Non-alcoholic fatty liver disease (NAFLD) has been recently identified as a risk factor of gastrointestinal tract cancers, especially hepatocellular carcinoma, and colorectal cancer. Whether NAFLD is a risk factor for cholangiocarcinoma (CCA) remains inconclusive. The aim of this study is to determine a potential association between NAFLD and CCA, stratifying by its subtypes; intrahepatic CCA (iCCA), and extrahepatic CCA (eCCA). A search was conducted for relevant studies published up to April 2017 using MEDLINE, EMBASE, Scopus and Cochrane databases. Odds ratio (OR) and adjusted OR with 95% confidence interval (CI) were estimated using a random-effects model. Subgroup analyses were conducted with study characteristics. Seven case-control studies were included in the analysis, with a total of 9,102 CCA patients (5,067 iCCA and 4,035 eCCA) and 129,111 controls. Overall, NAFLD was associated with an increased risk for CCA, with pooled OR of 1.95 (95%CI: 1.36–2.79, I 2 =76%). When classified by subtypes, NAFLD was associated with both iCCA and eCCA, with ORs of 2.22 (95%CI: 1.52–3.24, I 2 =67%) and 1.55 (95%CI: 1.03–2.33, I 2 =69%), respectively. The overall pooled adjusted ORs were 1.97 (95%CI: 1.41–2.75, I 2 =71%), 2.09 (95%CI, 1.49–2.91, I 2 =42%) and 2.05 (95%CI, 1.59–2.64, I 2 =0%) for all CCAs, iCCA, and eCCA, respectively. This meta-analysis suggests that NAFLD may potentially increase the risk of CCA development. The magnitude of NAFLD on CCA risk is greater for iCCA than eCCA subtype, suggestive of a common pathogenesis of iCCA and hepatocellular carcinoma. Further studies to confirm this association are warranted. The protocol for this study was registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42016046573).

Background: The gold standard for the diagnosis of liver fibrosis and nonalcoholic fatty liver disease (NAFLD) is liver biopsy. Various noninvasive modalities, e.g., ultrasonography, elastography and clinical predictive scores, have been used as alternatives to liver biopsy, with limited performance. Recently, artificial intelligence (AI) models have been developed and integrated into noninvasive diagnostic tools to improve their performance. Methods: We systematically searched for studies on AI-assisted diagnosis of liver fibrosis and NAFLD on MEDLINE, Scopus, Web of Science and Google Scholar. The pooled sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic odds ratio (DOR) with their 95% confidence intervals (95% CIs) were calculated using a random effects model. A summary receiver operating characteristic curve and the area under the curve was generated to determine the diagnostic accuracy of the AI-assisted system. Subgroup analyses by diagnostic modalities, population and AI classifiers were performed. Results: We included 19 studies reporting the performances of AI-assisted ultrasonography, elastrography, computed tomography, magnetic resonance imaging and clinical parameters for the diagnosis of liver fibrosis and steatosis. For the diagnosis of liver fibrosis, the pooled sensitivity, specificity, PPV, NPV and DOR were 0.78 (0.71–0.85), 0.89 (0.81–0.94), 0.72 (0.58–0.83), 0.92 (0.88–0.94) and 31.58 (11.84–84.25), respectively, for cirrhosis; 0.86 (0.80–0.90), 0.87 (0.80–0.92), 0.85 (0.75–0.91), 0.88 (0.82–0.92) and 37.79 (16.01–89.19), respectively; for advanced fibrosis; and 0.86 (0.78–0.92), 0.81 (0.77–0.84), 0.88 (0.80–0.93), 0.77 (0.58–0.89) and 26.79 (14.47–49.62), respectively, for significant fibrosis. Subgroup analyses showed significant differences in performance for the diagnosis of fibrosis among different modalities. The pooled sensitivity, specificity, PPV, NPV and DOR were 0.97 (0.76–1.00), 0.91 (0.78–0.97), 0.95 (0.87–0.98), 0.93 (0.80–0.98) and 191.52 (38.82–944.81), respectively, for the diagnosis of liver steatosis. Conclusions: AI-assisted systems have promising potential for the diagnosis of liver fibrosis and NAFLD. Validations of their performances are warranted before implementing these AI-assisted systems in clinical practice. Trial registration: The protocol was registered with PROSPERO (CRD42020183295).

Whether aspirin use is protective against cholangiocarcinoma (CCA) remains unclear. We determined the association between aspirin use and other risk factors for each CCA subtype individually. In a hospital‐based case‐control study, 2395 CCA cases (1169 intrahepatic, 995 perihilar, and 231 distal) seen at the Mayo Clinic, Rochester, MN, from 2000 through 2014 were enrolled. Controls selected from the Mayo Clinic Biobank were matched two to one with cases by age, sex, race, and residence (n = 4769). Associations between aspirin use, other risk factors, and CCA risk were determined. Aspirin was used by 591 (24.7%) CCA cases and 2129 (44.6%) controls. There was a significant inverse association of aspirin use with all CCA subtypes, with adjusted odds ratios (AORs) of 0.35 (95% confidence interval [CI], 0.29‐0.42), 0.34 (95% CI 0.27‐0.42), and 0.29 (95% CI 0.19‐0.44) for intrahepatic, perihilar, and distal CCA, respectively (P < 0.001 for all). Primary sclerosing cholangitis was more strongly associated with perihilar (AOR = 453, 95% CI 104‐999) than intrahepatic (AOR = 93.4, 95% CI 27.1‐322) or distal (AOR = 34.0, 95% CI 3.6‐323) CCA, whereas diabetes was more associated with distal (AOR = 4.2, 95% CI 2.5‐7.0) than perihilar (AOR = 2.9, 95% CI 2.2‐3.8) or intrahepatic (AOR = 2.5, 95% CI 2.0‐3.2) CCA. Cirrhosis not related to primary sclerosing cholangitis was associated with both intrahepatic and perihilar CCA, with similar AORs of 14. Isolated inflammatory bowel disease without primary sclerosing cholangitis was not associated with any CCA subtype. Conclusions: Aspirin use was significantly associated with a 2.7‐fold to 3.6‐fold decreased risk for the three CCA subtypes; our study demonstrates that individual risk factors confer risk of different CCA subtypes to different extents. (Hepatology 2016;64:785‐796)

Background: The global prevalence of non-alcoholic fatty liver disease (NAFLD) continues to rise. Non-invasive diagnostic modalities including ultrasonography and clinical scoring systems have been proposed as alternatives to liver biopsy but with limited performance. Artificial intelligence (AI) is currently being integrated with conventional diagnostic methods in the hopes of performance improvements. We aimed to estimate the performance of AI-assisted systems for diagnosing NAFLD, non-alcoholic steatohepatitis (NASH), and liver fibrosis. Methods: A systematic review was performed to identify studies integrating AI in the diagnosis of NAFLD, NASH, and liver fibrosis. Pooled sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and summary receiver operating characteristic curves were calculated. Results: Twenty-five studies were included in the systematic review. Meta-analysis of 13 studies showed that AI significantly improved the diagnosis of NAFLD, NASH and liver fibrosis. AI-assisted ultrasonography had excellent performance for diagnosing NAFLD, with a sensitivity, specificity, PPV, NPV of 0.97 (95% confidence interval (CI): 0.91–0.99), 0.98 (95% CI: 0.89–1.00), 0.98 (95% CI: 0.93–1.00), and 0.95 (95% CI: 0.88–0.98), respectively. The performance of AI-assisted ultrasonography was better than AI-assisted clinical data sets for the identification of NAFLD, which provided a sensitivity, specificity, PPV, NPV of 0.75 (95% CI: 0.66–0.82), 0.82 (95% CI: 0.74–0.88), 0.75 (95% CI: 0.60–0.86), and 0.82 (0.74–0.87), respectively. The area under the curves were 0.98 and 0.85 for AI-assisted ultrasonography and AI-assisted clinical data sets, respectively. AI-integrated clinical data sets had a pooled sensitivity, specificity of 0.80 (95%CI: 0.75–0.85), 0.69 (95%CI: 0.53–0.82) for identifying NASH, as well as 0.99–1.00 and 0.76–1.00 for diagnosing liver fibrosis stage F1–F4, respectively. Conclusion: AI-supported systems provide promising performance improvements for diagnosing NAFLD, NASH, and identifying liver fibrosis among NAFLD patients. Prospective trials with direct comparisons between AI-assisted modalities and conventional methods are warranted before real-world implementation. Protocol registration: PROSPERO (CRD42021230391)

Volatile organic compounds (VOCs) profile for diagnosis and monitoring therapeutic response of hepatocellular carcinoma (HCC) has not been well studied. We determined VOCs profile in exhaled breath of 97 HCC patients and 111 controls using gas chromatography–mass spectrometry and Support Vector Machine algorithm. The combination of acetone, 1,4-pentadiene, methylene chloride, benzene, phenol and allyl methyl sulfide provided the highest accuracy of 79.6%, with 76.5% sensitivity and 82.7% specificity in the training set; and 55.4% accuracy, 44.0% sensitivity, and 75.0% specificity in the test set. This combination was correlated with the HCC stages demonstrating by the increased distance from the classification boundary when the stage advanced. For early HCC detection, d-limonene provided a 62.8% sensitivity, 51.8% specificity and 54.9% accuracy. The levels of acetone, butane and dimethyl sulfide were significantly altered after treatment. Patients with complete response had a greater decreased acetone level than those with remaining tumor post-treatment (73.38 ± 56.76 vs. 17.11 ± 58.86 (× 10⁶ AU, p = 0.006). Using a cutoff of 35.9 × 10⁶ AU, the reduction in acetone level predicted treatment response with 77.3% sensitivity, 83.3% specificity, 79.4%, accuracy, and AUC of 0.784. This study demonstrates the feasibility of exhaled VOCs as a non-invasive tool for diagnosis, monitoring of HCC progression and treatment response.

Artificial intelligence (AI) using a convolutional neural network (CNN) has demonstrated promising performance in radiological analysis. We aimed to develop and validate a CNN for the detection and diagnosis of focal liver lesions (FLLs) from ultrasonography (USG) still images. The CNN was developed with a supervised training method using 40,397 retrospectively collected images from 3,487 patients, including 20,432 FLLs (hepatocellular carcinomas (HCCs), cysts, hemangiomas, focal fatty sparing, and focal fatty infiltration). AI performance was evaluated using an internal test set of 6,191 images with 845 FLLs, then externally validated using 18,922 images with 1,195 FLLs from two additional hospitals. The internal evaluation yielded an overall detection rate, diagnostic sensitivity and specificity of 87.0% (95%CI: 84.3–89.6), 83.9% (95%CI: 80.3–87.4), and 97.1% (95%CI: 96.5–97.7), respectively. The CNN also performed consistently well on external validation cohorts, with a detection rate, diagnostic sensitivity and specificity of 75.0% (95%CI: 71.7–78.3), 84.9% (95%CI: 81.6–88.2), and 97.1% (95%CI: 96.5–97.6), respectively. For diagnosis of HCC, the CNN yielded sensitivity, specificity, and negative predictive value (NPV) of 73.6% (95%CI: 64.3–82.8), 97.8% (95%CI: 96.7–98.9), and 96.5% (95%CI: 95.0–97.9) on the internal test set; and 81.5% (95%CI: 74.2–88.8), 94.4% (95%CI: 92.8–96.0), and 97.4% (95%CI: 96.2–98.5) on the external validation set, respectively. CNN detected and diagnosed common FLLs in USG images with excellent specificity and NPV for HCC. Further development of an AI system for real-time detection and characterization of FLLs in USG is warranted.