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In the United States, non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and associated with higher mortality according to data from earlier National Health and Nutrition Examination Survey (NHANES) 1988-1994. Our goal was to determine the NAFLD prevalence in the recent 1999-2012 NHANES, risk factors for advanced fibrosis (stage 3-4) and mortality. NAFLD was defined as having a United States Fatty Liver Index (USFLI) > 30 in the absence of heavy alcohol use and other known liver diseases. The probability of low/high risk of having advanced fibrosis was determined by the NAFLD Fibrosis Score (NFS). In total, 6000 persons were included; of which, 30.0% had NAFLD and 10.3% of these had advanced fibrosis. Five and eight-year overall mortality in NAFLD subjects with advanced fibrosis was significantly higher than subjects without NAFLD ((18% and 35% vs. 2.6% and 5.5%, respectively) but not NAFLD subjects without advanced fibrosis (1.1% and 2.8%, respectively). NAFLD with advanced fibrosis (but not those without) is an independent predictor for mortality on multivariate analysis (HR = 3.13, 95% CI 1.93-5.08, p<0.001). In conclusion, in this most recent NHANES, NAFLD prevalence remains at 30% with 10.3% of these having advanced fibrosis. NAFLD per se was not a risk factor for increased mortality, but NAFLD with advanced fibrosis was. Mexican American ethnicity was a significant risk factor for NAFLD but not for advanced fibrosis or increased mortality.

Background/Aims: Due to increases in obesity and type 2 diabetes, the prevalence of nonalcoholic fatty liver disease (NAFLD) has also been increasing. Current forecast models may not include non-obese NAFLD. Here, we used the Bayesian approach to forecast the prevalence of NAFLD through the year 2040.Methods: Prevalence data from 245 articles involving 2,699,627 persons were used with a hierarchical Bayesian approach to forecast the prevalence of NAFLD through 2040. Subgroup analyses were performed for age, gender, presence of metabolic syndrome, region, and smoking status. Sensitivity analysis was conducted for clinical setting and study quality.Results: The forecasted 2040 prevalence was 55.7%, a three-fold increase since 1990 and a 43.2% increase from the 2020 prevalence of 38.9%. The estimated average yearly increase since 2020 was 2.16%. For those aged <50 years and ≥50 years, the 2040 prevalence were not significantly different (56.7% vs. 61.5%, P=0.52). There was a significant difference in 2040 prevalence by sex (males: 60% vs. 50%) but the trend was steeper for females (annual percentage change: 2.5% vs. 1.5%, P=0.025). There was no difference in trends overtime by region (P=0.48). The increase rate was significantly higher in those without metabolic syndrome (3.8% vs. 0.84%, P=0.003) and smokers (1.4% vs. 1.1%, P=0.011). There was no difference by clinical/community setting (P=0.491) or study quality (P=0.85).Conclusion: By 2040, over half the adult population is forecasted to have NAFLD. The largest increases are expected to occur in women, smokers, and those without metabolic syndrome. Intensified efforts are needed to raise awareness of NAFLD and to determine long-term solutions addressing the driving factors of the disease.

Previous studies, mostly small and single center, have shown gaps in the evaluation and monitoring of patients with chronic hepatitis B (CHB) virus infection. We aimed to examine the rates and predictors of adherence to guidelines for CHB care in a large nationwide cohort. We identified adult patients with CHB infection from the Truven MarketScan databases of commercially insured and Medicare patients with private insurance supplement (2007-2014) using International Classification of Diseases, Ninth Revision, Clinical Modification codes. The initial evaluation cohort had at least 6 months follow-up, whereas at least 12 months was required for the long-term monitoring cohort. We analyzed 55,317 eligible patients with CHB infection: mean age 46 ± 12 years, 58% men, and 14.8% with cirrhosis. Over a mean follow-up of 3.2 ± 2.3 years, 55.8% had specialist (gastroenterology or infectious diseases) visits. For initial evaluation, 59% of patients received both alanine aminotransferase (ALT) and hepatitis B virus (HBV) DNA tests, whereas only 33% had ALT, HBV DNA, and hepatitis B e antigen tests, with higher frequencies among patients with specialist visits. For long-term monitoring, only 25% had both ALT and HBV DNA tests performed annually. Among patients at higher risk of developing hepatocellular carcinoma (patients with cirrhosis, male patients without cirrhosis older than 40 years, and female patients without cirrhosis older than 50), less than 40% underwent annual hepatocellular carcinoma surveillance, with 25% never receiving surveillance during the study period. Predictors of optimal initial evaluation and long-term monitoring were compensated cirrhosis (odds ratio: 1.60 and 1.47, respectively) and specialist visits (odds ratio: 1.86 and 1.31, respectively) (both P < 0.001). In this large cohort of patients with CHB infection with private insurance or Medicare with private insurance supplement, we observed poor adherence to the recommended initial evaluation and long-term monitoring. Among the predictors of adherence were specialist visits. Further efforts are needed to identify barriers and improve access to care.

Nonalcoholic fatty liver disease (NAFLD) and infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) are major causes of liver disease in adults. However, data for children and adolescents are limited. Our study aimed to characterize the prevalence, trend, and risk factors of infection of HBV and HCV and possible NAFLD for this population. We analyzed 6,647 children and adolescents (aged 6-21 years) from the 1999-2016 National Health and Nutrition Examination Survey. Among individuals aged 6-21 years, HBV prevalence decreased after 2011, from 0.72% in 1999-2004 and 0.85% in 2005-2010 to 0.27% in 2011-2016 (P < 0.001), whereas HCV prevalence increased to 0.26% in 2011-2016 after an initial decline from 0.15% in 1999-2004 to 0.02% in 2005-2010 (P = 0.01). Possible NAFLD prevalence also increased by approximately 40% in individuals aged 12-21 years, from 8.54% in 1999-2004 to 10.1% in 2005-2010 and then 11.8% in 2011-2016 (P = 0.033), with most possible NAFLD individuals being male, being obese, or having higher glucose, fasting insulin, hemoglobin A1c, homeostatic model assessment of insulin resistance, liver enzymes, lipids, and uric acid (all P < 0.01). On multivariate logistic regression, hypertension (odds ratio 4.79, 95% confidence interval 1.44-15.9) and dyslipidemia (odds ratio 11.6, 95% confidence interval 5.65-23.9) increased risk for possible NAFLD but not income:poverty ratio, hours spent on computer use, or added sugars. Although HBV prevalence has decreased in recent years among US children and adolescents, HCV and possible NAFLD have increased. Public health efforts must seek further understanding of the driving factors of this increase so that age-appropriate interventions can be developed and implemented.

Detailed subgroup incidence rates for steatotic liver disease (SLD)-related hepatocellular carcinoma (HCC) are critical to inform practice and public health interventions but remain sparse. We aimed to fill in this gap. In a retrospective cohort study of adults with SLD from the United States (US) Merative Marketscan Research Databases (1/2007 to 12/2021), we estimated HCC incidence stratified by sex, age, cirrhosis, diabetes mellitus (DM), and a combination of all these 4 factors. We excluded patients with significant alcohol use and chronic viral hepatitis. We analyzed data from 741,816 patients with SLD (mean age 51.5 ± 12.8 years, 46% male, 14.7% cirrhosis). During a 2,410,166 person-years (PY) follow-up, 1,740 patients developed HCC. The overall HCC incidence yielded 0.72 per 1,000 PY (95% confidence interval [CI, 0.68, 0.75]). The incidence was higher in males (0.95, 95% CI [0.89, 1.01]) compared to females (0.52, 95% CI [0.48, 0.56]) (p < 0.001). For those with cirrhosis, the incidence was significantly higher at 4.29 (95% CI [4.06, 4.51]) compared to those without cirrhosis (0.14, 95% CI [0.13, 0.16]) (p < 0.001). Additionally, the incidence was higher in patients with DM (1.19, 95% CI [1.12, 1.26]) compared to those without DM (0.41, 95% CI [0.38, 0.44]) (p < 0.001). Chronic kidney disease (CKD) was also associated with a higher HCC incidence of 2.20 (95% CI [2.00, 2.41]) compared to those without CKD (0.58, 95% CI [0.55, 0.62]) (p < 0.001). Similarly, individuals with cardiovascular disease (CVD) had a higher HCC incidence of 1.89 (95% CI [1.75, 2.03]) compared to those without CVD (0.51, 95% CI [0.48, 0.54]) (p < 0.001). Finally, the incidence of HCC was significantly higher in patients with non-liver cancer (3.90, 95% CI [3.67, 4.12]) compared to those without other cancers (0.29, 95% CI [0.26, 0.31]) (p < 0.001). On further stratification, HCC incidence incrementally rose by 10-year age intervals, male sex, cirrhosis, and DM, reaching 19.06 (95% CI [16.10, 22.01]) and 8.44 (95% CI [6.78, 10.10]) in males and females, respectively, but only 0.04 for non-diabetic, noncirrhotic aged <40 years patients in both sexes. The main limitation of this methodology is the potential misclassification of the International Classification of Diseases (ICD) codes inherent in claims database studies. This nationwide study provided robust granular estimates for SLD-related HCC incidence stratified by several key risk factors. In addition to cirrhosis, future surveillance strategies, prevention, public health initiatives, and future research models should also take into account the impact of sex, age, and DM.

BackgroundNAFLD is increasing in Asia including Japan, despite its lower obesity rate than the West. However, NAFLD can occur in lean people, but data are limited. We aimed to investigate the epidemiology of NAFLD in Japan with a focus on lean NAFLD.MethodsWe searched PubMed, Cochrane Library, EMBASE, Web of Science, and the Japan Medical Abstracts Society (inception to 5/15/2019) and included 73 eligible full-text original research studies (n = 258,531). We used random-effects model for pooled estimates, Bayesian modeling for trend and forecasting, contacted authors for individual patient data and analyzed 14,887 (7752 NAFLD; 7135 non-NAFLD—8 studies) patients.ResultsThe overall NAFLD prevalence was 25.5%, higher in males (p < 0.001), varied by regions (p < 0.001), and increased over time (p = 0.015), but not by per-person income or gross prefectural productivity, which increased by 0.64% per year (1983–2012) and is forecasted to reach 39.3% in 2030 and 44.8% in 2040. The incidence of NAFLD, HCC, and overall mortality were 23.5, 7.6 and 5.9 per 1000 person-years, respectively. Individual patient-level data showed a lean NAFLD prevalence of 20.7% among the NAFLD population, with lean NAFLD persons being older and with a higher all-cause mortality rate (8.3 vs. 5.6 per 1000 person-years for non-lean NAFLD, p = 0.02). Older age, male sex, diabetes, and FIB-4 were independent predictors of mortality, but not lean NAFLD.ConclusionNAFLD prevalence has increased in Japan and may affect half of the population by 2040. Lean NAFLD individuals makeup 20% of the NAFLD population, were older, and had higher mortality.

Screening for metabolic dysfunction-associated steatotic liver disease (MASLD) across the entire general population is not currently a recommended strategy. However, it is not uncommon to receive a medical check-up or health check-up for a various of reasons. We tried to investigate whether advanced fibrosis screening in MASLD patients is cost-effective for adults aged 40–49 years during medical or health check-up. The target group for analysis was adults who received medical check-ups for various reasons in the United States. We constructed a hybrid model of the decision tree model and Markov model to compare expected costs and quality-adjusted life-years (QALYs) between ‘screening’ and ‘no screening’ groups from healthcare system perspectives. Patients diagnosed MASLD with advanced fibrosis by FIB4 and VCTE were given intensive lifestyle intervention (ILI). The incremental cost-effectiveness ratio (ICER) was calculated for a 30-year horizon. Assuming effect of ILI is limited to regression of liver fibrosis, ICER of the FIB-4-based two steps algorithm was $103,405 per QALY in adults aged 40–49 years, which was slightly above the threshold value ($100,000/QALY). And in those in adults aged 50–59 and 60–69 years, the ICER was $137,593 and $197,901 per QALY, respectively. If we assume the effect of ILI can improve liver fibrosis as well as cardiovascular disease events, ICERs of screening in aged 40–49 and 50–59 years were $74,596, and $95,974 per QALY, respectively. In an analysis that included additional positive effect on extrahepatic cancer by ILI, estimated ICERs were below the threshold in those in aged 40–49 and 50–59 years. Advanced fibrosis screening in MASLD patients using the FIB-4-based two-step algorithm and ILI was cost-effective for adults aged 40–49 years, taking into account both liver fibrosis and cardiovascular disease.

Our study assessed the cost-effectiveness of screening for hepatic fibrosis in cases suspected of metabolic dysfunction-associated steatotic liver disease (MASLD) using serological noninvasive tests like the fatty liver index (FLI) and hepatic steatosis index (HSI). We applied a decision tree and Markov model from a healthcare system perspective to estimate life-years, quality-adjusted life-years (QALYs), costs, and the incremental cost-effectiveness ratio (ICER) for screening versus no screening in the United States. Prevalence of advanced hepatic fibrosis in individuals suspected of having MASLD was significantly higher when defined by FLI (10.6% vs. 1.3%, P  < 0.001) and HSI (8.6% vs. 2.2%, P  < 0.001), compared to those without MASLD. Screening (base case) for suspected MASLD defined by FLI had an ICER of $78,647 per QALY and by HSI, $84,874 per QALY, both of which were considered cost-effective based on the implicit ICER threshold of $100,000/QALY in the United States. However, screening for other subgroups without evidence of MASLD was not deemed cost-effective. When applying medical costs and fibrosis distribution data from Korea, similar results were observed. Implementing a two-step screening algorithm for advanced hepatic fibrosis in patients with suspected MASLD based on HSI or FLI calculation is cost-effective in primary care settings.

Background Circulating cell-free DNA (cfDNA) methylation has been demonstrated to be a promising approach for non-invasive cancer diagnosis. However, the high cost of whole genome bisulfite sequencing (WGBS) hinders the clinical implementation of a methylation-based cfDNA early detection biomarker. We proposed a novel strategy in low-pass WGBS (~ 5 million reads) to detect methylation changes in circulating cell-free DNA (cfDNA) from patients with liver diseases and hepatocellular carcinoma (HCC). Methods The effective small sequencing depth were determined by 5 pilot cfDNA samples with relative high-depth WGBS. CfDNA of 51 patients with hepatitis, cirrhosis, and HCC were conducted using low-pass WGBS. The strategy was validated in an independent WGBS cohort of 32 healthy individuals and 26 early-stage HCC patients. Fifteen paired tumor tissue and buffy coat samples were used to characterize the methylation of hepatitis B virus (HBV) integration regions and genome distribution of cfDNA. Results A significant enrichment of cfDNA in intergenic and repeat regions, especially in previously reported HBV integration sites were observed, as a feature of cfDNA and the bias of cfDNA release. Methylation profiles nearby HBV integration sites were a better indicator for hypomethylation of tumor genome comparing to Alu and LINE (long interspersed nuclear element) repeats, and were able to facilitate the cfDNA-based HCC prediction. Hypomethylation nearby HBV integration sites (5 kb flanking) was detected in HCC patients, but not in patients with hepatitis and cirrhosis (Methyl HBV5k , median:0.61 vs 0.72, P  = 0.0003). Methylation levels of integration sites certain candidate regions exhibited an area under the receiver operation curve (AUC) value > 0.85 to discriminate HCC from non-HCC samples. The validation cohort achieved the prediction performance with an AUC of 0.954. Conclusions Hypomethylation around viral integration sites aids low-pass cfDNA WGBS to serve as a non-invasive approach for early HCC detection, and inspire future efforts on tumor surveillance for oncovirus with integration activity.