correlations were observed between pathology, radiology, and each image analysis modality (r =0.75–0.97, p <0.0001), with the strongest correlations in the pediatric cohort. Statistically significant relationships were observed between each method and with body mass index (r =0.37–0.56, p from <0.0001 to <0.05) and with albumin (r =0.55–0.64, p <0.05) but not with alanine aminotransferase or aspartate aminotransferase. Although pathologist assessments correlated (r =0.64–0.86, 0.92–0.97, and 0.78–0.91 for microvesicular, macrovesicular, and overall steatosis, respectively), the absolute values of hepatic steatosis visual assessment were susceptible to intra- and inter-observer variability, particularly for microvesicular steatosis. Image analysis, pathologist assessments, radiology measurements, and several clinical parameters all showed correlations in this study, providing evidence for the utility of each method in different clinical and research settings. [Copyright &y& Elsevier]

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in children; its rise has been related to the increasing prevalence of obesity. Significant advancements have been made in the investigation of the etiopathogenesis and genetic risk factors for the disease. Pediatric fatty liver disease often displays a histologic pattern distinct from that found in adults, and liver biopsy remains the gold standard for diagnosis of nonalcoholic steatohepatitis (NASH). Lifestyle modifications that result in weight loss remain the first-line treatment of NAFLD in children. Recent adult and pediatric clinical trials on the use of antioxidants combined with lifestyle intervention for NAFLD have demonstrated encouraging results, and additional trials are underway. In this review, the authors provide an overview of current concepts in epidemiology, histologic features, diagnosis, pathophysiology, genetic risk factors, and treatment of NAFLD in children. [ABSTRACT FROM AUTHOR]

Aim: In this study, we aimed to investigate the relationship between the histological fibrosis stage of nonalcoholic fatty liver disease (NAFLD) and serum connective tissue growth factor (CTGF) to determine the usefulness of this relationship in clinical practice. Methods: Serum samples were collected from 51 patients with biopsy-proven NAFLD and 28 healthy controls, and serum levels of CTGF were assayed by ELISA. Results: Levels of CTGF were significantly higher in patients with NAFLD compared with controls (P=0.001). The serum CTGF levels were significantly increased, that correlated with histological fibrosis stage, in patients with NAFLD [in patients with no fibrosis (stage 0) 308.2 ± 142.9, with mild fibrosis (stage 1-2) 519.9 ± 375.2 and with advanced fibrosis (stage 3-4) 1353.2 ± 610 ng/l, P < 0.001]. Also serum level of CTGF was found as an independent predictor of histological fibrosis stage in patients with NAFLD (β = 0.662, t=5.6, P <0.001). The area under the ROC curve was estimated 0.931 to separate patients with severe fibrosis from patients with other fibrotic stages. Conclusion: Serum levels of CTGF may be a clinical utility for distinguishing NAFLD patients with and without advanced fibrosis. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world. It encompasses a spectrum of disease ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Growing evidence links NAFLD to cardiovascular (CV) disease; however, the association between the histologic severity of NAFLD and CV risk remains poorly understood.Aim: To assess the relationship between severity of liver injury and CV risk markers in a large, well-characterized group of patients with biopsy-proven NAFLD.Methods: Our cohort consisted of 83 consecutive patients undergoing liver biopsy for clinical suspicion of NAFLD. Patients were subsequently divided into three groups: normal biopsy (n=11) simple steatosis (n=36), and NASH (n=36). CV risk markers included: triglyceride/high-density lipoprotein (HDL), total cholesterol/HDL, and low-density lipoprotein/HDL ratios.Results: All lipid ratios were found to be significantly associated with NAFLD (p<0.05) after adjusting for age and gender. More importantly, there was a stepwise, statistically significant increase in lipid ratios from patients with normal biopsies to patients with simple steatosis to those with NASH (p<0.05). A positive correlation was found between the lipid ratios and NAFLD activity score (NAS) as well as the individual histological features of the NAS (steatosis, inflammation, and ballooning) with the strongest correlation being with NAS (rho (95% CI) 0.41 (0.21, 0.62), p<0.001).Conclusion: In patients with NAFLD, the histologic severity of liver injury and inflammation is strongly associated with an increased CV risk and an atherogenic lipid profile. [ABSTRACT FROM AUTHOR]

Aim: We reported previously that hypoadiponectinemia enhances hepatic oxidative stress and accelerates progression of nonalcoholic steatohepatitis (NASH) in mice. However, the precise mechanism and preventive effects of adiponectin on NASH remain unclear. The aim of this study was to examine the effects of adiponectin on steatohepatitis using adiponectin-knockout (KO) mice and adenovirus-mediated adiponectin expression system. Methods: We used male KO mice and C57BL6/J (WT) mice fed methionine choline-deficient (MCD)-diet as a steatohepatitis model. Liver histology, hepatic oxidative stress markers, and hepatic gene expression levels were investigated. In addition, Hepa 1–6 cells, a mouse liver cell line, were cultured with or without recombinant adiponectin, and gene expressions were investigated by real-time RT-PCR. Results: After 2-week feeding of MCD diet, hepatic steatosis was enhanced and plasma alanine aminotransferase elevated in KO mice than in WT mice. In KO mice liver, thiobarbituric acid reactive substances increased, glutathione levels decreased, and mRNA expression levels of antioxidant enzymes (catalase, superoxide dismutase-1) downregulated. Adenovirus-mediated adiponectin expression prevented these changes in KO mice. Moreover, Kupffer cell infiltration was enhanced and mRNA levels of anti-inflammatory M2 macrophage markers (interleukin-10, arginase-1) were decreased in KO mice liver. In the in vitro study, adiponectin significantly increased catalase gene expression in Hepa 1–6 cells. Conclusions: Lack of adiponectin enhanced, and adiponectin administration prevented steatohepatitis progression in mice. These changes were due to the anti-oxidative effects of adiponectin, and its effects on Kupffer cells recruitment and phenotype polarization. Augmentation of adiponectin effects could be a useful preventive approach for NASH progression. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. With no Food and Drug Administration approved drugs, current treatment options include dietary restrictions and lifestyle modification. NAFLD is closely associated with metabolic disorders such as obesity, type 2 diabetes, and dyslipidemia. Hence, clinically various pharmacological approaches using existing drugs such as antidiabetic, anti-obesity, antioxidants, and cytoprotective agents have been considered in the management of NAFLD and nonalcoholic steatohepatitis (NASH). However, several pharmacological therapies aiming to alleviate NAFLD-NASH are currently being examined at various phases of clinical trials. Emerging data from these studies with drugs targeting diverse molecular mechanisms show promising outcomes. This review summarizes the current understanding of the pathogenic mechanisms of NAFLD and provides an insight into the pharmacological targets and emerging therapeutics with specific interventional mechanisms. In addition, we also discuss the importance and utility of new approach methodologies and regulatory perspectives for NAFLD-NASH drug development. [ABSTRACT FROM AUTHOR]

The post antiretroviral therapy (ART) era for human immunodeficiency virus (HIV) infection resulted in a dramatically increased proportion of deaths attributed to liver-related causes in patients with HIV treated with ART. Additionally, as patients become older as a result of effective ART, liver-related conditions and application of safe therapies are now major concerns in the setting of HIV infection. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver diseases that range from hepatic steatosis at the most clinically benign end of the spectrum, through an intermediate lesion, nonalcoholic steatohepatitis (NASH), to cirrhosis at the opposite extreme. Epidemiology studies have estimated that about 20–30% of adults in the United States and other Western countries have NAFLD, and of these about 10% (2–3% of adults) meet the diagnostic criteria of NASH. Studies of animals and humans with obesity-related fatty liver disease have revealed much about the mechanisms that mediate this common pathology. The pathogenesis of NASH is multifactorial and includes insulin resistance, excessive intracellular fatty acids, oxidant stress, mitochondrial dysfunction and the role of innate immunity. This review will briefly discuss the epidemiology of NAFLD and focus on current understanding of the pathogenesis of NASH. [ABSTRACT FROM AUTHOR]

Abstract: Pathological assessment is considered as the gold standard for the diagnosis of nonalcoholic steatohepatitis (NASH). However, there is no agreement of histological features required for the diagnosis of NASH. In the present study, eight experienced hepatopathologists read liver biopsy specimen slides of 21 cases of NASH and suspected NASH independently and were asked to assess histopathological features and render a diagnosis. Interobserver variation among pathologists was evaluated by kappa statistics. Significant, good agreement was present in evaluation of the extent of steatosis and grade of fibrosis. Agreement was moderate concerning the localization of steatosis, localization of fibrosis, and glycogen nuclei. Only slight or poor agreement was seen in evaluation of type of steatosis, ballooning, intralobular necroinflammatory change, portal inflammation, and degree of neutrophilic infiltration. Thus the agreement varied for histological variables. Significant, moderate agreement was seen in the diagnosis of NASH but agreement was poor in the diagnosis of suggestive NASH. The agreement for the diagnosis of NASH was not high as for the individual histological findings that were thought to be the basis of the diagnosis. In conclusion, some histological features in NASH might prove useful for the development of a standardized and reliable pathological diagnosis and scoring system. [Copyright &y& Elsevier]

Abstract: A condition defined as nonalcoholic fatty liver disease (NAFLD) is frequently found in humans. Deemed as a benign condition until recently, more emphasis is now put on the potential harmful evolution of the inflammatory form, that is, nonalcoholic steatohepatitis (NASH), toward end-stage liver disease. This review highlights the major morphologic and pathophysiological features of NASH. The link between experimental biochemical findings in animal models and clinical and therapeutic approaches in humans is discussed. Once all the other causes of persistent elevation of serum transaminase levels have been excluded, the diagnosis of NASH can be only confirmed by liver histology. Other noninvasive diagnostic tools, however, are being investigated to assess specific subcellular functions and to allow the follow-up of patients at higher risk for major liver dysfunction. A better understanding of various pathogenic aspects of NASH will help in identifying potential therapeutic approaches in these patients. [Copyright &y& Elsevier]

Background: Wilson's disease is one of the most common hereditary causes of unclear hepatopathy. Patient & Method: A 34-year old male patient with a history of hyperlipidemia was admitted with symptoms of abdominal pain and slight hematuria. Abnormal liver function tests, ultrasound reports and liver biopsy were suggestive of nonalcoholic steatohepatitis (NASH). The patient received preliminary treatment for NASH. However, on subsequent follow-up, NASH remained unresolved and liver histology showed fibrosis progression from fibrosis stage 1 to stage 3. Results: Biochemical tests revealed that the levels of serum ceruloplasmin were decreased (7mg/dl) while the urinary excretion of copper was found to be increased (174.2 μg/day). Wilson's disease was confirmed by diagnostic mutation analysis involving Direct Sequencing. Heterogeneity in the patient's ATP7B gene confirmed Wilson's disease. Administration of D-penicillamine resulted in a decrease in fat deposition in the liver and no further progression in fibrosis after 10 months. Conclusion: Adult patient presenting NASH as first symptoms need to be examined for Wilson's disease and other metabolic conditions affecting the liver, prior to initiation of treatment. (Mahmood S, Inada N, Izumi A, Kawanaka M, Kobashi H, Yamada G. Wilson's disease masquerading as nonalcoholic steatohepatitis. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a widespread hepatic disorder in the United States and other Westernized countries. Nonalcoholic steatohepatitis (NASH), an advanced stage of NAFLD, can progress to end-stage liver disease, including cirrhosis and liver cancer. Poor understanding of mechanisms underlying NAFLD progression from simple steatosis to NASH has limited the development of effective therapies and biomarkers. An accumulating body of studies has suggested the importance of DNA methylation, which plays pivotal roles in NAFLD pathogenesis. DNA methylation signatures that can affect gene expression are influenced by environmental and lifestyle experiences such as diet, obesity, and physical activity and are reversible. Hence, DNA methylation signatures and modifiers in NAFLD may provide the basis for developing biomarkers indicating the onset and progression of NAFLD and therapeutics for NAFLD. Herein, we review an update on the recent findings in DNA methylation signatures and their roles in the pathogenesis of NAFLD and broaden people's perspectives on potential DNA methylation-related treatments and biomarkers for NAFLD. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) infection remains a global public problem despite the availability of an effective vaccine. In the past decades, nonalcoholic fatty liver disease (NAFLD) has surpassed HBV as the most common cause of chronic liver disease worldwide. The prevalence of concomitant chronic hepatitis B (CHB) and NAFLD thus reaches endemic proportions in geographic regions where both conditions are common. Patients with CHB and NAFLD are at increased risk of liver disease progression to cirrhosis and hepatocellular carcinoma. Due to the complexity of the pathogenesis, accurate diagnosis of NAFLD in CHB patients can be challenging. Liver biopsy is considered the gold standard for diagnosing and determining disease severity, but it is an invasive procedure with potential complications. There is a growing body of literature on the application of novel noninvasive serum biomarkers and advanced radiological modalities to diagnose and evaluate NAFLD, but most have not been adequately validated, especially for patients with CHB. Currently, there is no approved therapy for NAFLD, although many new agents are in different phases of development. This review provides a summary of the epidemiology, clinical features, diagnosis, and management of the NAFLD and highlights the unmet needs in the areas of CHB and NAFLD coexistence. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are considered major global medical burdens with high prevalence and steeply rising incidence. Despite the characterization of numerous pathophysiologic pathways leading to metabolic disorder, lipid accumulation, inflammation, fibrosis, and ultimately end-stage liver disease or liver cancer formation, so far no causal pharmacological therapy is available. Drug development for NAFLD and NASH is limited by long disease duration and slow progression and the need for sequential biopsies to monitor the disease stage. Additional non-invasive biomarkers could therefore improve design and feasibility of such. Here, the current concepts on preclinical models, biomarkers and clinical endpoints and trial designs are briefly reviewed. [ABSTRACT FROM AUTHOR]

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) encompasses diseases from simple steatosis, to steatohepatitis, to fibrosis, and cirrhosis. The pediatric NAFLD fibrosis index (PNFI) and the enhanced liver fibrosis (ELF) test are potential noninvasive markers for fibrosis. We prospectively evaluated the performance of PNFI and ELF in assessing fibrosis in children with biopsy-proven NAFLD. Methods: We analyzed 111 consecutive children with NAFLD. The stage of fibrosis was scored according to the Nonalcoholic Steatohepatitis Clinical Research Network. PNFI was calculated based on age, waist circumference, and levels of triglycerides. The ELF test was used to determine levels of hyaluronic acid, the amino-terminal propeptide of type III collagen, and tissue inhibitor of metalloproteinase-1. Results: Some degree of fibrosis was detected in 68.5% of patients (62 had stage 1, 5 had stage 2, and 9 had stage 3). PNFI and ELF test values was higher among patients with fibrosis (P < .001). The area under the receiver operating characteristic (ROC) curve for predicting fibrosis using the PNFI and ELF test was 0.761 and 0.924, respectively. The best performance was obtained by combining PNFI and ELF test with (area under the receiver operating characteristic curve = 0.944). The combined results from the PNFI and ELF test predicted the presence or absence of fibrosis in 86.4% of children with NAFLD. Conclusions: In children with NAFLD, the combined results from the PNFI and ELF test can accurately assess the presence of liver fibrosis and identify patients that should be evaluated by liver biopsy. [ABSTRACT FROM AUTHOR]