Real-time automated diagnosis of precancerous lesions and early esophageal squamous cell carcinoma using a deep learning model (with videos).

BACKGROUND AND AIMS: We developed a system for computer-assisted diagnosis (CAD) for real-time automated diagnosis of precancerous lesions and early esophageal squamous cell carcinomas (ESCCs) to assist the diagnosis of esophageal cancer. METHODS: A total of 6473 narrow-band imaging (NBI) images, including precancerous lesions, early ESCCs, and noncancerous lesions, were used to train the CAD system. We validated the CAD system using both endoscopic images and video datasets. The receiver operating characteristic curve of the CAD system was generated based on image datasets. An artificial intelligence probability heat map was generated for each input of endoscopic images. The yellow color indicated high possibility of cancerous lesion, and the blue color indicated noncancerous lesions on the probability heat map. When the CAD system detected any precancerous lesion or early ESCCs, the lesion of interest was masked with color. RESULTS: The image datasets contained 1480 malignant NBI images from 59 consecutive cancerous cases (sensitivity, 98.04%) and 5191 noncancerous NBI images from 2004 cases (specificity, 95.03%). The area under curve was 0.989. The video datasets of precancerous lesions or early ESCCs included 27 nonmagnifying videos (per-frame sensitivity 60.8%, per-lesion sensitivity, 100%) and 20 magnifying videos (per-frame sensitivity 96.1%, per-lesion sensitivity, 100%). Unaltered full-range normal esophagus videos included 33 videos (per-frame specificity 99.9%, per-case specificity, 90.9%). CONCLUSIONS: A deep learning model demonstrated high sensitivity and specificity for both endoscopic images and video datasets. The real-time CAD system has a promising potential in the near future to assist endoscopists in diagnosing precancerous lesions and ESCCs.

Mild alcohol consumption is not associated with increased fibrosis in patients with chronic hepatitis C.

BACKGROUND: Excessive alcohol consumption is associated with an increased risk for fibrosis progression and cirrhosis in patients with chronic hepatitis C virus (HCV) infection. However, the impact of mild-moderate alcohol use on the severity of liver fibrosis is unclear. GOALS: The objective of this retrospective study was to assess the impact of mild alcohol consumption on liver fibrosis in patients with chronic HCV. STUDY: 857 patients with well-characterized chronic HCV were enrolled. All underwent liver biopsy to assess hepatic fibrosis. The duration of HCV infection was determined by detailed questionnaires and personal interviews. Alcohol use history was estimated by the Skinner Alcohol Examination Questionnaire. Mild alcohol use was defined as 1 to 3 alcoholic beverages/day (<30 grams/d). Participants were divided into 4 groups based on their average lifetime daily alcohol consumption (essentially none, <1, 1 to 3 or >3 drinks/d) and into quartiles based on their presumed duration of HCV infection (<23, 23 to 31, 31 to 38, or >38 y). RESULTS: Mean alcohol consumption was 2.7 drinks/d; mean duration of HCV infection was 29 years. Daily alcohol consumption was not significantly higher among participants with advanced fibrosis (bridging fibrosis or cirrhosis) when compared with those with none or portal fibrosis (3.2 vs. 2.2 drinks/d, respectively, P=NS). The degree of fibrosis increased significantly with the duration of HCV infection (P<0.0001) and was independent of mild-moderate alcohol consumption. CONCLUSIONS: Mild alcohol use does not seem to adversely affect the severity of fibrosis in patients with chronic HCV.

The plasma lipidomic signature of nonalcoholic steatohepatitis.

UNLABELLED: Specific alterations in hepatic lipid composition characterize the spectrum of nonalcoholic fatty liver disease (NAFLD), which extends from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). However, the plasma lipidome of NAFLD and whether NASH has a distinct plasma lipidomic signature are unknown. A comprehensive analysis of plasma lipids and eicosanoid metabolites quantified by mass spectrometry was performed in NAFL (n = 25) and NASH (n = 50) subjects and compared with lean normal controls (n = 50). The key findings include significantly increased total plasma monounsaturated fatty acids driven by palmitoleic (16:1 n7) and oleic (18:1 n9) acids content (P < 0.01 for both acids in both NAFL and NASH). The levels of palmitoleic acid, oleic acid, and palmitoleic acid to palmitic acid (16:0) ratio were significantly increased in NAFLD across multiple lipid classes. Linoleic acid (8:2n6) was decreased (P < 0.05), with a concomitant increase in gamma-linolenic (18:3n6) and dihomo gamma-linolenic (20:3n6) acids in both NAFL and NASH (P < 0.001 for most lipid classes). The docosahexanoic acid (22:6 n3) to docosapentenoic acid (22:5n3) ratio was significantly decreased within phosphatidylcholine (PC), and phosphatidylethanolamine (PE) pools, which was most marked in NASH subjects (P < 0.01 for PC and P < 0.001 for PE). The total plasmalogen levels were significantly decreased in NASH compared with controls (P < 0.05). A stepwise increase in lipoxygenase (LOX) metabolites 5(S)-hydroxyeicosatetraenoic acid (5-HETE), 8-HETE, and 15-HETE characterized progression from normal to NAFL to NASH. The level of 11-HETE, a nonenzymatic oxidation product of arachidonic (20:4) acid, was significantly increased in NASH only. CONCLUSIONS: Although increased lipogenesis, desaturases, and LOX activities characterize NAFL and NASH, impaired peroxisomal polyunsaturated fatty acid (PUFA) metabolism and nonenzymatic oxidation is associated with progression to NASH.

Recent advances in nonalcoholic fatty liver disease.

PURPOSE OF REVIEW: This review focuses on recent advances in the study of the epidemiology, pathogenesis, natural history and treatment of nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS: Study of hepatic lipid metabolism, insulin resistance, mitochondrial dysfunction and oxidative stress, genetic variants and predisposition to altered metabolism and cell injury have contributed to our current understanding of NAFLD. Differential expression of microRNA in fatty liver and its implication in disease pathogenesis and therapeutic potential have continued to advance over the year. The pathogenesis of hepatocellular carcinoma in steatohepatitis continues to be explored. The diagnostic utility of imaging and noninvasive markers seems promising in estimating the severity of steatosis and fibrosis. Liver biopsy remains the gold standard for accurately assessing NAFLD and steatohepatitis. Lifestyle modification and weight loss improve both metabolic profile and liver histology. Pharmacotherapy for the treatment of NAFLD remains lacking. SUMMARY: The underlying mechanism and pathogenesis of NAFLD remain elusive despite ongoing researches to make significant advances in the understanding of its natural history, pathogenesis and management. Pharmacotherapy has yet to indicate a promising therapeutic intervention. Current treatment focuses on managing underlying cardio-metabolic risks.

Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) are associated with known triggers of the unfolded protein response (UPR). The aims were to (1) evaluate the activity of UPR in NAFL and NASH and (2) correlate expression of UPR pathways with liver histology. METHODS: Messenger RNA (mRNA) and protein expression were measured by quantitative real-time PCR and Western blot, respectively. Apoptosis was assessed by TUNEL assay. Liver histology was scored using the NASH clinical research network criteria. RESULTS: Compared with subjects with the metabolic syndrome and normal liver histology (n = 17), both NAFL (n = 21) and NASH (n = 21) were associated with increased eukaryotic initiation factor-2alpha (eIF-2alpha) phosphorylation. Activating transcription factor 4 (ATF4) mRNA and protein, C/EBP homologous protein (CHOP), and growth arrest, DNA damage-34 (GADD34) mRNA were not increased in NAFL or NASH. Whereas immunoglobulin heavy chain binding protein mRNA was significantly increased in NASH, unspliced X-box protein-1 (XBP-1) protein did not increase. Also, endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein mRNA levels were inversely related to spliced XBP-1 mRNA in NASH. NASH was specifically associated with low sXBP-1 protein and increased JNK phosphorylation. This correlated with increased TUNEL activity in NASH. The histologic severity correlated with sXBP-1 mRNA and JNK phosphorylation. CONCLUSIONS: There is a variable degree of UPR activation in NAFL and NASH. Although both NAFL and NASH are associated with eIF-2alpha phosphorylation, there is a failure to activate downstream recovery pathways, ie, ATF4-CHOP-GADD34. NASH is specifically associated with (1) failure to generate sXBP-1 protein and (2) activation of JNK.

Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression.

UNLABELLED: The expression of microRNA in nonalcoholic steatohepatitis (NASH) and their role in the genesis of NASH are not known. The aims of this study were to: (1) identify differentially expressed microRNAs in human NASH, (2) tabulate their potential targets, and (3) define the effect of a specific differentially expressed microRNA, miR-122, on its targets and compare these effects with the pattern of expression of these targets in human NASH. The expression of 474 human microRNAs was compared in subjects with the metabolic syndrome and NASH versus controls with normal liver histology. Differentially expressed microRNAs were identified by the muParaflo microRNA microarray assay and validated using quantitative real-time polymerase chain reaction (PCR). The effects of a specific differentially expressed miRNA (miR-122) on its predicted targets were assessed by silencing and overexpressing miR-122 in vitro. A total of 23 microRNAs were underexpressed or overexpressed. The predicted targets of these microRNAs are known to affect cell proliferation, protein translation, apoptosis, inflammation, oxidative stress, and metabolism. The miR-122 level was significantly decreased in subjects with NASH (63% by real-time PCR, P < 0.00001). Silencing miR-122 led to an initial increase in mRNA levels of these targets (P < 0.05 for all) followed by a decrease by 48 hours. This was accompanied by an increase in protein levels of these targets (P < 0.05 for all). Overexpression of miR-122 led to a significant decrease in protein levels of these targets. CONCLUSIONS: NASH is associated with altered hepatic microRNA expression. Underexpression of miR-122 potentially contributes to altered lipid metabolism implicated in the pathogenesis of NASH.

Recent advances in nonalcoholic fatty liver disease.

PURPOSE OF REVIEW: This review focuses on recent advances in the study of the epidemiology, pathogenesis, natural history and treatment of nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS: Study of hepatic lipid metabolism with respect to the contribution of de-novo lipogenesis to hepatic steatosis and insulin resistance and the dysregulation of cellular adaptive response to stress, that is, the unfolded protein response has added to our current understanding of NAFLD. microRNA has recently emerged and has been shown to be differentially expressed in patients with nonalcoholic steatohepatitis. Its mechanism of action remains to be further explored. There is no proven pharmacotherapy for the treatment of NAFLD. Lifestyle intervention to achieve weight loss and increase exercise is persistently associated with improved liver histology. The diagnostic utility of noninvasive markers and imaging modalities in assessing fibrosis remains to be elucidated. SUMMARY: The underlying mechanism and pathogenesis of NAFLD remain elusive. Although research effort has advanced the understanding of the natural history, pathogenesis and management of the disease, there is no proven therapy for this medical condition. At present, treatment concentrates on managing underlying metabolic risk factors.

Hepatitis C infection and nonalcoholic fatty liver disease.

In hepatitis C virus (HCV) infection, significant hepatic steatosis or superimposed nonalcoholic steatohepatitis is associated with disease severity and poor response to antiviral therapy. Nonalcoholic fatty liver disease (NAFLD) and HCV are common causes of chronic liver disease in Western countries and are strongly linked to concurrent obesity, insulin resistance, and the metabolic syndrome. With the escalating prevalence of obesity in North America, insulin resistance and the metabolic syndrome are major public health problems that have a significant impact on morbidity and mortality associated with NAFLD and HCV. This article focuses on the current understanding of the interplay between host and viral factors that are involved in the interaction between NAFLD and HCV.

Recent advances in nonalcholic fatty liver disease.

PURPOSE OF REVIEW: The purpose of this review is to summarize recent advances in defining the clinical features, pathophysiology, natural history, and treatment of nonalcoholic fatty liver disease. RECENT FINDINGS: Nonalcoholic fatty liver disease is present in approximately 30% of the US population. A histologic grading and staging system has been developed and validated. Nonalcoholic fatty liver disease increases the risk of developing the metabolic syndrome. The presence and severity of nonalcoholic fatty liver disease correlates with the severity of obesity, fat distribution, age, and presence of other features of the metabolic syndrome. Fifteen to 20% of subjects with nonalcoholic steatohepatitis develop cirrhosis. Hepatic steatosis is associated with an increase in both free fatty acid delivery to the liver for re-esterification and increased de-novo lipogenesis. Several mechanisms of hepatocyte injury and death including free fatty acid toxicity, increased free cholesterol, cytokine-mediated injury and activation of the unfolded protein response have been defined. While many therapeutic targets have been identified and pilot studies performed, a definitive treatment for nonalcoholic steatohepatitis remains to be established. SUMMARY: Nonalcoholic fatty liver disease is a widely prevalent disease that is critically linked to insulin resistance and the metabolic syndrome. While much new information on the pathogenesis and natural history of nonalcoholic steatohepatitis is available, an effective therapy remains to be established.

Role of microRNAs in non-alcoholic steatohepatitis.

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is not entirely understood. Recently, the role of microRNA in this liver disease entity and its implication in disease pathogenesis and therapeutic potential has advanced rapidly over the year. While the regulation of miRNA function and its mechanism of actions on translational control of target mRNA expression remain unknown, advances in miRNA research allow identification and biochemical characterization of events that limit protein expression, which is crucial in various forms of human diseases and their subsequent development. It is hoped that further understanding of the role of microRNA in NAFLD will advance potential therapeutics and preventive measures to modify and alter this disease process.

Abnormalities of lipid metabolism in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver abnormality in the United States and is strongly associated with the metabolic syndrome. Although many of the risk factors are well defined, the pathogenesis of NAFLD remains poorly understood. Recent studies have implicated several important cellular processes and signaling pathways that are affected by abnormal lipid metabolism, resulting in specific biochemical, histological, and clinical changes associated with NAFLD. Pharmacotherapy for NAFLD is limited and treatments are mainly to minimize risk factors. Understanding the disease pathogenesis is therefore important in identifying individuals with increased susceptibility for disease progression so lifestyle and risk modifications can be initiated early on. In this review, recent advances in the study of abnormal lipid metabolism and its impacts on histology and dysregulation of various cellular processes implicated in the genesis of NAFLD will be discussed.

A lipidomic analysis of nonalcoholic fatty liver disease.

UNLABELLED: The spectrum of nonalcoholic fatty liver disease (NAFLD) includes a nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The specific types and amounts of lipids that accumulate in NAFLD are not fully defined. The free fatty acid (FFA), diacylglycerol (DAG), triacylglycerol (TAG), free cholesterol (FC), cholesterol ester, and phospholipid contents in normal livers were quantified and compared to those of NAFL and NASH, and the distribution of fatty acids within these classes was compared across these groups. Hepatic lipids were quantified by capillary gas chromatography. The mean (nmol/g of tissue) DAG (normal/NAFL/NASH: 1922 versus 4947 versus 3304) and TAG (13,609 versus 128,585 versus 104,036) increased significantly in NAFLD, but FFA remained unaltered (5533 versus 5929 versus 6115). There was a stepwise increase in the mean TAG/DAG ratio from normal livers to NAFL to NASH (7 versus 26 versus 31, P < 0.001). There was also a similar stepwise increment in hepatic FC (7539 versus 10,383 versus 12,863, P < 0.05 for NASH). The total phosphatidylcholine (PC) decreased in both NAFL and NASH. The FC/PC ratio increased progressively (0.34 versus 0.69 versus 0.71, P < 0.008 for both). Although the levels for linoleic acid (18:2n-6) and alpha-linolenic acid (18:3n-3) remained unaltered, there was a decrease in arachidonic acid (20:4n-6) in FFA, TAG, and PC (P < 0.05 for all) in NASH. Eicosapentanoic acid (20:5n-3) and docosahexanoic acid (22:6n-3) were decreased in TAG in NASH. The n-6:n-3 FFA ratio increased in NASH (P < 0.05). CONCLUSIONS: NAFLD is associated with numerous changes in the lipid composition of the liver. The potential implications are discussed.

The impact of fat distribution on the severity of nonalcoholic fatty liver disease and metabolic syndrome.

UNLABELLED: The patterns of fat distribution and their relationship to severity of nonalcoholic fatty liver disease (NAFLD) are unknown. The objectives of this study were to define the fat distribution patterns and their relationship to histological severity and metabolic parameters in subjects with NAFLD. Anthropometric indices and total body fat were measured in 123 subjects. Fat distribution patterns were defined as: general, abdominal, limb, truncal, and dorsocervical lipohypertrophy (DCL) a novel finding in NAFLD. Eighty-one (66%) of the subjects were obese, and 94 (76%) had abdominal obesity. Thirty-five (28.5%) had DCL. Whereas body mass index (BMI) correlated best with the presence of diabetes (r = 0.22, P < 0.05), waist circumference (WC) correlated best with hypertension (r = 0.2, P < 0.05), hypertriglyceridemia (r = 0.37, P < 0.001), and insulin resistance (homeostasis model of assessment for insulin resistance [r = 0.68, P < 0.0001]). None of the patterns of fat distribution were significantly associated with severity of hepatic steatosis. Abdominal obesity (WC) correlated with inflammation (r = 0.2, P < 0.05) only. DCL correlated significantly with the severity of all histological parameters except steatosis. Whereas DCL was the single greatest contributor to the variability in severity of histological parameters, a model combining BMI, WC, and DCL showed the greatest contribution to the variability in severity of individual histological parameters. The addition of steatosis grade to the model significantly increased its contribution to the range of lobular inflammation. CONCLUSION: WC predicts metabolic risk profile with the most significance. However, DCL is most strongly associated with severity of steatohepatitis. WC and BMI added modestly to the contribution of DCL to severity of nonalcoholic steatohepatitis.