Updates in characteristics and survival rates of cirrhosis in a nationwide cohort of real-world U.S. patients, 2003-2021.

BACKGROUND: Adverse outcomes of cirrhosis remain a top priority. AIMS: We examined the distribution of cirrhosis causes, HCC incidence and mortality and related changes over time in a nationwide U.S. METHODS: A retrospective study of a national sample of commercially insured patients with cirrhosis from Optum's de-identified Clinformatics® Data Mart Database (CDM). RESULTS: A total of 628,743 cirrhosis cases were identified with 45% having NAFLD, 19.5% HCV, and 16.3% ALD. African Americans had the highest rate of decompensation (60.6%), while Asians had the highest rate of HCC (2.4%), both p < 0.001. African Americans more frequently had HCV (28.4%) while Hispanic/Latinos more frequently had NAFLD (49.2%, p < 0.001). Patients in the 2014-2021 cohort were significantly older (63.0 ± 12.8 vs. 57.0 ± 14.3), less frequently decompensated (54.5% vs. 58.3%) but more frequently had HCC (1.7% vs. 0.6%) and NAFLD (46.5% vs. 44.2%), all p < 0.001. The overall annual incidence of HCC was 0.76% (95% CI: 0.75-0.77) with a 5-year cumulative incidence of 4.03% (95% CI: 3.98-4.09), with significant variation by sex, race/ethnicity, and cirrhosis aetiology. The overall median years of survival were 11.4 (95% CI: 11.3-11.5) with a 5-year cumulative survival of 73.4% (95% CI: 73.3%-73.6%), also with significant disparities in similar subgroups (lowest in cryptogenic cirrhosis and worse in 2014-2021 vs. 2003-2013). The 2014-2021 period was independently associated with worse survival (aHR: 1.14, 95% CI: 1.08-1.20). CONCLUSIONS: HCC incidence and survival vary by aetiology among patients with cirrhosis, with cryptogenic cirrhosis having the lowest survival and lower survival in the more recent time period.

Incidence and predictors of hepatocellular carcinoma in NAFLD without diagnosed cirrhosis: a nationwide real-world U.S. study.

BACKGROUND: A substantial proportion of patients with nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) do not have cirrhosis. Data regarding the incidence and predictors of HCC development in NAFLD without cirrhosis are limited. We conducted a large, national study of NAFLD patients without documented cirrhosis to examine the incidence and predictors for HCC development. METHODS: This retrospective study included 751,603 NAFLD patients (54% female) without documented cirrhosis derived from the deidentified Optum Clinformatics® Data Mart Database. Patients with cirrhosis, platelets < 120,000/µL or FIB-4 values > 2.67 were excluded. RESULTS: The mean age was 53.7 ± 15.0 years, 45.9% were male, 39.5% had diabetes, 57.6% were White, 18.4% Hispanic, 8.2% Black and 4.9% were Asian. The mean platelet count was 264,000 ± 72,000/µL, and 96.3% of patients had a FIB-4 < 1.30. Over 1,686,607 person-years of follow-up, there were 76 incident cases of HCC, resulting in an HCC incidence rate of 0.05 per 1000 person-years. There was a higher HCC incidence rate among patients with platelets ≤ 150,000/µL, versus those with platelets > 150,000/µL (0.23 per 1000 person-years, vs. 0.04 per 1000 person-years, p = 0.02) but not in subgroup analyses for age, sex, race/ethnicity or diabetes. Using multivariable Cox proportional hazards model adjusted multiple confounders, platelet count ≤ 150,000/µL remained an independent predictor of HCC development (adjusted HR 5.80, 95% CI 1.67-20.1, p = 0.006). CONCLUSION: HCC incidence in NAFLD without documented cirrhosis was below the threshold for cost-effective HCC surveillance in overall and multiple subgroup analyses. Platelet count < 150,000/µL may be a useful predictor of HCC development in this population.

Updates in Characteristics and Survival Rates of Hepatocellular Carcinoma in a Nationwide Cohort of Real-World US Patients, 2003-2021.

Background & Aim: Causes of hepatocellular carcinoma (HCC) may change as treatments become available for some liver diseases. We examined the distribution of HCC cause and survival of a nationwide cohort of insured patients. Methods: Optum's de-identified Clinformatics® Data Mart Database (CDM), 2003-2021. Results: A total of 34707 patients with HCC were included: mean age: 68.3±11.6 years, 61% male, 62% Caucasian, 74% cirrhosis. Non-alcoholic fatty liver disease (NAFLD) was the most common etiology (38.9%), then hepatitis C virus (HCV) (25.3%), cryptogenic (18.0%), alcohol-associated liver disease (9.4%), other liver diseases (5.8%) and hepatitis B virus (HBV) at 2.6%. NAFLD patients were the oldest (mean age 71.1±11.2) and had the highest Charlson Comorbidity Index (CCI) (mean 10.5±3.9), while HCV were the youngest (mean age 64.2±9.2 years) and HBV had the lowest CCI (mean 7.2±4.4) (both P<0.0001). The overall 5-year survival was 18.8% (95% CI 18.2-19.3) but was lower in the recent 2014-2021 period vs 2003-2013 (18.1% vs 19.5%, P=0.003). The 2014-2021 cohort (inclusive of HCV treatment advances) was significantly older, with more females, fewer Caucasians, more African Americans, more Hispanics, fewer Asians, more cirrhosis, more NAFLD, and higher CCI (all P<0.001). On multivariable analysis, males (aHR: 1.13), Caucasians (aHR: 1.46), African Americans (aHR: 1.53) and Hispanics (aHR: 1.28) vs Asians, 2014-2021 (vs 2003-2013) cohort (aHR: 1.12), NAFLD (aHR: 1.14) or cryptogenic liver disease (aHR: 1.45) were associated with increased mortality (all P<0.001). Conclusion: HCC patients in more recent time 2014-2021 were more likely to be older, more likely to have nonviral etiology, and had worse survival compared to those from 2003 to 2013.

HIV-related mortality in the United States during the COVID-19 pandemic: A population-based study.

BACKGROUND: US progress toward ending the HIV epidemic was disrupted during the COVID-19 pandemic. OBJECTIVES: To determine the impact of the pandemic on HIV-related mortality and potential disparities. METHODS: Using data from the Centers for Disease Control and Prevention and the United States (US) Census Bureau, HIV-related mortality data of decedents aged ≥25 years between 2012 and 2021 were analyzed. Excess HIV-related mortality rates were estimated by determining the difference between observed and projected mortality rates during the pandemic. The trends of mortality were quantified with joinpoint regression analysis. RESULTS: Of the 79,725 deaths documented in adults aged 25 years and older between 2012 and 2021, a significant downward trend was noted in HIV-related mortality rates before the pandemic, followed by a surge during the pandemic. The observed mortality rates were 18.8% (95% confidence interval [CI]: 13.1%-25.5%) and 25.4% (95%CI: 19.9%-30.4%) higher than the projected values in 2020 and 2021, respectively. Both of these percentages were higher than that in the general population in 2020 (16.4%, 95%CI: 14.9%-17.9%) and 2021 (19.8%, 95%CI: 18.0%-21.6%), respectively. Increased HIV-related mortality was observed across all age subgroups, but those aged 25-44 years demonstrated the greatest relative increase and the lowest COVID-19-related deaths when compared to middle- and old-aged decedents. Disparities were observed across racial/ethnic subgroups and geographic regions. CONCLUSIONS: The pandemic led to a reversal in the attainments made to reduce the prevalence of HIV. Individuals living with HIV were disproportionately affected during the pandemic. Thoughtful policies are needed to address the disparity in excess HIV-related mortality.

Statin Use and Reduced Hepatocellular Carcinoma Risk in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Recent evidence suggests potential clinical benefits of statin in cancer chemoprevention and treatment. Nonalcoholic fatty liver disease (NAFLD) is expected to become the leading cause of hepatocellular carcinoma (HCC). We aimed to investigate the association between statin initiation and the risk of HCC among patients with NAFLD. METHODS: In this study using the Optum de-identified Clinformatics database, Cox proportional hazards regression model was performed to determine the risk of HCC in statin initiators versus nonusers. We incorporated inverse probability of treatment weighting (IPTW) to minimize potential confounding. RESULTS: Among 272,431 adults with NAFLD diagnosis, IPTW model shows that statin initiators had 53% less risk of developing HCC compared with nonusers (hazard ratio [HR], 0.47; 95% confidence interval, 0.36-0.60). In the subcohort with fibrosis-4 index data available, statin initiation was associated with 56% hazard reduction of developing HCC in NAFLD after adjusting for fibrosis-4 index score (HR, 0.44; 0.30-0.65). The association between statin initiation and lower risk of HCC development was observed for both lipophilic statin (HR, 0.49; 0.37-0.65) and hydrophilic statin (HR, 0.40; 0.21-0.76). Moreover, we observed greater hazards reduction as the dose and duration of statin use increased. NAFLD patients with more than 600 cumulative defined daily doses of statin had 70% reduction in hazards of developing HCC (HR, 0.30; 0.20-0.43). CONCLUSIONS: Our study provides strong evidence for the association between statin initiation and reduced risk of HCC development in NAFLD patients. These findings imply that statin can be used as a protective medication for NAFLD patients to reduce the risk of HCC.

Characteristics and outcomes of hepatocellular carcinoma patients with macrovascular invasion following surgical resection: a meta-analysis of 40 studies and 8,218 patients.

Background: Guidelines recommend that hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) and/or hepatic vein tumor thrombosis (HVTT) should undergo systemic therapy. However, recent data suggest that surgical resection may be beneficial in selected cases, but outcomes are heterogenous. We aimed to estimate pooled overall survival (OS), recurrence free survival (RFS) and complication rates in HCC patients with macrovascular invasion (MVI) following surgical resection. Methods: In this systematic review and meta-analysis, two investigators independently searched PubMed, Embase, and Cochrane databases from inception to Nov 10, 2020, without language restrictions, for studies reporting outcomes of adult HCC patients with MVI who underwent liver resection with curative intent. Results: We screened 8,598 articles and included 40 studies involving 8,218 patients. Among all patients with MVI, the pooled median OS was 14.39 months [95% confidence interval (CI): 10.99-18.84], 1-year OS was 54.47% (95% CI: 46.12-62.58%) and 3-year OS was 23.20% (95% CI: 16.61-31.42%). Overall, 1- and 3-year RFS were 27.70% (95% CI: 21.00-35.57%) and 10.06% (95% CI: 6.62-15.01%), respectively. Among patients with PVTT, median OS was 20.41 months in those with segmental/2nd order involvement compared to 12.91 months if 1st order branch was involved and 6.41 months if the main trunk was involved. The pooled rate of major complications was 6.17% (95% CI: 3.53-10.56%). Conclusions: Overall median survival was 14.39 months for HCC patients with MVI following resection. Median survival was higher in PVTT with segmental/2nd order involvement at 20.41 versus 6.41 months if the main trunk was involved.

Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical bayesian approach.

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.

Meta-analysis: global prevalence, trend and forecasting of non-alcoholic fatty liver disease in children and adolescents, 2000-2021.

BACKGROUND: NAFLD is increasing in children. AIMS: To determine the recent trend and forecast the future global prevalence of paediatric NAFLD METHODS: We searched PubMed, Embase, Web of Science and Cochrane library databases from inception to 1 May 2021 for studies of children and adolescents (≤21 years) with NAFLD. Obesity was defined with weight at ≥95th percentile and overweight as 85th to <95th percentile as per the Center for Disease Control BMI-for-age percentile cut-offs. RESULTS: From 3350 titles and abstracts, we included 74 studies (276,091 participants) from 20 countries/regions. We included 14 studies in the general NAFLD prevalence analysis, yielding an overall prevalence of 7.40% (95% CI: 4.17-12.81) regardless of the diagnostic method, and 8.77% (95% CI: 3.86-18.72) by ultrasound. Among continents with more than one study, the prevalence of NAFLD was 8.53% (95% CI: 5.71-12.55) for North America, 7.01% (95% CI: 3.51-13.53) for Asia, and 1.65% (95% CI: 0.97-2.80) for Europe. NAFLD prevalence regardless of the diagnostic method was 52.49% (95% CI: 46.23-58.68, 9159 participants) and 39.17% (95% CI: 30.65-48.42, 5371 participants) among obese and overweight/obese participants, respectively. For the general population, trend analysis from 2000 to 2017 indicates an increasing global prevalence of paediatric NAFLD from 4.62% to 9.02% at a yearly increase of 0.26%, whereas forecast analysis predicts a prevalence of 30.7% by 2040. CONCLUSION: The prevalence of paediatric NAFLD varies by region and is 52.49% overall among the obese population and 7.40% in the general population. It is predicted to reach 30.7% by 2040.

Global and regional long-term survival following resection for HCC in the recent decade: A meta-analysis of 110 studies.

Surgical resection for HCC remains a major curative treatment option, but it is unclear whether there are differences in outcomes by region and whether outcomes have improved over time. We aimed to estimate pooled overall survival (OS), recurrence-free survival (RFS), and complication rates in patients with hepatocellular carcinoma (HCC) following curative surgical resection and to compare outcomes by region and by time period. In this systematic review and meta-analysis, we searched Pubmed, Embase, and Cochrane databases from inception to May 15, 2020. We selected studies reporting OS, RFS, and complications in adult patients with HCC undergoing curative surgical resection. Two authors independently searched the literature and extracted the data. We screened 6983 articles and included 110 eligible studies with 82,392 patients, with study periods spanning from 1980-2017. The global pooled 1-year and 5-year survival rates were 88.9% (95% confidence interval [CI] 87.1-90.4) and 56.2% (95% CI 52.8-59.6) for OS and 71.1% (95% CI 67.6-74.3) and 35.2% (95% CI 32.5-38.0) for RFS, respectively. Five-year OS was higher in Asia (57.03%) than in other regions (Europe 48.3%; North America 48.0%; and South America 49.5%); p = 0.002. Five-year RFS was higher in patients with hepatitis B virus versus patients with hepatitis C virus (34.8% vs. 24.1%; p = 0.02). There was no significant improvement in 5-year OS and RFS over time. The pooled rate for complications was 27.6% (95% CI 23.4-32.3), with 9.7% (95% CI 6.3-14.7) classified as major. One-year OS after surgical resection for HCC is excellent (~90%). However, 5-year OS (~55%) and RFS (~35%) are still poor, suggesting that long-term care is suboptimal. Greater efforts are required to improve survival through enhanced surveillance and preventing recurrence through antiviral therapy.

2019 Global NAFLD Prevalence: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The increasing rates of obesity and type 2 diabetes mellitus may lead to increased prevalence of nonalcoholic fatty liver disease (NAFLD). We aimed to determine the current and recent trends on the global and regional prevalence of NAFLD. METHODS: Systematic search from inception to March 26, 2020 was performed without language restrictions. Two authors independently performed screening and data extraction. We performed meta-regression to determine trends in NAFLD prevalence. RESULTS: We identified 17,244 articles from literature search and included 245 eligible studies involving 5,399,254 individuals. The pooled global prevalence of NAFLD was 29.8% (95% confidence interval [CI], 28.6%-31.1%); of these, 82.5% of included articles used ultrasound to diagnose NAFLD, with prevalence of 30.6% (95% CI, 29.2%-32.0%). South America (3 studies, 5716 individuals) and North America (4 studies, 18,236 individuals) had the highest NAFLD prevalence at 35.7% (95% CI, 34.0%-37.5%) and 35.3% (95% CI, 25.4%-45.9%), respectively. From 1991 to 2019, trend analysis showed NAFLD increased from 21.9% to 37.3% (yearly increase of 0.7%, P < .0001), with South America showing the most rapid change of 2.7% per year, followed by Europe at 1.1%. CONCLUSIONS: Despite regional variation, the global prevalence of NAFLD is increasing overall. Policy makers must work toward reversing the current trends by increasing awareness of NAFLD and promoting healthy lifestyle environments.

Clinical Profiles of Asians with NAFLD: A Systematic Review and Meta-Analysis.

INTRODUCTION: NAFLD is increasingly prevalent in Asia, where people suffer more metabolic comorbidities at a lower body mass index (BMI), suggesting potential differences in their clinical profile. Therefore, we attempted to characterize the clinical profile of Asians with NAFLD via a meta-analytic approach. METHODS: We searched PubMed, EMBASE, and Cochrane databases from January 1, 2000, to January 17, 2019. Two authors independently reviewed and selected 104 articles (2,247,754 persons) that identified NAFLD in Asians and reported relevant data, especially BMI and ALT, and excluded individuals with other liver disease and excessive alcohol consumption. Individual patient-level data were obtained from seven cohorts in Asia to complement meta-analyzed data. RESULTS: Overall, the mean age was 52.07 (95% CI: 51.28-52.85) years, with those from Southeast Asia (42.66, 95% CI: 32.23-53.11) being significantly younger. The mean BMI was 26.2 kg/m2, higher in moderate-severe versus mild hepatic steatosis (28.3 vs. 25.7) patients and NFS ≥ -1.455 versus <-1.455 (27.09 vs. 26.02), with 34% having nonobese NAFLD. The mean ALT was 31.74 U/L, higher in NFS < -1.455 versus ≥-1.455 (33.74 vs. 27.83), though no differences were found by obesity or steatosis severity. The majority of males (85.7%) and females (60.7%) had normal to minimally elevated ALT (1-1.5 × 95% ULN). Individual patient-level data analysis (N = 7,668) demonstrated similar results. CONCLUSION: About one-third of Asians with NAFLD were nonobese, and the majority did not have markedly elevated ALT. Therefore, abnormal ALT or BMI is not recommended as a criterion for NAFLD screening in this population. Additionally, there were significant differences in the clinical profiles of NAFLD among the different regions of Asia.

Systematic review with meta-analysis: prevalence of hepatic steatosis, fibrosis and associated factors in chronic hepatitis B.

BACKGROUND: As the prevalence of hepatitis steatosis (HS) increases, the prevalence of HS among those with chronic hepatitis B (CHB) may also be increasing but data on the effect of HS on CHB disease progression are lacking. AIMS: To determine the prevalence of HS in CHB and associated factors, prevalence of fibrosis and its association with HS. METHODS: Two researchers independently searched the literature and extracted data. We included full-length original articles of adults with CHB that evaluated. Prevalence estimates were pooled using a random-effects model. Associations between HS and fibrosis were assessed by pooled odds ratios (ORs) or mean differences (MD). RESULTS: Of the 2821 records screened, 54 eligible studies (28 648 patients) were analysed. The pooled prevalence of HS in CHB was 32.8% (95% CI, 28.9-37.0) with higher prevalence in men and obese patients. Older age, male sex and metabolic factors were associated with HS while an inverse association was observed between HS and HBeAg (OR 0.82, 95% CI, 0.75-0.91) and HBV DNA levels (MD -0.38, 95% CI -1.16--0.42). The pooled prevalence of significant fibrosis (≥F2 or ≥F3) was similar between patients with CHB with or without HS (40.1% vs 42.22%, P = 0.68). HS was not significantly associated with fibrosis (pooled OR 0.87, 95% CI 0.54-1.39, 20 studies, 6232 patients). CONCLUSIONS: Approximately 30% of patients with CHB had HS, which was positively associated with male sex, diabetes and metabolic factors, and was negatively associated with HBeAg and HBV DNA. HS was not significantly associated with increased fibrosis.

Fatty Liver Index and Development of Cardiovascular Disease: Findings from the UK Biobank.

BACKGROUND: Nonalcoholic fatty liver disease is common and is associated with rising morbidity and mortality in the UK. Cardiovascular disease is the main cause of death in people with nonalcoholic fatty liver disease. AIMS: To determine the association between baseline cardiovascular risk factors with fatty liver index, and to investigate the association between fatty liver index and the incidence of cardiovascular disease in the UK. METHODS: This study is a population-based retrospective cohort study using the UK Biobank database. RESULTS: The mean fatty liver index in the study cohort was 44.9, and 33.7% met the criteria for nonalcoholic fatty liver disease. Fatty liver index was significantly associated with a wide range of cardiovascular risk factors at baseline. During a mean follow-up of 7.86 years, the combined incidence of cardiovascular disease was 6.92 per 1000-person years at risk. We found significant association between fatty liver index and incident cardiovascular disease in the fully adjusted model. We found significant association between fatty liver index and incident cardiovascular disease in subgroups stratified by BMI as well as subgroups with fatty liver index < 30, < 60, and ≥ 60. CONCLUSIONS: Fatty liver index not only predicts NAFLD diagnosis, but also indicates baseline and future development of cardiovascular disease on long-term follow-up across weight categories and fatty liver index spectrum. These findings can inform clinicians and other stakeholders on cardiovascular disease management and preventive efforts. Patients with high fatty liver index should be counseled on the increased future risk of developing cardiovascular disease.

NASH/Liver Fibrosis Prevalence and Incidence of Nonliver Comorbidities among People with NAFLD and Incidence of NAFLD by Metabolic Comorbidities: Lessons from South Korea.

BACKGROUND: NAFLD incidence, NASH prevalence, NAFLD fibrosis prevalence, incidence of metabolic comorbidities, and mortality data in the NAFLD population remain limited. AIMS: We used a meta-analytic approach to "stage" NAFLD among the Korean population. METHODS: We searched PubMed, Embase, Cochrane Library, and KoreaMed from inception until June 29, 2019, and calculated pooled estimates via the random-effects model. RESULTS: We screened 1,485 studies and analyzed 191 eligible studies: 179 (3,556,579 participants) for NAFLD prevalence and outcome analysis and 32 (1,089,785 participants) for NAFLD incidence analysis. NAFLD prevalence was 31.46% overall and 50-60% in those with metabolic risks. The incidence (per 1,000 person-years) of NAFLD was 42.8 overall and 70-77% in those with metabolic risk. The incidence (per 1,000 person-years) of new-onset T2DM, hypertension, cardiovascular disease, and chronic kidney disease was found to be 16.9, 47.9, 100.6, and 13.9, respectively. From biopsy data, 30.21% of the NAFLD population had moderate-to-severe steatosis (9 studies, 2,461 participants) and 52.27% had NASH (7 studies, 1,168 participants) and 85.41% had fibrosis

The epidemiology of NAFLD and lean NAFLD in Japan: a meta-analysis with individual and forecasting analysis, 1995-2040.

BACKGROUND: NAFLD 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. METHODS: We 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. RESULTS: The 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. CONCLUSION: NAFLD 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.

Epidemiology of COVID-19: A systematic review and meta-analysis of clinical characteristics, risk factors, and outcomes.

Coronavirus disease 2019 (COVID-19) has become a pandemic, but its reported characteristics and outcomes vary greatly amongst studies. We determined pooled estimates for clinical characteristics and outcomes in COVID-19 patients including subgroups by disease severity (based on World Health Organization Interim Guidance Report or Infectious Disease Society of America/American Thoracic Society criteria) and by country/region. We searched Pubmed, Embase, Scopus, Cochrane, Chinese Medical Journal, and preprint databases from 1 January 2020 to 6 April 2020. Studies of laboratory-confirmed COVID-19 patients with relevant data were included. Two reviewers independently performed study selection and data extraction. From 6007 articles, 212 studies from 11 countries/regions involving 281 461 individuals were analyzed. Overall, mean age was 46.7 years, 51.8% were male, 22.9% had severe disease, and mortality was 5.6%. Underlying immunosuppression, diabetes, and malignancy were most strongly associated with severe COVID-19 (coefficient = 53.9, 23.4, 23.4, respectively, all P < .0007), while older age, male gender, diabetes, and hypertension were also associated with higher mortality (coefficient = 0.05 per year, 5.1, 8.2, 6.99, respectively; P = .006-.0002). Gastrointestinal (nausea, vomiting, abdominal pain) and respiratory symptoms (shortness of breath, chest pain) were associated with severe COVID-19, while pneumonia and end-organ failure were associated with mortality. COVID-19 is associated with a severe disease course in about 23% and mortality in about 6% of infected persons. Individuals with comorbidities and clinical features associated with severity should be monitored closely, and preventive efforts should especially target those with diabetes, malignancy, and immunosuppression.

Racial and Socioeconomic Disparities in Hospitalization of Pediatrics with Liver Disease from 2005 to 2015.

BACKGROUND: Adult liver-related hospitalizations have recently increased in the USA, but data are limited for the pediatric population. AIMS: Utilizing the Office of Statewide Health Planning and Development hospital claims database (covering > 98% of all California hospitalizations), we aimed to characterize the demographic, clinical, and socioeconomic factors of liver disease-associated admissions among children between 2005 and 2015. METHODS: We used ICD-9 codes to identify admissions associated with liver disease in patients up to 21 years of age. Patient characteristics were described as percentages and evaluated using the χ2 test. We used linear regression to examine changes over time. RESULTS: We analyzed 37,372 eligible admissions. Overall, close to one-third (28%) and one-half (48.0%) of admissions occurred in the age group 0-5 years and 16-21 years, respectively, with the remaining 23.1% occurring in the age group between 5 and 15 years. Over half (54.9%) were in males. By race, blacks made up half of the admission (49.7%), while by ethnicity, Hispanic also accounted for half of the admission (49.7%). Medicaid and Medicare payors were also disproportionately represented (54.6%). The most common liver disease was Alagille syndrome (29.2%) in 2005. Between 2005 and 2015, both the number of pediatric liver-associated admissions and the proportion of pediatric liver admissions over total admissions increased from 3130 to 3429 and 1.2% to 1.6%, respectively (both p = 0.001). By 2015, while Alagille syndrome admissions decreased to 26.4% (p = 0.004), NAFLD admission increased to 19.7% (p < 0.001). CONCLUSION: Major disparities exist in inpatient liver disease burden for blacks and Hispanics with liver disease, while NAFLD emerged as a rapidly rising liver disease in pediatrics.

ALT Levels for Asians With Metabolic Diseases: A Meta-analysis of 86 Studies With Individual Patient Data Validation.

The current alanine aminotransferase (ALT) upper limit of normal was defined using selected healthy Caucasian blood donors. Given the global rise in obesity and different body habitus in Asians, we aimed to perform a systematic review and meta-analysis combined with bootstrap modeling and individual patient data validation to estimate the ALT upper threshold for Asians, including the overweight and diabetics. We included studies from PubMed, Embase, and Cochrane database searches that identified individuals without known liver diseases (i.e., viral hepatitis, alcohol, and ultrasound-detected nonalcoholic fatty liver disease). The mean ALT (U/L) was estimated using a random-effects mixed model and upper threshold (95th-percentile value, U/L) via a bootstrap model with 10,000 resamples. We screened 4,995 studies and identified 86 studies that reported ALT values for 526,641 individuals without excessive alcohol intake or known liver diseases, yielding a mean ALT of 19 and ALT upper threshold of 32. The ALT upper threshold was 37 in males versus 31 in females, 39 in overweight versus 28 in normal-weight individuals, and 36 for diabetics versus 33 for nondiabetics. We validated our study level data with individual patient level data in 6,058 individuals from five study centers in Japan. Consistent with our study-level data, we found that the ALT upper threshold in our individual patient data analysis was indeed higher in overweight versus normal-weight individuals (39 vs. 32) and in diabetics versus nondiabetics (42 vs. 33). Conclusion: We provide validated reference ranges for ALT upper threshold derived from Asians without known liver disease, including individuals with ultrasound-detected nonalcoholic fatty liver disease who are normal weight, overweight, nondiabetic, and diabetic, to inform practice.

Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis.

BACKGROUND: Although non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, it is increasingly being identified in non-obese individuals. We aimed to characterise the prevalence, incidence, and long-term outcomes of non-obese or lean NAFLD at a global level. METHODS: For this systematic review and meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Library from inception to May 1, 2019, for relevant original research articles without any language restrictions. The literature search and data extraction were done independently by two investigators. Primary outcomes were the prevalence of non-obese or lean people within the NAFLD group and the prevalence of non-obese or lean NAFLD in the general, non-obese, and lean populations; the incidence of NAFLD among non-obese and lean populations; and long-term outcomes of non-obese people with NAFLD. We also aimed to characterise the demographic, clinical, and histological characteristics of individuals with non-obese NAFLD. FINDINGS: We identified 93 studies (n=10 576 383) from 24 countries or areas: 84 studies (n=10 530 308) were used for the prevalence analysis, five (n=9121) were used for the incidence analysis, and eight (n=36 954) were used for the outcomes analysis. Within the NAFLD population, 19·2% (95% CI 15·9-23·0) of people were lean and 40·8% (36·6-45·1) were non-obese. The prevalence of non-obese NAFLD in the general population varied from 25% or lower in some countries (eg, Malaysia and Pakistan) to higher than 50% in others (eg, Austria, Mexico, and Sweden). In the general population (comprising individuals with and without NAFLD), 12·1% (95% CI 9·3-15·6) of people had non-obese NAFLD and 5·1% (3·7-7·0) had lean NAFLD. The incidence of NAFLD in the non-obese population (without NAFLD at baseline) was 24·6 (95% CI 13·4-39·2) per 1000 person-years. Among people with non-obese or lean NALFD, 39·0% (95% CI 24·1-56·3) had non-alcoholic steatohepatitis, 29·2% (21·9-37·9) had significant fibrosis (stage ≥2), and 3·2% (1·5-5·7) had cirrhosis. Among the non-obese or lean NAFLD population, the incidence of all-cause mortality was 12·1 (95% CI 0·5-38·8) per 1000 person-years, that for liver-related mortality was 4·1 (1·9-7·1) per 1000 person-years, cardiovascular-related mortality was 4·0 (0·1-14·9) per 1000 person-years, new-onset diabetes was 12·6 (8·0-18·3) per 1000 person-years, new-onset cardiovascular disease was 18·7 (9·2-31·2) per 1000 person-years, and new-onset hypertension was 56·1 (38·5-77·0) per 1000 person-years. Most analyses were characterised by high heterogeneity. INTERPRETATION: Overall, around 40% of the global NAFLD population was classified as non-obese and almost a fifth was lean. Both non-obese and lean groups had substantial long-term liver and non-liver comorbidities. These findings suggest that obesity should not be the sole criterion for NAFLD screening. Moreover, clinical trials of treatments for NAFLD should include participants across all body-mass index ranges. FUNDING: None.