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Endoscopy guidelines recommend adhering to policies such as resect and discard only if the optical biopsy is accurate. However, accuracy in predicting histology can vary greatly. Computer-aided diagnosis (CAD) for characterization of colorectal lesions may help with this issue. In this study, CAD software developed at the University of Adelaide (Australia) that includes serrated polyp differentiation was validated with Japanese images on narrow-band imaging (NBI) and blue-laser imaging (BLI). CAD software developed using machine learning and densely connected convolutional neural networks was modeled with NBI colorectal lesion images (Olympus 190 series - Australia) and validated for NBI (Olympus 290 series) and BLI (Fujifilm 700 series) with Japanese datasets. All images were correlated with histology according to the modified Sano classification. The CAD software was trained with Australian NBI images and tested with separate sets of images from Australia (NBI) and Japan (NBI and BLI). An Australian dataset of 1235 polyp images was used as training, testing, and internal validation sets. A Japanese dataset of 20 polyp images on NBI and 49 polyp images on BLI was used as external validation sets. The CAD software had a mean area under the curve (AUC) of 94.3% for the internal set and 84.5% and 90.3% for the external sets (NBI and BLI, respectively). The CAD achieved AUCs comparable with experts and similar results with NBI and BLI. Accurate CAD prediction was achievable, even when the predicted endoscopy imaging technology was not part of the training set. [ABSTRACT FROM AUTHOR]

Abstract: Hepatocellular carcinoma (HCC) is a major world health problem. Screening and diagnosis of early lesions of HCC allows prompt treatment to improve clinical outcomes. Early lesions of HCC include premalignant lesions and small HCCs. The former consists of hepatocellular cytological changes (large cell change, small cell change and iron-free foci), dysplastic foci and dysplastic nodules (low-grade and high-grade); while the latter is subdivided into early HCC and progressed HCC. There is significant overlap in pathological and radiological features between high-grade dysplastic nodules and early HCC making a precise diagnosis demanding even among experts. Various conventional and emerging potential diagnostic markers have been evaluated in assisting pathological diagnosis of early HCC. Translation of the concept of early HCC to daily clinical practice in term of diagnosis and tumour staging is challenging to clinicians, radiologists and pathologists. [Copyright &y& Elsevier]

Summary: Liver transplantation has been increasingly used over the past four decades as an effective treatment for end-stage liver disease. Although the demand exceeds the supply of cadaveric organs, the donor pool has expanded with the increasing use of split-liver grafts, non-heart-beating donor livers and living-related donors. Histopathologists play a role in the pre-transplant and post-transplant period; their input is crucial in both identifying and monitoring post-transplant complications. The degree of acute cellular rejection is best assessed histologically, and biopsy interpretation informs changes to the immunosuppressive regimen. Chronic rejection is characterised by progressive ductopenia; a number of lesions have been identified that predict the likelihood of progression to chronic rejection. Other post-transplant complications readily assessed on liver core biopsies include vascular and biliary complications, infectious, recurrent and de novo disease. De novo hepatitis with ‘autoimmune’ features is described as is idiopathic chronic hepatitis, but the relationship of these lesions to alloimmune pathways remains uncertain. Although liver transplantation is generally performed in specialist centres, an increasing number of histopathologists working in non-specialist units are being exposed to post-transplant biopsies and need to be aware of the spectrum of changes that can occur. [Copyright &y& Elsevier]

Abstract: The liver is an important site for primary and secondary tumours. In western countries, the commonest malignant neoplasm of the liver is metastatic carcinoma, but hepatocellular carcinoma is a common and important cause of death elsewhere. There is a strong association with infection by hepatitis-B and -C; the latter explains the growing incidence of hepatocellular carcinoma in western countries. It is a complication of cirrhosis of any cause; male sex is an important risk factor. Such associations do not exist for the rare variant fibrolamellar carcinoma, which carries a better prognosis than the common form (where survival is measured in weeks). Cholangiocarcinoma, a malignant tumour of bile ducts, accounts for about 15% of primary intrahepatic malignancies; recent epidemiological studies have shown dramatic increases in its incidence. There is a strong association with primary sclerosing cholangitis and, in the Far East, with hepatolithiasis and infection by liver flukes. Epithelioid haemangioendothelioma and angiosarcoma are the commonest malignant mesenchymal tumours in the liver. A number of benign tumours and tumour-like lesions may mimic malignant neoplasms. [Copyright &y& Elsevier]

Surveillance post–endoscopic resection (ER) currently warrants biopsy samples from the resection site scar in most cases, although clinical practice is variable. A classification with standard criteria for scars has not yet been established. We aimed to create and validate a novel classification for post-ER scars by using specific criteria based on advanced imaging. Key endoscopic features for scars with and without recurrence were (1) dark brown color, elongated/branched pit pattern, and dense capillary pattern and (2) whitish, pale appearance, round/slightly large pits, and irregular sparse vessels. Scars were first assessed with high-definition white-light endoscopy (HD-WLE) followed by interrogation with narrow-band imaging (NBI). Scars with at least 2 concordant characteristics were diagnosed with "high confidence" for NBI for scar (NBI-SCAR) classification. The final endoscopic predictions were correlated with histopathology. The primary outcome was the difference in sensitivity between NBI-SCAR and HD-WLE predictions. Secondary outcomes included the validation of our findings in 6 different endoscopy settings (Australia, United States, Japan, Brazil, Singapore, and Malaysia). The validation took place in 2 sessions separated by 2 to 3 weeks, each with 10 one-minute videos of post-ER scars on underwater NBI with dual focus. Inter-rater and intrarater reliability were calculated with Fleiss' free-marginal kappa and Bennett et al. S score, respectively. One hundred scars from 82 patients were included. Ninety-five scars were accurately predicted with high confidence by NBI-SCAR in the exploratory phase. NBI-SCAR sensitivity was significantly higher compared with HD-WLE (100% vs 73.7%, P <.05). In the validation phase, similar results were found for endoscopists who routinely perform colonoscopies and use NBI (sensitivity of 96.4%). The inter-rater and intrarater reliability throughout all centers were, respectively, substantial (κ =.61) and moderate (average S =.52) for this subset. NBI-SCAR has a high sensitivity and negative predictive value for excluding recurrence for endoscopists experienced in colonoscopy and NBI. In this setting, this approach may help to accurately evaluate or resect scars and potentially mitigate the burden of unnecessary biopsy samples. [ABSTRACT FROM AUTHOR]

Background & Aims Pharmacologic treatments for nonalcoholic steatohepatitis (NASH) are limited. Lifestyle interventions are believed to be effective in reducing features of NASH, although the effect of regular exercise, independent of dietary change, is unclear. We performed a randomized controlled trial to study the effect of exercise on hepatic triglyceride content (HTGC) and biomarkers of fibrosis in patients with NASH. Methods Twenty-four patients (mean age, 52 ± 14 y; body mass index, 33 ± 6 kg/m 2 ) with sedentary lifestyles (<60 min/wk of moderate–vigorous activity) and biopsy-proven NASH were assigned randomly to groups that exercised (n = 12) or continued standard care (controls, n = 12) for 12 weeks while maintaining their weight. The exercise (cycling and resistance training) was supervised at an accredited sports center and supervised by a certified exercise specialist and recorded 3 times per week on nonconsecutive days. We measured HTGC, body composition, circulating markers of inflammation, fibrosis, and glucose tolerance at baseline and at 12 weeks. Results Compared with baseline, exercise significantly reduced HTGC (reduction of 16% ± 24% vs an increase of 9% ± 15% for controls; P < .05), visceral fat (reduction of 22 ± 33 cm 2 vs an increase of 14 ± 48 cm 2 for controls; P < .05), plasma triglycerides (reduction of 0.5 ± 1.0 mmol/L vs an increase of 0.3 ± 0.4 mmol/L for controls; P < .05), and γ-glutamyltransferase (reduction of 10 ± 28 U/L – 1 vs a reduction of 17 ± 38 U/L −1 for controls; P < .05). There were no effects of exercise on liver enzyme levels, metabolic parameters, circulatory markers of inflammation (levels of interleukin 6, tumor necrosis factor-α, or C-reactive protein) and fibrosis. Conclusions In a randomized controlled trial, 12 weeks of exercise significantly reduced HTGC, visceral fat, and plasma triglyceride levels in patients with NASH, but did not affect circulating markers of inflammation or fibrosis. Exercise without weight loss therefore affects some but not all factors associated with NASH. Clinical care teams should consider exercise as part of a management strategy of NASH, but weight management strategies should be included. Larger and longer-term studies are required to determine the effects of exercise in patients with NASH. ISRCTN registry.com: ISRCTN16070927. [ABSTRACT FROM AUTHOR]

Background & Aims: A third of the population are estimated to have NAFLD of varying severity. Serum immunoglobulins are frequently elevated in patients with chronic liver disease, but little is known about serum immunoglobulin levels in patients with NAFLD. Aim of this study was to evaluate serum immunoglobulin levels (IgA, IgG, and IgM) in a large cohort of patients with biopsy-proven NAFLD and determine if immunoglobulin levels are associated with clinical or histological features. Methods: Patients seen in a tertiary fatty liver clinic between 1999 and 2009 were included. Liver biopsies were assessed using the Kleiner score. Immunoglobulin levels and other blood tests were taken at time of biopsy. Results: 285 patients (110 simple steatosis and 175 NASH) had serum immunoglobulins measured within 6months of liver biopsy. 130 (46%) patients had elevated (>1× upper limit of normal) serum IgA levels, 28 (10%) patients had elevated IgG and 22 (8%) raised IgM. Serum IgA levels were elevated more frequently in patients with NASH compared with subjects with simple steatosis (55% vs. 31%, p <0.001). Overall, 55 (19%) patients had advanced liver fibrosis (Kleiner stage 3–4). There was a significant positive association between serum IgA levels and the stage of fibrosis (p <0.001). Serum IgA, age, platelets, AST/ALT ratio and BMI were all independently with advanced fibrosis following multivariate analysis. A model constructed from these independent predictors accurately predicted advanced fibrosis (AUROC 0.87). Conclusions: The serum IgA level was frequently elevated in patients with NAFLD and was an independent predictor of advanced fibrosis. [Copyright &y& Elsevier]

Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain. The most common NSS (NFS, FIB-4, BARD, APRI) and the Hepamet fibrosis score (HFS) were assessed in 1,173 European patients with NAFLD from tertiary centres. Performance for fibrosis risk stratification and for the prediction of long-term hepatic/extrahepatic events, hepatocarcinoma (HCC) and overall mortality were evaluated in terms of AUC and Harrell's c-index. For longitudinal data, NSS-based Cox proportional hazard models were trained on the whole cohort with repeated 5-fold cross-validation, sampling for testing from the 607 patients with all NSS available. Cross-sectional analysis revealed HFS as the best performer for the identification of significant (F0-1 vs. F2-4, AUC = 0.758) and advanced (F0-2 vs. F3-4, AUC = 0.805) fibrosis, while NFS and FIB-4 showed the best performance for detecting histological cirrhosis (range AUCs 0.85-0.88). Considering longitudinal data (follow-up between 62 and 110 months), NFS and FIB-4 were the best at predicting liver-related events (c-indices>0.7), NFS for HCC (c-index = 0.9 on average), and FIB-4 and HFS for overall mortality (c-indices >0.8). All NSS showed limited performance (c-indices <0.7) for extrahepatic events. Overall, NFS, HFS and FIB-4 outperformed APRI and BARD for both cross-sectional identification of fibrosis and prediction of long-term outcomes, confirming that they are useful tools for the clinical management of patients with NAFLD at increased risk of fibrosis and liver-related complications or death. Non-invasive scoring systems are increasingly being used in patients with non-alcoholic fatty liver disease to identify those at risk of advanced fibrosis and hence clinical complications. Herein, we compared various non-invasive scoring systems and identified those that were best at identifying risk, as well as those that were best for the prediction of long-term outcomes, such as liver-related events, liver cancer and death. [Display omitted] • Different non-invasive scoring systems (NSS) have been proposed to stratify patients according to the risk of advanced fibrosis. • In the cross-sectional analysis, HFS showed the best performance for the identification of advanced fibrosis. • NFS and FIB-4 showed the best performance for the detection of histological cirrhosis. • After a median follow-up of ~7 years, NFS, HFS and FIB-4 performed similarly well for the prediction of HCC and overall mortality. • All NSS had limited performance for extrahepatic events, although those incorporating diabetes performed slightly better. [ABSTRACT FROM AUTHOR]

Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most genome-wide association studies (GWASs) have adopted radiologically assessed hepatic triglyceride content as the reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a GWAS encompassing the full spectrum of histologically characterised NAFLD. The GWAS involved 1,483 European NAFLD cases and 17,781 genetically matched controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance. Case-control analysis identified signals showing p values ≤5 × 10−8 at 4 locations (chromosome [chr] 2 GCKR/C2ORF16 ; chr4 HSD17B13 ; chr19 TM6SF2 ; chr22 PNPLA3) together with 2 other signals with p <1 × 10−7 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits showed that the PNPLA3 signal (rs738409) had genome-wide significance for steatosis, fibrosis and NAFLD activity score and a new signal (PYGO1 rs62021874) had close to genome-wide significance for steatosis (p = 8.2 × 10−8). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR single nucleotide polymorphism also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (≥F3), the signals on chr2, chr19 and chr22 maintained their genome-wide significance. Except for GCKR/C2ORF16 , the genome-wide significance signals were replicated. This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting that Wnt signalling pathways may be relevant in NAFLD pathogenesis. Non-alcoholic fatty liver disease is a common disease where excessive fat accumulates in the liver and may result in cirrhosis. To understand who is at risk of developing this disease and suffering liver damage, we undertook a genetic study to compare the genetic profiles of people suffering from fatty liver disease with genetic profiles seen in the general population. We found that particular sequences in 4 different areas of the human genome were seen at different frequencies in the fatty liver disease cases. These sequences may help predict an individual's risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments. • Genome-wide association study involved 1,483 biopsied NAFLD cases and 17,781 controls. • Main analysis shows genome-wide significance for PNPLA3, TM6SF2, HSD17B13 and GCKR. • Sub-analyses show significance near LEPR for NASH and near PYGO1 for steatosis. • Except for GCKR , the genome-wide significant signals were replicated. [ABSTRACT FROM AUTHOR]

Background and Aims There remains uncertainty about the natural history of non-alcoholic fatty liver disease (NAFLD). The spectrum of NAFLD includes non-alcoholic fatty liver (NAFL; steatosis without hepatocellular injury) and steatohepatitis (NASH; steatosis with hepatocyte ballooning degeneration ± fibrosis). Our aim was to assess the histological severity of NAFLD in a cohort with serial biopsy data, and determine factors predicting progression. Methods Patients with two liver biopsies more than a year apart were identified. Clinical and laboratory data were collected from the time of liver biopsy. Results 108 patients had serial biopsies (median interval 6.6 years, range 1.3–22.6). 81 (75%) patients had NASH and 27 had NAFL. Overall, 45 (42%) patients had fibrosis progression, 43 (40%) had no change in fibrosis, while 20 (18%) had fibrosis regression. Importantly, no significant difference in the proportion exhibiting fibrosis progression was found between those with NAFL or NASH at index biopsy (37% vs. 43%, p = 0.65). Progression to NASH was seen in 44% of patients with baseline NAFL. Of 10 patients with NAFL who had fibrosis progression, 3 progressed by 1 stage, 5 by 2 stages and 2 by 3 stages; all had NASH on follow-up biopsy. Of concern, 6 of 27 (22%) patients with baseline NAFL, reached stage 3 fibrosis at follow-up biopsy. Among the patients with NAFL, 80% of those having fibrosis progression were diabetic at the follow-up liver biopsy compared with 25% of non-progressors ( p = 0.005). Conclusions Contrary to current dogma, this study suggests that steatosis can progress to NASH and clinically significant fibrosis. [ABSTRACT FROM AUTHOR]

Corrigendum to: "Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort" (J Hepatol [2020] 505-515). [Extracted from the article]

Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS 'Liver Investigation: Testing Marker Utility in Steatohepatitis' consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace. [ABSTRACT FROM AUTHOR]

Abstract: Highly active antiretroviral therapy has revolutionised HIV management. However, many of these drugs are potentially hepatotoxic. Here, we report the first adult case of efavirenz induced acute liver failure successfully treated by liver transplantation. Furthermore, genetic analysis revealed our patient to be a slow efavirenz metaboliser, contributing to the severity of clinical presentation. [Copyright &y& Elsevier]

There are two challenges associated with the interpretability of deep learning models in medical image analysis applications that need to be addressed: confidence calibration and classification uncertainty. Confidence calibration associates the classification probability with the likelihood that it is actually correct – hence, a sample that is classified with confidence X % has a chance of X % of being correctly classified. Classification uncertainty estimates the noise present in the classification process, where such noise estimate can be used to assess the reliability of a particular classification result. Both confidence calibration and classification uncertainty are considered to be helpful in the interpretation of a classification result produced by a deep learning model, but it is unclear how much they affect classification accuracy and calibration, and how they interact. In this paper, we study the roles of confidence calibration (via post-process temperature scaling) and classification uncertainty (computed either from classification entropy or the predicted variance produced by Bayesian methods) in deep learning models. Results suggest that calibration and uncertainty improve classification interpretation and accuracy. This motivates us to propose a new Bayesian deep learning method that relies both on calibration and uncertainty to improve classification accuracy and model interpretability. Experiments are conducted on a recently proposed five-class polyp classification problem, using a data set containing 940 high-quality images of colorectal polyps, and results indicate that our proposed method holds the state-of-the-art results in terms of confidence calibration and classification accuracy. [ABSTRACT FROM AUTHOR]