Adams, Leon A.

INTRODUCTION: The recent US Food and Drug Administration approval of resmetirom for treating metabolic dysfunction-associated steatohepatitis in patients necessitates patient selection for significant fibrosis or higher (≥F2). No existing vibration-controlled transient elastography (VCTE) algorithm targets ≥F2. METHODS: The mAchine Learning ADvanceD fibrosis and rIsk metabolic dysfunction-associated steatohepatitis Novel predictor (ALADDIN) study addressed this gap by introducing a machine-learning-based web calculator that estimates the likelihood of significant fibrosis using routine laboratory parameters with and without VCTE. Our study included a training set of 827 patients, a testing set of 504 patients with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease from 6 centers, and an external validation set of 1,299 patients from 9 centers. Five algorithms were compared using area under the curve (AUC) in the test set: ElasticNet, random forest, gradient boosting machines, XGBoost, and neural networks. The top 3 (random forest, gradient boosting machines, and XGBoost) formed an ensemble model. RESULTS: In the external validation set, the ALADDIN-F2-VCTE model, using routine laboratory parameters with VCTE (AUC 0.791, 95% confidence interval [CI]: 0.764–0.819), outperformed VCTE alone (0.745, 95% CI 0.717–0.772, P < 0.0001), FibroScan-aspartate aminotransferase (0.710, 0.679–0.748, P < 0.0001), and Agile-3 model (0.740, 0.710–0.770, P < 0.0001) regarding the AUC, decision curve analysis, and calibration. The ALADDIN-F2-Lab model, using routine laboratory parameters without VCTE, achieved an AUC of 0.706 (95% CI: 0.668–0.749) and outperformed Fibrosis-4, steatosis-associated fibrosis estimator, and LiverRisk scores. DISCUSSION: Along with the steatosis-associated fibrosis estimator model developed to target significant fibrosis or higher, ALADDIN-F2-VCTE (https://aihepatology.shinyapps.io/ALADDIN1) uniquely supports a refined noninvasive approach to patient selection for resmetirom without the need for liver biopsy. In addition, ALADDIN-F2-Lab (https://aihepatology.shinyapps.io/ALADDIN2) offers an effective alternative when VCTE is unavailable.

Background: Following the adoption of new nomenclature for steatotic liver disease, we aimed to build consensus on the use of International Classification of Diseases codes and recommendations for future research and advocacy. Methods: Through a two-stage Delphi process, a core group (n = 20) reviewed draft statements and recommendations (n = 6), indicating levels of agreement. Following revisions, this process was repeated with a large expert panel (n = 243) from 73 countries. Results: Consensus ranged from 88.8% to 96.9% (mean = 92.3%). Conclusions: This global consensus statement provides guidance on harmonizing the International Classification of Diseases coding for steatotic liver disease and future directions to advance the field.

Background and Aims: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. Approach and Results: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of “agree” responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% “agree”). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. Conclusions: This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce the prevalence of fatty liver disease and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.

Background and Aims Electronic health record (EHR)‐based research allows the capture of large amounts of data, which is necessary in NAFLD, where the risk of clinical liver outcomes is generally low. The lack of consensus on which International Classification of Diseases (ICD) codes should be used as exposures and outcomes limits comparability and generalizability of results across studies. We aimed to establish consensus among a panel of experts on ICD codes that could become the reference standard and provide guidance around common methodological issues. Approach and Results Researchers with an interest in EHR‐based NAFLD research were invited to collectively define which administrative codes are most appropriate for documenting exposures and outcomes. We used a modified Delphi approach to reach consensus on several commonly encountered methodological challenges in the field. After two rounds of revision, a high level of agreement (>67%) was reached on all items considered. Full consensus was achieved on a comprehensive list of administrative codes to be considered for inclusion and exclusion criteria in defining exposures and outcomes in EHR‐based NAFLD research. We also provide suggestions on how to approach commonly encountered methodological issues and identify areas for future research. Conclusions This expert panel consensus statement can help harmonize and improve generalizability of EHR‐based NAFLD research.

Background and Aims Chronic hepatitis B (CHB) can lead to hepatocellular carcinoma (HCC). While both tenofovir disoproxil (TDF) and entecavir (ETV) have been shown to reduce the risk of HCC, their comparative effectiveness is unclear. We estimated the comparative effectiveness of these two agents in reducing the risk of HCC in patients with CHB, through a systematic review and meta‐analysis. Approach and Results We searched multiple electronic databases from January 1, 1998, to October 31, 2019, for randomized controlled trials and observational comparative effectiveness studies in adults with CHB treated with ETV compared to TDF, reporting the incidence of HCC (minimum follow‐up 12 months). Primary outcome was incidence of HCC, calculated as incidence rate ratio (IRR) with 95% confidence interval (CI, unadjusted analysis) and hazard ratio (HR) with 95% CI (adjusted analysis, where reported). Of 1,971 records identified, 14 studies (263,947 person‐years) were included for quantitative analysis. On unadjusted meta‐analysis of 14 studies, the risk of HCC was not statistically different between ETV and TDF (IRR, 1.28; 95% CI, 0.99‐1.66). When using available adjusted data (multivariate or propensity‐matched data), the risk of HCC among patients treated with ETV was 27% higher when compared to TDF (seven studies; 95% CI, 1.01‐1.60, P = 0.04). Additional analysis of adjusted data when separately reported among patients with cirrhosis demonstrated an adjusted HR of 0.90 (95% CI, 0.66‐1.23), suggesting no difference between ETV‐treated and TDF‐treated groups. The overall confidence in estimates was very low (observational studies, high heterogeneity). Conclusions TDF may be associated with lower risk of HCC when compared to ETV.

AbstractThe accuracy of theFramingham risk score (FRS) in identifying patients with nonalcoholic fatty liver disease (NAFLD) at higher 10‐year coronary heart disease (CHD) risk remains unknown. We aimed at evaluating both the baseline probability ofCHDas predicted by theFRSand the actual long‐term occurrence ofCHDinNAFLDpatients. This was a longitudinal study of a community‐based cohort. A total of 309NAFLDpatients were followed up for 11.5 ± 4.1 years (total 3554 person‐years). The overall calculated 10‐yearCHDrisk was significantly higher in theNAFLDcohort than the absoluteCHDrisk predicted by theFRSfor persons of the same age and gender (10.9 ± 9.3% vs. 9.9 ± 5.9%, respectively,P < 0.0001), and higher in men than women (12.6 ± 10.3% vs. 9.6 ± 8.1%, respectively,P = 0.006). New onsetCHDoccurred in 34 patients (11% vs. 10.9% predicted at baseline,P = NS), whereas 279 (89%) patients did not developCHD. Using multivariable analysis, theFRSwas the only variable significantly associated with new onsetCHD(OR = 1.13, 95%CI = 1.05–1.21;P = 0.001). AFRScut‐point of 11 in women, and 6 in men had a sensitivity of 80% and 74%, respectively, and a negative predictive value of 97% and 93% respectively.NAFLDpatients have a higher 10‐yearCHDrisk than the general population of the same age and gender. TheFRSaccurately predicts the higher 10‐yearCHDrisk inNAFLDpatients, and helps identify those patients expected to derive the most benefit from early intervention to preventCHDevents.

Abstract Non-alcoholic fatty liver disease (NAFLD) is common and may progress to cirrhosis and its complications. The pathogenesis of steatosis and cellular injury is thought to be related mostly to insulin resistance and oxidative stress. Therefore, management entails identification and treatment of metabolic risk factors, improving insulin sensitivity, and increasing antioxidant defences in the liver. Weight loss and exercise improve insulin sensitivity. Bariatric surgery may improve liver histology in patients with morbid obesity. Insulin sensitising drugs showed promise in pilot trials as have a number of hepatoprotective agents. Further randomised, well controlled trials are required to determine the efficacy of these drugs.