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Summary: Background: Recently, a panel of multi‐society experts proposed steatotic liver disease (SLD) as an alternative terminology for metabolic dysfunction‐associated fatty liver disease (MAFLD) or nonalcoholic fatty liver disease (NAFLD). Aims: We compared the impact of SLD, subtype of SLD, MAFLD and NAFLD on all‐cause and cause‐specific mortality. Methods: A total of 7811 individuals in the third National Health and Nutrition Examination Survey and linked mortality through 2019 were analysed. SLD was defined based on ultrasonographic hepatic steatosis. SLD, subtype of SLD and MAFLD were defined using the proposed definitions. The Cox proportional hazard model assessed all‐cause/cause‐specific mortality. Results: During a median follow‐up of 27.1 years, individuals with SLD and MAFLD experienced approximately 13%–23% higher risk of all‐cause mortality (hazard ratio [HR]: 1.15, 95% confidence interval [CI]: 1.02–1.29 for SLD; HR: 1.23, 95% CI: 1.09–1.38 for MAFLD; HR: 1.13, 95% CI: 1.01–1.27 for metabolic dysfunction‐associated steatotic liver disease [MASLD]). Individuals with MetALD demonstrated a higher risk of all‐cause (HR: 1.68, 95% CI: 1.10–2.57) and cancer‐related mortality (HR: 2.40, 95% CI: 1.23–4.66). MASLD with advanced fibrosis had an increased risk of all‐cause mortality compared to MASLD without advanced fibrosis. Conclusions: SLD, especially MASLD and MetALD, is associated with increased all‐cause mortality among adults in the US. Given this significant association between SLD or subtype of SLD (MASLD and MetALD) and all‐cause mortality, adopting the proposed SLD criteria may help identify a sub‐group of individuals with SLD who are at an increased risk for all‐cause mortality. [ABSTRACT FROM AUTHOR]

Summary Background Aim Methods Results Conclusions Economic hardship associated with chronic liver disease (CLD) may delay timely access to healthcare.To estimate the national burden of financial hardship across the spectrum of CLD in the United States (US) during the coronavirus disease 2019 (COVID‐19) pandemic.A cross‐sectional analysis was performed using the 2020–2021 US National Health Interview Survey database. The questionnaire defined financial hardship from medical bills and cost‐related nonadherence to medications in patients with CLD. We used weighted survey analysis to obtain the national estimates.While 6.9% (95% confidence interval [CI]: 6.7%–7.2%) out of 60,689 US adults (weighted sample: 251 million) reported financial hardship and inability to pay medical bills; 10.6% (95% CI: 8.3%–13.4%), 18.2% (95% CI: 14.5%–22.6%), 22.6% (95% CI: 11.0%–41.0%) with hepatitis, CLD/cirrhosis, and liver cancer experienced an inability to pay their medical bills due to financial hardship, respectively. 19.8% (95% CI: 15.9%–24.5%) and 23.3% (95% CI: 12.5%–39.3%) with CLD/cirrhosis and liver cancer, respectively experienced cost‐related nonadherence to medications, compared to a tenth of US adults (10.7%, 95% CI: 10.3%–11.2%). CLD/cirrhosis demonstrated an independent association with financial hardship from medical bills and cost‐related nonadherence to medications. Overall, these disparities were more pronounced in individuals aged <65 years old. In addition, over 40% of individuals with CLD/cirrhosis reported difficulties accessing medical care during the COVID‐19 pandemic. CLD/cirrhosis showed an independent association with difficulties accessing medical care due to COVID‐19.Financial hardship from medical bills and cost‐related nonadherence to medication can negatively impact individuals with CLD and need further evaluation. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction‐associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease and 10%–20% occurs in lean individuals. There is little data in the literature regarding outcomes in an ethnically‐diverse patient populations with MASLD. Thus, we aim to investigate the natural history and ethnic disparities of MASLD patients in a diverse population, and stratified by body mass index categories. Methods: We conducted a retrospective multicenter study on patients with MASLD at the Banner Health System from 2012 to 2022. Main outcomes included mortality and incidence of cirrhosis, cardiovascular disease, diabetes mellitus (DM), liver‐related events (LREs), and cancer. We used competing risk and Cox proportional hazard regression analysis for outcome modelling. Results: A total of 51 452 (cross‐sectional cohort) and 37 027 (longitudinal cohort) patients were identified with 9.6% lean. The cohort was 63.33% European ancestry, 27.96% Hispanic ancestry, 3.45% African ancestry, and 2.31% Native American/Alaskan ancestry. Median follow‐up was 45.8 months. After adjusting for confounders, compared to European individuals, Hispanic and Native American/Alaskan patients had higher prevalence of cirrhosis and DM, and individuals of Hispanic, African, and Native American/Alaskan ancestry had higher mortality and incidence of LREs and DM. Lean patients had higher mortality and incidence of LREs compared with non‐lean patients. Conclusion: Native American/Alaskan, Hispanic, and African patients had higher mortality and incidence of LREs and DM compared with European patients. Further studies to explore the underlying disparities and intervention to prevent LREs in lean patients, particularly several ethnic groups, may improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusion Several reports show a significant association between metabolic dysfunction‐associated steatotic liver disease (MASLD) and arterial stiffness (estimated pulse wave velocity [ePWV]) as a surrogate marker of vascular age. We investigate whether ePWV as arterial stiffness in MASLD is associated with all‐cause/cause‐specific mortality.This cohort study was based on the third National Health and Nutrition Examination Survey (NHANES, 1988–1994) and NHANES 2007–2014 and linked mortality datasets through 2019. Cox regression models assessed the association between ePWV categorized by quartile and all‐cause/cause‐specific mortality among individuals with MASLD.During the follow‐up of a median of 26.3 years (interquartile range: 19.9–27.9), higher levels of ePWV among individuals with MASLD were associated with increased all‐cause mortality, which remained significant after adjusting for demographic, lifestyle, clinical, and metabolic risk factors. Furthermore, higher ePWV in MASLD was associated with higher cardiovascular mortality. There was a 44% (hazard ratio: 1.44, 95% confidence interval: 1.32–1.58) increase in all‐cause mortality and a 53% (hazard ratio: 1.53, 95% confidence interval: 1.32–1.77) increase in cardiovascular mortality for every 1 m/s increase in ePWV in MASLD. However, there was no significant association between ePWV and cancer‐related mortality. Sensitivity analyses using the NHANES 2007–2014 dataset showed results identical to the original analysis.Higher ePWV in MASLD was associated with a higher risk of all‐cause and cardiovascular mortality beyond traditional cardiovascular risk factors. Screening for ePWV in individuals with MASLD may be an effective and beneficial approach to reducing all‐cause and cardiovascular mortality. [ABSTRACT FROM AUTHOR]

Background & Aims: The cost‐effectiveness to screen hepatic fibrosis in at‐risk population as recommended by several professional societies has been limited. This study aimed to investigate the cost‐effectiveness of this screening strategy in the expanded at‐risk population recently proposed by several societies. Methods: A combined model of the decision tree and Markov models was developed to compare expected costs, quality‐adjusted life‐years (QALYs) and incremental cost‐effectiveness ratio (ICER) between screening and no screening groups. The model included liver disease‐related health states and cardiovascular disease (CVD) states as a base‐case analysis. Screening strategy consisted of fibrosis‐4 index (FIB‐4) followed by vibration‐controlled transient elastography (VCTE) and intensive lifestyle intervention (ILI) as a treatment for diagnosed patients. Results: Cost‐effectiveness analysis showed that screening the at‐risk population entailed $298 incremental costs and an additional 0.0199 QALY per patient compared to no screening (ICER $14 949/QALY). Screening was cost‐effective based on the implicit ICER threshold of $25 000/QALY in Korea. When the effects of ILI on CVD and extrahepatic malignancy were incorporated into the cost‐effectiveness model, the ICER decreased by 0.85 times from the base‐case analysis (ICER $12 749/QALY). In contrast, when only the effects of liver disease were considered in the model, excluding cardiovascular disease effects, ICER increased from the baseline case analysis to $16 305. Even when replacing with medical costs in Japan and U.S., it remained cost‐effective with the estimate below the countries' ICER threshold. Conclusions: Our study provides compelling evidence supporting the cost‐effectiveness of FIB‐4‐based screening the at‐risk population for advanced hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Background and Aims: Sex steroid hormones and sex hormone-binding globulin (SHBG) have a role in predisposing individuals to nonalcoholic fatty liver disease (NAFLD), but their effects are known to differ between men and women. The testosterone- to-estradiol ratio (T/E2 ratio) and free androgen index (FAI) were known biomarkers for the hormonal milieu. We investigated whether sex steroid hormones, T/E2 ratio, FAI, and SHBG were associated with NAFLD in US adults. Methods: A cross-sectional analysis using the 2013--2016 National Health and Nutrition Examination Survey (NHANES) was performed. NAFLD was defined by utilizing the Hepatic Steatosis Index (HSI) and the US fatty liver index (USFLI) without other causes of chronic liver disease. Results: Out of 8687 subjects (49.5% male), low total testosterone levels were associated with progressively higher odds of NAFLD in men. Increasing T/E2 ratio was inversely associated with higher odds of NAFLD in men. Low serum SHBG levels were independently associated with an increased risk of NAFLD regardless of sex and menopausal status. Increasing FAI was independently associated with NAFLD. When we additionally adjusted for SHBG, T/E2 ratio, not total testosterone, was inversely associated with NAFLD in a dose-dependent manner. Increasing FAI was associated with higher odds of NAFLD in premenopausal women and marginally associated with NAFLD in postmenopausal women. Conclusion: The T/E2 ratio and SHBG were inversely associated with an increased risk of NAFLD in men. In women, increasing FAI was associated with NAFLD, whereas SHBG was inversely associated with NAFLD. [ABSTRACT FROM AUTHOR]

Background: Depression has been associated with nonalcoholic fatty liver disease (NAFLD). Data addressing the impact of depression on NAFLD‐related mortality are evolving. We aim to study the association of depression in NAFLD and all‐cause/cause‐specific mortality in the United States. Methods: A total of 11,877 individuals with NAFLD in the 2007–2016 National Health and Nutrition Examination Survey with the availability of linked mortality through 2019 were analysed. NAFLD was defined by utilizing the hepatic steatosis index in the absence of known causes of chronic liver disease. Depression and functional impairment due to depression were assessed using the Patient Health Questionnaire. Results: During the median follow‐up of 7.6 years, individuals with depression among individuals with NAFLD had a 35% higher all‐cause mortality than those without depression (hazard ratio [HR]: 1.35, 95% confidence interval [CI]: 1.03–1.75) after adjusting for demographic, lifestyle and clinical risk factors. NAFLD with functional impairment due to depression had a 62% higher all‐cause mortality than NAFLD without functional impairment (HR: 1.62, 95% CI: 1.10–2.39). Depression in NAFLD was associated with an approximately 50% increase in the risk for cardiovascular mortality, with a 2‐fold higher cardiovascular mortality in those with functional impairment compared to those without (HR: 2.07, 95% CI: 1.30–3.30). However, there was no significant difference in cancer‐ and accident‐related mortalities in NAFLD with or without depression. Conclusions: Depression among individuals with NAFLD was associated with a higher risk for all‐cause and cardiovascular mortality in the United States. [ABSTRACT FROM AUTHOR]

Background and Aim: Early‐onset colorectal cancer (CRC) is a growing global health concern, especially in the Asia‐Pacific region. However, comprehensive research on this topic from the region is lacking. Our study aims to investigate trends in early‐onset CRC in Asia over 10 years, filling this research gap. Methods: This study utilized data from the Global Burden of Disease Study 2019 to assess temporal trends in early‐onset CRC in the Asia‐Pacific. The analysis included estimating annual frequencies and age‐standardized rates (ASRs) of early‐onset CRC incidence, death, and disability‐adjusted life‐years (DALYs) by gender. Results: The incidence of early‐onset CRC significantly increased in both regions with higher increase and in the Western Pacific region. Notable increases were observed among males in the Western Pacific and females in Southeast Asia (SEA). Mortality rates remained stable in the Western Pacific but increased by 10.6% in SEA, especially among females. DALYs due to CRC also increased significantly in SEA, with a greater rise among females. The Western Pacific had the highest CRC incidence, and in SEA, the mortality rate was higher in females than males. Conclusions: Our study reveals a substantial increase in early‐onset CRC in the Asia‐Pacific underscoring the urgency for effective interventions. Thus, a comprehensive approach comprising controlled risk reduction, health promotion to heightened disease awareness, and implementation of effective screening strategies should be executed timely to mitigate the burden of early‐onset CRC. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Verma et al papers. To view these articles, visit https://doi.org/10.1111/apt.17891 and https://doi.org/10.1111/apt.17913 [ABSTRACT FROM AUTHOR]

We studied the trends in liver cancer‐related mortality before and during the COVID‐19 pandemic. Quarterly age‐standardized mortality and quarterly percentage change (QPC) for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) were estimated using the US national mortality database 2017–2021. Quarterly age‐standardized mortality from HCC decreased steadily with an average QPC of −0.4% (95% confidence interval [CI]: −0.6% to −0.2%). A decrease in hepatitis C virus and hepatitis B virus‐related HCC mortality of −2.2% (95% CI: −2.4% to −1.9%) and −1.1% (95% CI: −2.0% to −0.3%) was noted. In contrast, mortality for HCC from nonalcoholic fatty liver disease (3.0%, 95% CI: 2.0%–4.0%) and alcohol‐related liver disease (1.3%, 95% CI: 0.8%–1.9%) demonstrated a linear increase. There was a linear increase in the quarterly age‐standardized ICC‐related mortality (0.8%, 95% CI: 0.5%–1.0%). While ICC‐related mortality continued to increase, HCC‐related mortality tended to decline mainly due to a decline in mortality due to viral hepatitis. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Patients with pre‐existing cirrhosis and exposure to coronavirus disease‐19 (COVID‐19) may portend a poor prognosis. We evaluated the temporal trends in aetiology‐based hospitalisations and potential predictors of in‐hospital mortality in hospitalisation with cirrhosis before and during the COVID‐19 pandemic. Methods: Based on the US National Inpatient Sample 2019–2020, we determined quarterly trends in aetiology‐based hospitalisations with cirrhosis and decompensated cirrhosis and identified predictors of in‐hospital mortality in hospitalisation with cirrhosis. Results: We analysed 316,418 hospitalisations, representing 1,582,090 hospitalisations with cirrhosis. Hospitalisations for cirrhosis increased at a relatively higher rate during the COVID‐19 era. Hospitalisation rates for alcohol‐related liver disease (ALD)‐related cirrhosis increased significantly (quarterly percentage change [QPC]: 3.6%, 95% CI: 2.2%–5.1%), with a notably higher rate during the COVID‐19 era. In contrast, hospitalisation rates for hepatitis C virus (HCV)‐related cirrhosis decreased steadily with a trend of −1.4% of QPC (95% CI: −2.5% to −0.1%). Quarterly trends in the proportion of ALD‐ (QPC: 1.7%, 95% CI: 0.9%–2.6%) and nonalcoholic fatty liver disease‐related (QPC: 0.7%, 95% CI: 0.1%–1.2%) hospitalisations with cirrhosis increased significantly but declined steadily for viral hepatitis. The COVID‐19 era and COVID‐19 infection were independent predictors of in‐hospital mortality during hospitalisation with cirrhosis and decompensated cirrhosis. Compared with HCV‐related cirrhosis, ALD‐related cirrhosis was associated with a 40% higher risk of in‐hospital mortality. Conclusion: In‐hospital mortality in cirrhosis was higher in the COVID‐19 era than in the pre‐COVID‐19 era. ALD is the leading aetiology‐specific cause of in‐hospital mortality in cirrhosis with an independent detrimental impact of the COVID‐19 infection. [ABSTRACT FROM AUTHOR]

Muscle strength in non-alcoholic fatty liver disease and all-cause and cause-specific mortality Keywords: death; handgrip strength; hepatic steatosis; nhanes; sarcopenia EN death handgrip strength hepatic steatosis nhanes sarcopenia 513 516 4 01/27/23 20230201 NES 230201 Abbreviations BMI body mass index CI confidence interval HIS hepatic steatosis index HR hazard ratio NAFLD non-alcoholic fatty liver disease NHANES National Health and Nutrition Examination Survey UCOD underlying cause of death Key points Higher muscle strength among individuals with non-alcoholic fatty liver disease is associated with a lower risk of all-cause and cardiovascular mortality independent of known demographic, clinical and metabolic risk factors. 8 Range of combined grip strength/body mass index for women: quartile 1: <1.437, quartile 2: >=1.437 and <1.712, quartile 3: >=1.712 and <2.025, quartile 4: >=2.025. First, we used a non-invasive marker to define NAFLD, which may misclassify the true prevalence of NAFLD, because NHANES 2011-2014 data lack radiological or histological information, which is considered the gold standard for the diagnosis of NAFLD. [Extracted from the article]

Backgrounds and Aims: A potent and safe antiviral agent may impact chronic hepatitis C (HCV)‐related end‐stage liver disease (ESLD). We assess aetiology‐based hospitalizations for ESLD in the United States, 2016–2019. Methods: We utilized the National Inpatient Sample (NIS) from 2016 to 2019. We defined ESLD as either decompensated cirrhosis or hepatocellular carcinoma, criteria obtained from the International Classification of Diseases, Tenth Revision. Results: National hospitalization rates for non‐alcoholic fatty liver disease (NAFLD) increased significantly from 67.1/100 000 persons in 2016 to 93.6 in 2019 with an average annual percentage change (AAPC) of 12.1%, while chronic hepatitis C (HCV) decreased significantly from 71.2/100 000 persons in 2016 to 58.5 in 2019 (−6.5% AAPC). Hospitalizations for ESLD in alcohol‐related liver disease (ALD) increased as well. Conclusions: Hospitalization rates for NAFLD‐ and ALD‐related ESLD increased steadily, while those for HCV‐related ESLD decreased during the direct‐acting antivirals era. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Gawrieh et al papers. To view these articles, visit https://doi.org/10.1111/apt.17849 and https://doi.org/10.1111/apt.17886 [ABSTRACT FROM AUTHOR]

Background & Aims: With the recent improvement in the treatment of hepatitis C virus (HCV) infection, a better understanding of the infection burden is needed. We aimed to (a) estimate the trends in the national prevalence of HCV infection based on the type of health insurance coverage and (b) identify at‐risk populations for HCV infection in the United States (US) general population. Methods: Population‐based analyses using the National Health and Nutrition Examination Survey (2013‐2018) were performed with a focus on HCV infection. We analysed the prevalence of HCV infection based on the health insurance status before the direct‐acting antiviral (DAA) era (2013‐2014) and during the DAA era (2015‐2018). Results: The age‐adjusted prevalence of active HCV infection (HCV RNA [+]) was 0.92% (95% confidence interval, 0.71%‐1.19%) in the US non‐institutionalized civilian population. Although the prevalence of active HCV infection has remained stable, the prevalence of resolved HCV infection has increased after the introduction of DAA. In terms of health insurance coverage, the prevalence of active HCV infection decreased, and the prevalence of resolved HCV infection increased among individuals who had health insurance, especially private health insurance. The independent risk factors of active HCV infection were 40‐69 years group, male, less than high school education, unmarried, below poverty status, being born in the US, history of blood transfusion and not having private health insurance. Conclusion: The burden of active HCV infection has decreased among individuals who had health insurance, especially private health insurance, during the DAA era. [ABSTRACT FROM AUTHOR]

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) has been associated with sarcopenia. However, mortality in the setting of NAFLD‐related sarcopenia remains undefined. We aim to determine the all‐cause and cause‐specific mortality from sarcopenia among adults with NAFLD in the USA. Methods: 11 065 individuals in the Third National Health and Nutrition Examination Survey were studied and linked mortality through 2015 was analysed. NAFLD was diagnosed based on presence of ultrasonographic hepatic steatosis without other known liver diseases. Sarcopenia was defined as skeletal muscle index determined by bioelectrical impedance analysis. The Cox proportional hazard model was used to assess all‐cause mortality and cause‐specific mortality, and hazard ratio (HR) adjusted for known risk factors. Results: During a median follow‐up of 23 years or more, sarcopenia was associated with increased all‐cause mortality (HR 1.27, 95% confidence interval [CI] 1.11‐1.44). Only in individuals with NAFLD, sarcopenia was associated with a higher risk for all‐cause mortality, while this association was absent in those without NAFLD. Individuals with both sarcopenia and NAFLD had a higher risk for all‐cause mortality (HR 1.28 95% CI 1.06‐1.55) compared with those without sarcopenia and NAFLD. Furthermore, sarcopenia was associated with a higher risk for cancer‐ and diabetes‐related mortality among those with NAFLD. This association was not noted in those without NAFLD. Conclusion: In this nationally representative sample of US adults, sarcopenia was associated with a higher risk for all‐cause, cancer‐ and diabetes‐related mortality in individuals with NAFLD. [ABSTRACT FROM AUTHOR]

Background and Aim: While many studies demonstrated an association between visceral adiposity and colorectal adenoma (CRA), the effect of longitudinal changes in body fat composition on CRA is unclear. We investigated the longitudinal association between changes in visceral adiposity and CRA occurrence. Methods: Between 2006 and 2018, 732 (62.8%) of the 1165 subjects in a prospective cohort voluntarily underwent follow‐up abdominal fat computed tomography and colonoscopy. We defined incident and recurrent CRA as adenoma detected at follow‐up colonoscopy from negative and positive adenoma at baseline colonoscopy, respectively. Multilevel survival analysis examined the longitudinal association between changes in visceral fat and CRA. Results: During a median follow‐up of 7.4 years, 400 (54.6%) subjects developed CRA. In multivariable analysis, increasing changes in visceral adipose tissue (VAT) area were associated with higher risk of incident adenoma (hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.00–1.46 for change per 10 cm2 increase; HR 1.79, 95% CI 1.08–2.97 for highest vs lowest quartile, P values for trend = 0.045). Likewise, increasing changes in VAT area were independently associated with a higher risk of recurrent adenoma (HR 1.35, 95% CI 1.13–1.62 for change per 10 cm2 increase; HR 1.62, 95% CI 1.04–2.52 for highest vs lowest quartile, P values for trend = 0.001). Changes in subcutaneous adipose tissue area were not independently associated with CRA. Conclusion: Increasing changes in VAT area were longitudinally associated with a higher risk of incident and recurrent CRA, independent of risk factors, suggesting that visceral adiposity may be an important target in CRA prevention. [ABSTRACT FROM AUTHOR]

We examined trends in mortality from hepatitis C virus (HCV) infection and alcoholic liver disease (ALD) in the setting of drug overdose. Using US Census and national mortality records (2009‐2018), we identified deaths with HCV infection, ALD and drug overdose. HCV‐related mortality without drug overdose increased up to 2014, followed by a marked decrease. Mortality from HCV and drug overdose increased significantly. Whereas ALD‐related mortality without drug overdose continued to rise, no significant trend from ALD with drug overdose was noted. HCV‐related mortalities reduced after the introduction of DAA agents, while drug overdose‐related mortality in HCV was constantly increased. [ABSTRACT FROM AUTHOR]

Background: Patients from rural and low‐income households may have suboptimal access to liver disease care, which may translate into worse HCC outcomes. The authors provide a comprehensive update of HCC incidence and outcomes among US adults, focusing on the effect of rural geography and household income on tumor stage and mortality. Methods: The authors retrospectively evaluated adults with HCC using Surveillance, Epidemiology, and End Results data from 2004 to 2017. HCC incidence was reported per 100,000 persons and was compared using z‐statistics. Tumor stage at diagnosis used the Surveillance, Epidemiology, and End Results staging system and was evaluated with multivariate logistic regression. HCC mortality was evaluated using Kaplan‐Meier and multivariate Cox proportional hazards methods. Results: HCC incidence plateaued for most groups, with the exception of American Indians/Alaska Natives (2004‐2017: APC, 4.17%; P <.05) and patients in the lowest household income category (<$40,000; 2006‐2017: APC, 2.80%; P <.05). Compared with patients who had HCC in large metropolitan areas with a population >1 million, patients in more rural regions had higher odds of advanced‐stage HCC at diagnosis (odds ratio, 1.10; 95% CI, 1.00‐1.20; P =.04) and higher mortality (hazard ratio, 1.05; 95% CI, 1.01‐1.08; P =.02). Compared with the highest income group (≥$70,000), patients with HCC who earned <$40,000 annually had higher odds of advanced‐stage HCC (odds ratio, 1.15; 95% CI, 1.01‐1.32; P =.03) and higher mortality (hazard ratio, 1.23; 95% CI, 1.16‐1.31; P <.001). Conclusions: Patients from rural regions and lower‐income households had more advanced tumor stage at diagnosis and significantly higher HCC mortality. These disparities likely reflect suboptimal access to consistent high‐quality liver disease care, including HCC surveillance. Patients from rural and low‐income households have suboptimal access to high‐quality liver disease care, which affects timely receipt of surveillance for hepatocellular carcinoma (HCC). This study of a large national cancer registry demonstrates that patients from rural regions and low‐income households have more advanced HCC tumor stage at diagnosis and overall lower HCC survival. [ABSTRACT FROM AUTHOR]

Summary: Background: Non‐alcoholic fatty liver disease (NAFLD) affects obese and non‐obese individuals. However, mechanisms underlying non‐obese non‐alcoholic steatohepatitis (NASH) remain unclear. Aims: To attempt to identify metabolic perturbations associated with non‐obese and obese NAFLD using a lipidomics approach. Methods: A cross‐sectional analysis of 361 subjects with biopsy‐proven NAFLD (157 NAFL and 138 NASH) and healthy controls (n = 66) was performed. Individuals were categorised as obese or non‐obese based on the Asian cut‐off for body mass index. Circulating lipidomic profiling of sera was performed based on the histological severity of NAFLD. Circulating lipidomic alterations were validated with an independent validation set (154 NAFLD subjects [93 NAFL and 61 NASH] and 21 healthy controls). Results: Saturated sphingomyelin (SM) species were significantly associated with visceral adiposity in non‐obese NAFLD (SM d38:0; P < 0.001) but not in obese NAFLD. Additionally, SM levels were significantly associated with systemic and adipose tissue insulin resistance (SM d38:0; P = 0.002 and <0.001, respectively). Five potential lipid metabolites for non‐obese subjects and seven potential lipids for obese subjects were selected to predict NAFLD and NASH. These lipid combinations showed good diagnostic performance for non‐obese (area under the curve [AUC] for NAFLD/NASH = 0.916/0.813) and obese (AUC for NAFLD/NASH = 0.967/0.812) subjects. Moreover, distinctly altered patterns of diacylglycerol (DAG), triacylglycerol (TAG) and SM levels were confirmed in the validation set depending on the histological severity of NAFLD. Conclusion: Non‐obese and obese NAFLD subjects exhibit unique circulating lipidomic signatures, including DAGs, TAGs and SMs. These lipid combinations may be useful biomarkers for non‐obese and obese NAFLD patients. [ABSTRACT FROM AUTHOR]

Background and Aim: The association between palatin‐like phospholipase domain‐containing 3 (PNPLA3) I148M (rs738409) polymorphism and mortality is not well understood. We investigated the impact of PNPLA3 I148M (rs738409) polymorphism on overall and cardiovascular mortality based on the presence of nonalcoholic fatty liver disease (NAFLD). Methods: The third National Health and Nutrition Examination Survey (NHANES) from 1991 to 1994 and National Health and Nutrition Examination Survey III‐linked mortality data through 31 December 2015 were utilized in this study. Results: Of 4814 participants, 50.7% were homozygous for the C‐allele and 12.6% were homozygous for the G‐allele. During a follow up of 20 years, there were a total of 1255 deaths, 422 attributed to cardiovascular disease. There was a significant association with overall mortality among those with the PNPLA3 I148M (rs738409) GG genotype (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.02–1.77) or G‐allele (HR 1.22, 95% CI 1.09–1.36) in the general population. NAFLD with homozygous PNPLA3 I148M (rs738409) GG genotype had higher overall mortality after adjusting for multiple metabolic risk factors (HR 1.45, 95% CI 1.01–2.08). The PNPLA3 I148M (rs738409) G‐allele had a tendency of increased cardiovascular mortality in the total population. This association was not noted in those with NAFLD. Conclusions: The homozygous PNPLA3 I148M (rs738409) GG genotype showed an increase in overall mortality in the general population and NAFLD independent of multiple metabolic risk factors. [ABSTRACT FROM AUTHOR]

Background & Aims: Healthy diet has been recommended for nonalcoholic fatty liver disease (NAFLD), although it is not clear whether improving diet quality can prevent mortality. We aim to assess the impact of quality of diet on NAFLD and mortality in subjects with and without NAFLD. Methods: We performed cohort study using the Third National Health and Nutrition Examination Survey from 1988 to 1994 and linked mortality data through 2015. We used the Healthy Eating Index (HEI) scores to define diet quality, with higher HEI scores (Q4) indicating better adherence to dietary recommendations. NAFLD was defined as ultrasonographic hepatic steatosis. Results: Multivariate analysis showed that subjects with higher diet quality were inversely associated with NAFLD in a dose‐dependent manner. During the median follow‐up of 23 years, having a higher diet quality was associated with reduction in risk of all‐cause mortality in the age, sex, Race/ethnicity‐adjusted hazard ratio (HR) (Q4, HR: 0.60, 95% CI: 0.52‐0.68) and the multivariate model (Q4, HR: 0.81, 95% CI: 0.71‐0.92). Higher diet quality was associated with a lower risk for all‐cause mortality in subjects without NAFLD; however, this protective association with diet quality was not noted in those with NAFLD. Furthermore, a high diet quality was associated with a lower risk for cancer‐related mortality in the total population and among those without NAFLD. This association was not noted in those with NAFLD. Conclusions: High diet quality was inversely associated with NAFLD and was positively associated with a lower risk for cancer‐related and all‐cause mortality in those without NAFLD. [ABSTRACT FROM AUTHOR]

Background: Studies on association between fatty liver disease and overall mortality have yielded conflicting results. We evaluated the impact of fatty liver disease and advanced fibrosis on overall morality with a focus on body size and abdominal fat distribution measured by computed tomography. Methods: We performed a prospective cohort study including 34 080 subjects (mean age, 51.4 years; 58.6% men) who underwent abdominal ultrasonography and fat computed tomography, from 2007 to 2015. Fatty liver was diagnosed by ultrasonography, and advanced fibrosis was defined as high probability of advanced fibrosis based on three noninvasive methods, aspartate aminotransferase‐to‐platelet ratio index, non‐alcoholic fatty liver disease fibrosis score, and fibrosis‐4 score. Body size was categorized by body mass index into obese (≥ 25 kg/m2) or nonobese (< 25 kg/m2). Multivariate proportional Cox hazard regression analyses were performed. Results: The prevalence of fatty liver disease was 37.5%, while the prevalence of advanced fibrosis in fatty liver disease was 1.8%. During a median follow‐up of 87 months (interquartile range, 62–110), 296 deaths occurred. Fatty liver disease was not associated with higher overall mortality (multivariate‐adjusted hazard ratio [HR] 1.02, 95% confidence interval [CI] 0.77–1.34), while increased subcutaneous adiposity was associated with decreased mortality (HR 0.72, 95% CI 0.60–0.88). Advanced fibrosis resulted in a 3.5‐fold increase in overall mortality (adjusted HR 3.52, 95% CI 1.86–6.65), which was more pronounced in the nonobese. Conclusions: While fatty liver disease did not impact overall mortality, subcutaneous adiposity was associated with reduced overall mortality. Advanced fibrosis was an independent predictor of increase in overall mortality. [ABSTRACT FROM AUTHOR]

Background & Aims: Current estimates of the population‐based disease burden of liver failure or end‐stage liver disease (ESLD) are lacking. We investigated recent trends in hospitalizations and in‐hospital mortality among patients with ESLD in the United States (US). Methods: A retrospective analysis was performed utilizing the National Inpatient Sample from 2005 to 2014. We defined ESLD as either decompensated cirrhosis or hepatocellular carcinoma (HCC), criteria obtained from the International Classification of Diseases, Ninth Revision. Nationwide rates of hospitalization and in‐hospital mortality were analysed from 2005 to 2014. Results: Hospitalization rates for decompensated cirrhosis during this period increased from 105.3/100 000 persons to 159.9/100 000 persons. In terms of HCC, hospitalization rates increased from 13.6/100 000 to 22.1/100 000. In patients with non‐alcoholic fatty liver disease (NAFLD)‐related decompensated cirrhosis, the hospitalization rate increased from 13.4/100 000 to 32.1/100 000 with an annual incremental increase of 10.6%, a magnitude twofold higher than other aetiologies. The proportion of NAFLD among hospitalizations with ESLD steadily increased from 12.7% to 20.1% for decompensated cirrhosis while the proportion of chronic hepatitis C (HCV) and alcoholic liver disease (ALD) declined (from 29.3% to 27.6% for HCV; from 39.0% to 37.4% for ALD). Although the overall in‐hospital mortality rates for ESLD declined during the study, mortality rates for NAFLD‐related decompensated cirrhosis showed no significant change. Conclusions: Among aetiologies of chronic liver disease, NAFLD demonstrated the fastest growing rate of hospitalizations in non‐HCC patients with ESLD in the US. Our study highlights the need for a focus on NAFLD‐related hospitalizations and its impact on resource utilization. [ABSTRACT FROM AUTHOR]

Summary: Background: Currently, the relationship between depression and non‐alcoholic fatty liver disease (NAFLD) is not clearly defined. Aim: To determine whether depression is associated with NAFLD and NAFLD‐related advanced fibrosis in a large population sample. Methods: We performed a cross‐sectional analysis using the 2007‐2016 National Health and Nutrition Examination Survey database among adults (20 years or older) in the United States (US). Depression and functional impairment due to depression were assessed with the Patient Health Questionnaire (PHQ‐9). NAFLD was defined by utilising the US fatty liver index (USFLI), hepatic steatosis index (HSI) and the fatty liver index (FLI) in the absence of other causes of chronic liver disease. The presence and absence of advanced fibrosis in NAFLD were defined by Fibrosis‐4 score. Results: Of the 10 484 subjects (mean age 47.0 years; 48.8% men), the prevalence of depression and functional impairment due to depression was higher in subjects with NAFLD than in those without. Compared to subjects without depression, those with depression were 1.6‐2.2‐fold more likely to have NAFLD. In our multivariate analyses, depression_med was associated with increased risk of NAFLD using USFLI (odds ratio [OR] 1.48 95% confidence interval [CI] 1.17‐1.87), HSI (OR 1.51 95% CI 1.04‐2.19) and FLI (OR 2.01 95% CI 1.65‐2.48), respectively. The addition of diabetes, obesity and lipid profile to the model reduced the ORs for depression, but the significance persisted. Depression was not associated with NAFLD‐related advanced fibrosis. Conclusions: In a nationally representative sample of US adults, depression was independently associated with NAFLD. [ABSTRACT FROM AUTHOR]

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is known to increase the risk of adenomatous colonic polyps. However, the role of screening colonoscopy in patients with biopsy‐proven NAFLD in detecting advanced colorectal neoplasm is not clearly evidence‐based. Therefore, we investigated whether the histological severity of NAFLD is associated with advanced colorectal neoplasm. Methods: This study included patients ≥18 years old who underwent screening colonoscopy between 2013 and 2018 within a biopsy‐evaluated prospective NAFLD cohort. Advanced colorectal neoplasm was defined as an adenomatous polyp greater than 10 mm in diameter and/or with villous histology and/or with high‐grade dysplasia or adenocarcinoma. Results: Among the 476 patients with clinically suspected NAFLD, 379 patients were diagnosed with biopsy‐proven NAFLD and 97 patients had no evidence of NAFLD histologically, who were analyzed as healthy controls. The prevalence of advanced colorectal neoplasm was 11.1% (n = 53). Patients with advanced colorectal neoplasm had higher grade of steatosis (P = 0.004) and higher stage of hepatic fibrosis (P = 0.044) than those with normal colonoscopic findings or low‐grade adenomatous polyp. Multivariable logistic regression analysis revealed that the presence of nonalcoholic steatohepatitis (NASH) was an independent risk factor for both colorectal polyp (odds ratio [OR], 2.08; 95% confidential interval [CI], 1.12‐3.86; P = 0.020) and advanced colorectal neoplasm (OR, 2.81; 95% CI, 1.01‐7.87; P = 0.049). Conclusions: The presence of biopsy‐proven NASH was significantly associated with an increased risk of advanced colorectal neoplasm among patients with NAFLD. This finding may alert physicians to conduct screening colonoscopy in patients with NASH to detect advanced colorectal neoplasm early. [ABSTRACT FROM AUTHOR]

Background and Aims: The relationship between bisphenol A (BPA) and non‐alcoholic fatty liver disease (NAFLD) is undefined. We studied the impact of BPA on NAFLD. Methods: We performed a cross‐sectional analysis of data from the National Health and Nutrition Examination Survey (NHANES) 2005‐2014 among adults in the United States (US). NAFLD was diagnosed using the hepatic steatosis index (HSI) and the US fatty liver index (USFLI) in the absence of other causes of chronic liver diseases. The first sample using HSI consisted of 7605 adults. The second sample using USFLI consisted of 3631 participants with availability of fasting data. Results: Of the first 7605 participants (mean age 47 years, 48.4% male), the prevalence of NAFLD and abnormally elevated alanine aminotransferase (ALT) levels was correlated with urinary BPA levels (P < 0.05). Compared to the reference group with lowest quartile of urinary BPA levels, those with the third and fourth quartiles were 81% and 53% more likely to develop NAFLD defined by HSI. In a multivariate model, the ORs for NAFLD in the third and fourth quartiles were 1.69 (95% CI 1.39‐2.04) and 1.44 (95% CI 1.19‐1.76) respectively (P for trend <0.001). In the second sample using USFLI, high BPA levels (fourth quartile) remained an independent predictor of NAFLD (OR 1.44, 95% CI 1.05‐1.98, P for trend = 0.012). Conclusions: High levels of urinary BPA were associated with NAFLD in a nationally representative sample of adults in the US. The pathophysiology remains unclear and warrants further investigation. [ABSTRACT FROM AUTHOR]

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease in Western countries. Smoking and diabetes mellitus (DM) have been shown to increase mortality; however, whether NAFLD adds to the detrimental effect of smoking in DM and non‐DM patients is unknown. We evaluated the possible interactive effect of NAFLD and smoking on mortality risk in a US population‐based sample. Methods: Cross‐sectional data from 11 205 participants in the third National Health and Nutrition Examination Survey were analysed. NAFLD was defined as ultrasonographic hepatic steatosis without evidence of other liver diseases. Proportional hazards regression modelling was used to test for the multiplicative interaction of NAFLD and smoking on overall mortality, controlling for DM. Results: 36.5% of the participants had NAFLD of whom 21.1% were current smokers, while among non‐NAFLD subjects, 26.2% reported current smoking. Smoking was associated with a hazard ratio (HR) of 2.23 (95% confidence interval (CI): 1.87‐2.65) among non‐NAFLD subjects, and 2.31 (95% CI: 1.33‐2.92, P < 0.01) among NAFLD patients. In contrast, the HR for NAFLD was 1.01 (95% CI: 0.78‐1.31, P = 0.96) among smokers and 0.98 (95% CI: 0.87‐1.10, P = 0.73) among non‐smokers. There was no evidence of interaction between NAFLD and smoking (HR = 1.01, 95% CI: 0.74‐1.38, P = 0.94) in the combined model. Conclusion: We found that smoking increased mortality by two‐fold among the US population. Although the magnitude of the increase in mortality did not differ from that in non‐NAFLD subjects, smoking represents a modifiable determinant of long‐term outcomes in NAFLD patients. [ABSTRACT FROM AUTHOR]

Aims: We compared (a) demographic and clinical characteristics and (b) determinants of nonalcoholic steatohepatitis and significant fibrosis in non‐obese and obese nonalcoholic fatty liver disease. Methods: A cross‐sectional study of 664 Asian subjects (mean age 53.1 years; men 50.3%) with biopsy‐proven nonalcoholic fatty liver disease and controls was conducted. Subjects were divided by their body mass index into obese (body mass index ≥25 kg/m2) and non‐obese (body mass index <25 kg/m2). Results: Observations in subjects with non‐obese nonalcoholic fatty liver disease were in between non‐obese controls and subjects with obese nonalcoholic fatty liver disease for body mass index, sagittal abdominal diameter, aminotransferase levels, insulin resistance and abdominal visceral adipose tissue area. There was no significant difference in histology between non‐obese and obese subjects with nonalcoholic fatty liver disease except for lower grade of hepatic steatosis in nonobese nonalcoholic fatty liver disease and higher severity of hepatic fibrosis in nonobese nonalcoholic steatohepatitis. Predictors of nonalcoholic steatohepatitis in nonobese subjects included females (odds ratio 2.49), higher alanine aminotransferase (odds ratio 1.03), lower high‐density lipoprotein cholesterol (odds ratio 0.96), higher prevalence of diabetes (odds ratio 3.65) and higher visceral adipose tissue area (odds ratio 1.63 per standard deviation increase of visceral adipose tissue area) while age (odds ratio 1.04), higher aspartate aminotransferase (odds ratio 1.02), diabetes (odds ratio 2.76) and higher visceral adipose tissue area (odds ratio 1.57 per standard deviation increase) were associated with significant fibrosis in the non‐obese. Sagittal abdominal diameter was independently associated with nonalcoholic steatohepatitis or significant fibrosis among subjects with non‐obese nonalcoholic fatty liver disease. Conclusion: While there were a few phenotypic differences from obese subjects, non‐obese subjects with nonalcoholic fatty liver disease displayed a similar severity of histological liver damage. Potential factor(s) beyond obesity may play a role as non‐obese nonalcoholic fatty liver disease advances to more severe disease. [ABSTRACT FROM AUTHOR]

Summary: The Asian American population is characterized by remarkable diversity. Studying Asians as an aggregate group may obscure clinically meaningful heterogeneity. We performed a population‐based study using data from the US National Vital Statistics System. We determined the trends in age‐standardized mortality rates for chronic liver disease stratified by aetiology among the most populous US‐based Asian subgroups (Asian Indians, Chinese, Filipino, Japanese, Korean and Vietnamese) and compared it to non‐Hispanic whites. Annual percentage change was calculated to determine temporal mortality patterns using joinpoint analysis. Hepatitis C virus‐related mortality rates were higher in non‐Hispanic whites compared to individual Asian subgroups, but a sharp decline in mortality rates was noted in 2014 among non‐Hispanic whites and all Asian subgroups. Age‐standardized hepatitis B virus‐related mortality rates were higher in all Asian subgroups as compared to non‐Hispanic whites in 2016, with the highest mortality among Vietnamese followed by Chinese. Mortality rates for alcoholic liver disease have been steadily trending upwards in all Asian subgroups, with the highest mortality in Japanese. Overall, age‐standardized cirrhosis‐related mortality rates were highest in non‐Hispanic whites, followed by Japanese, and more distantly by Vietnamese and other subgroups. However, hepatocellular carcinoma‐related mortality rates were higher in most Asian subgroups led by Vietnamese, Japanese and Koreans compared to non‐Hispanic whites. In this population‐based study utilizing a nationally representative database, we demonstrated a marked heterogeneity in the mortality rates of aetiology‐specific chronic liver disease among Asian subgroups in the United States. [ABSTRACT FROM AUTHOR]

Summary: Background: Long term renal safety of antiviral agents against hepatitis B virus (HBV) has been debated. Aim: To compare longitudinal trends of renal function among HBV mono‐infected patients receiving entecavir (ETV), tenofovir disoproxil fumarate (TDF), and adefovir (ADV) in comparison to untreated subjects. Methods: A retrospective cohort consisting of 815 patients with chronic HBV infection was constructed. Serial estimated glomerular filtration rate (eGFR) was compared to the expected rate of age‐dependent decline in eGFR, derived from the National Health and Nutrition Examination Survey (NHANES) data. Generalised estimating equations and linear mixed‐effects models were used to compare trends in eGFR (in mL/min/1.73m2 as a "unit"). Results: In NHANES data (n = 23 051), each year of age was associated with a 0.86 unit decrease in eGFR in subjects without hypertension and 0.96 units with hypertension. The Stanford cohort consisted of patients who received ETV (n = 207), TDF (n = 191), ADV (n = 46) or no therapy (n = 371). After a median follow‐up 4.0 (interquartile range: 1.9‐6.5) years, there was no significant difference in the expected and observed rates of eGFR decline in untreated HBV patients. Patients receiving antiviral treatment experienced steeper reduction in renal function than expected. In the multivariable model, ETV was associated with eGFR loss at 1.81 units per year (P = 0.06, compared to untreated patients). TDF‐ and ADV‐treated patients experienced significantly higher rate of eGFR loss at 2.21 and 2.63 units per year, respectively (both P < 0.01). Conclusion: In this longitudinal cohort study, HBV patients receiving antiviral therapy, particularly TDF and ADV, experienced more rapid loss in eGFR. [ABSTRACT FROM AUTHOR]

Background & Aims: Testosterone plays a role in predisposing individuals to cardiovascular and metabolic diseases, but its effects differ between men and women. We investigated the association between serum total testosterone and non‐alcoholic fatty liver disease in adults in the US. Methods: A cross‐sectional analysis of data from participants in the 2011‐2012 National Health and Nutrition Examination Survey was performed. Subjects with significant alcohol consumption and those with viral hepatitis were excluded. We used the highest sex‐specific quartiles of serum total testosterone as references. Suspected non‐alcoholic fatty liver disease was diagnosed when serum alanine aminotransferase was >30 IU/L for men and >19 IU/L for women. Results: Of the 4758 subjects (49.4% men), the prevalence of suspected non‐alcoholic fatty liver disease was inversely correlated with the sex‐specific quartiles of testosterone in men and women. In a multivariate model, low total testosterone levels were associated with progressively higher odds of suspected non‐alcoholic fatty liver disease in men after adjusting for age, obesity and other metabolic risk factors (P values for trends <.01). When the women were divided into 2 groups according to menopausal status, a significant correlation was observed only in the post‐menopausal women (P values for trends <.01). The adjusted odds ratios for suspected non‐alcoholic fatty liver disease were 1.72‐1.99 in men and 2.15‐2.26 in post‐menopausal women (lowest quartile vs highest quartile). Conclusions: In this nationally representative sample of adults in the US, low total testosterone levels were associated with suspected non‐alcoholic fatty liver disease in men and post‐menopausal women independent of known risk factors. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aim: Telomere length and telomerase have been linked with cirrhosis and hepatocellular carcinoma. However, the impact of telomere length on nonalcoholic fatty liver disease and advanced fibrosis in a large national population sample is not well understood. Methods: Cross‐sectional data from the National Health and Nutrition Examination Survey 1999‐2002 were utilized. Suspected nonalcoholic fatty liver disease was diagnosed if serum alanine aminotransferase was >30 IU/L for men and >19 IU/L for women in the absence of other causes of chronic liver disease. Presence of advanced fibrosis was determined by the nonalcoholic fatty liver disease fibrosis score, aspartate aminotransferase to platelet ratio index and FIB‐4 score. Results: Of the 6738 participants (mean age 46.3 years, 48.4% male), suspected nonalcoholic fatty liver disease prevalence was inversely associated with leucocyte telomere length in young adults aged 20‐39 years, though this was not seen in the overall population. Percentage of participants with advanced fibrosis increased corresponding with leucocyte telomere length (longest to shortest). The shortest quartile of leucocyte telomere length was associated with a significantly higher odds ratio (95% confidence interval) of advanced fibrosis of 2.36 (1.32‐4.24) in a univariate model compared to the longest quartile, and 2.01 (1.13‐3.58) in a multivariate model adjusted for age, gender, ethnicity, waist circumference, smoking, diabetes, hypertension, total cholesterol and high‐density lipoprotein cholesterol (P for trend <.05 respectively). Conclusions: In this large nationally representative sample of American adults, leucocyte telomere shortening was associated with increased risk of advanced fibrosis in the setting of suspected nonalcoholic fatty liver disease independent of other known risk factors. [ABSTRACT FROM AUTHOR]

Key points: We studied the role of the large‐conductance Ca2+‐activated K+ channel (BK) and voltage‐dependent K+ channels (Kv) on [Ca2+]i responses to a wide range of hypoxia at different resting cell membrane potential (Em). BK/Kv were mostly closed at rest in normoxia. BK/Kv became basally active when cells were depolarized by elevated [KCl]o (>12 m m). Regardless of whether BK/Kv were closed or basally open, hypoxia‐induced elevation of [Ca2+]i was enhanced 2‐ to 3‐fold by inhibitors of BK/Kv. Hypoxia‐induced elevation of [Ca2+]i was enhanced ∼2‐fold by an inhibitor of Kv2, a major Kv in rat glomus cells. Hypoxia did not inhibit BK in inside‐out patches. Our study supports a scheme in which activation of BK/Kv strongly limits the magnitude of hypoxia‐induced [Ca2+]i rise, with Kv having a much greater effect than BK. Abstract: Large‐conductance KCa (BK) and other voltage‐dependent K+ channels (Kv) are highly expressed in carotid body (CB) glomus cells, but their role in hypoxia‐induced excitation is still not well defined and remains controversial. We addressed this issue by studying the effects of inhibitors of BK (IBTX) and BK/Kv (TEA/4‐AP) on [Ca2+]i responses to a wide range of hypoxia at different levels of resting cell membrane potential (Em). IBTX and TEA/4‐AP did not affect the basal [Ca2+]i in isolated glomus cells bathed in 5 m m KClo, but elicited transient increases in [Ca2+]i in cells that were moderately depolarized (11–20 mV) by elevation of [KCl]o (12–20 m m). Thus, BK and Kv were mostly closed at rest and activated by depolarization. Four different levels of hypoxia (mild, moderate, severe, anoxia) were used to produce a wide range of [Ca2+]i elevation (0–700 n m). IBTX did not affect the rise in [Ca2+]i, but TEA/4‐AP strongly (∼3‐fold) enhanced [Ca2+]i rise by moderate and severe levels of hypoxia. Guangxitoxin, a Kv2 blocker, inhibited the whole‐cell current by ∼50%, and enhanced 2‐fold the [Ca2+]i rise elicited by moderate and severe levels of hypoxia. Anoxia did not directly affect BK, but activated BK via depolarization. Our findings do not support the view that hypoxia inhibits BK/Kv to initiate or maintain the hypoxic response. Rather, our results show that BK/Kv are activated as glomus cells depolarize in response to hypoxia, which then limits the rise in [Ca2+]i. Inhibition of Kv may provide a mechanism to enhance the chemosensory activity of the CB and ventilation. [ABSTRACT FROM AUTHOR]

Background and Aim: We investigated the effects of PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7-TMC4 rs641738 variants on metabolic phenotypes and their combined effects on the histological severity of non-alcoholic fatty liver disease (NAFLD). Methods: We genotyped rs738409, rs58542926, and rs641738 in biopsy-proven NAFLD patients (n = 416) and healthy controls (n = 109). Homeostasis model assessment of insulin resistance and adipose tissue insulin resistance were calculated. Results: The rs738409 and rs58542926 variants, but not rs641738, were associated not only with non-alcoholic steatohepatitis (NASH) (odds ratio [OR], 2.00; 95% confidence interval [CI], 1.46-2.73 and OR, 1.91; 95% CI, 1.04-3.51) but also with significant fibrosis (≥ F2) (OR, 1.53; 95% CI, 1.11-2.11 and OR, 1.88; 95% CI, 1.02-3.46) in NAFLD, even after adjustment for metabolic risk factors. Of both variants, only rs738409 was associated with homeostasis model assessment of insulin resistance and adipose tissue insulin resistance even in healthy controls (P = 0.046 and 0.002, respectively) as well as in the entire study cohort (P = 0.016 and 0.048, respectively). PNPLA3 and TM6SF2 risk variants additively increased the risk of NASH and significant fibrosis (OR per risk allele, 2.03; 95% CI, 1.50-2.73 and 1.61; 95% CI, 1.19-2.17). Even in subjects with low insulin resistance, the risk of NASH or significant fibrosis increased as the number of risk alleles increased (P = 0.008 and 0.020, respectively). Conclusions: PNPLA3 and TM6SF2 determine the risk of NASH and significant fibrosis, even after adjustment for insulin resistance, and exert an additive effect on NASH and significant fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of heterogeneous metabolic subtypes. This study compared the diagnostic performances of noninvasive fibrosis tests in predicting advanced fibrosis among patients with NAFLD and examined the effects of the subgroups on their diagnostic performances. Methods: Three hundred fifteen patients with biopsy‐proven NAFLD were prospectively enrolled. Acoustic radiation force impulse imaging (ARFI) was performed to obtain liver stiffness measurements (LSMs). The aspartate aminotransferase‐to‐alanine aminotransferase ratio (AAR), aspartate aminotransferase‐to‐platelet ratio index (APRI), fibrosis 4 index (FIB‐4), NAFLD fibrosis score (NFS) and BARD score were calculated. The diagnostic performances of noninvasive fibrosis tests were evaluated using the area under the receiver operating characteristic curve (AUROC). Results: Fibrosis 4 index (FIB‐4) showed the highest AUROC for advanced fibrosis (0.866; 95% CI, 0.811‐0.922). AUROC subgroup analyses were performed to assess the effects of the subgroups on diagnostic performance. For patients with advanced fibrosis, the APRI, BARD, FIB‐4 and NFS AUROCs were significantly different among the radiological steatosis grades. Additionally, the AUROC of ARFI tended to decrease with increasing radiological steatosis severity. FIB‐4 and NFS showed significantly lower AUROCs for advanced fibrosis in obese NAFLD than in nonobese NAFLD (P = .002 and P < .001 respectively). However, only radiological steatosis severity was independently associated with advanced fibrosis in multivariable analysis. Conclusions: Steatosis severity may affect the diagnostic performances of noninvasive fibrosis tests in patients with NAFLD. The application of different tools should be tailored for various NAFLD subgroups to optimize noninvasive fibrosis assessments. [ABSTRACT FROM AUTHOR]

Background & Aims Physical activity ( PA) is inversely associated with nonalcoholic fatty liver disease ( NAFLD) prevalence. However, few studies evaluated the effect of PA on NAFLD incidence in regard to visceral adipose tissue ( VAT) and insulin resistance ( IR). We investigated whether PA at baseline and change in PA during follow-up have any effect on incident NAFLD. Methods We enrolled subjects who underwent health screenings between 2007 and 2008 and participated in voluntary follow-up between 2011 and 2013 (median 4.42 years). Incident NAFLD was defined as NAFLD absence at baseline and presence at follow-up by ultrasonography. PA was measured using a detailed questionnaire-based metabolic equivalent at baseline and follow-up; the difference during follow-up was calculated. Results Of the 1373 subjects enrolled, 288 (21.0%) developed NAFLD. Both total and leisure-time PA at baseline were inversely associated with incident NAFLD ( P for trend=.005 and .003 respectively). Decreased PA at follow-up was associated with increased incident NAFLD risk after adjusting for age, gender, body mass index, smoking, hypertension, diabetes and diet [hazard ratio ( HR) 1.45, 95% confidence interval ( CI) 1.04-2.02, 4th (most decreased PA) vs 1st quartile (increased PA), P=.028]. This relationship was attenuated but remained statistically significant after adjustment for VAT( HR 1.48, 95% CI 1.06-2.06, 4th vs 1st quartile) and IR( HR 1.59, 95% CI 1.11-2.27, 4th vs 1st quartile). Conclusions This study shows an independent protective effect of PA at baseline on incident NAFLD after 4-year follow-up. Furthermore, sustained or increased PA had a preventive effect on incident NAFLD independent of VAT and IR. [ABSTRACT FROM AUTHOR]

Type 1 diabetes results from autoimmune-mediated pancreatic beta-cell destruction and transforming growth factor-beta (TGF-β) is known to play a preventive role in type 1 diabetes in non-obese diabetic (NOD) mice. In this study, we investigated the role of Smad4, a key molecule for Smad-dependent TGF-β signaling, in T cells of NOD mice in the pathogenesis of autoimmune diabetes. We generated T-cell-specific Smad4 knockout (Smad4 tKO) NOD mice and assessed the pathological and immunological changes. Smad4 tKO showed earlier onset and increased incidence of diabetes than wild type (WT) NOD mice. Pathological features such as insulitis, anti-glutamic acid decarboxylase auto-antibody levels and serum IFN-γ levels were significantly increased in Smad4 tKO compared with WT NOD mice. Proportion and number of activated/memory CD4+ T cell were significantly increased in pancreatic lymph nodes of Smad4 tKO compared with WT NOD mice. However, the proportion and function of regulatory T cells was not different. Effector CD4+ T cells from Smad4 tKO were more resistant to suppression by regulatory T cells than effector cells from WT NOD mice. The proliferative potential of effector T cells from Smad4 tKO was significantly elevated compared with WT NOD mice, and activation of sterol regulatory element binding protein-1c (SREBP-1c) in T cells of Smad4 tKO NOD mice was correlated with this proliferative activity. We conclude that Smad4 deletion in T cells of NOD mice accelerated the development of autoimmune diabetes and increased the incidence of the disease by dysregulation of T cell activation at least in part via SREBP-1c activation. [ABSTRACT FROM AUTHOR]

Background and Aims Alcoholic liver diseases often evolve to acute-on-chronic liver failure (ACLF), which increases the risk of (multi-)organ failure and death. We investigated the development and characteristics of alcohol-related ACLF and evaluated prognostic scores for prediction of mortality in Asian patients with active alcoholism. Methods A total of 205 patients who were hospitalized with severe alcoholic liver disease were included in this retrospective cohort study, after excluding those with serious cardiovascular diseases, malignancy, or co-existing viral hepatitis. The Chronic Liver Failure (CLIF) Consortium Organ Failure score was used in the diagnosis and grading of ACLF, and the CLIF Consortium ACLF score (CLIF-C ACLFs) was used to predict mortality. Results Patients with ACLF had higher Maddrey discriminant function, model for end-stage liver disease (MELD), and MELD-sodium scores than those without ACLF. Infections were more frequently documented in patients with ACLF (33.3% vs 53.0%; P = 0.004). Predictive factors for ACLF development were systemic inflammatory response syndrome (odds ratio [OR], 2.239; P < 0.001), serum sodium level (OR, 0.939; P = 0.029), and neutrophil count (OR, 1.000; P = 0.021). For prediction of mortality at predefined time points (28-day and 90-day) in patients with ACLF, areas under the receiver-operating characteristic were significantly greater for the CLIF-C ACLFs than for Child-Pugh, MELD, and MELD-sodium scores. Conclusions Infection and systemic inflammatory response syndrome play an important role in the development of alcohol-related ACLF in Asian patients with active alcoholism. The CLIF-C ACLFs may be more useful for predicting mortality in ACLF cases than liver-specific scoring systems. [ABSTRACT FROM AUTHOR]

R2543 --> 616.2 --> Carotid body (CB) glomus cells serve as peripheral chemoreceptors that detect changes in arterial O2 pressure (pO2) and pH, and adjust the level of ventilation to help maintain a normal level of blood pO2 and pH. Severe levels of hypoxia and acidosis are well known to cause sustained rise in cytosolic Ca2+ concentration ([Ca2+]c) in CB glomus cells. We showed recently that isolated gloms cells exhibit spontaneous [Ca2+]c oscillations and that mild levels of hypoxia increase the frequency and amplitude of Ca2+oscillations to augment the secretory response. To understand how mild levels of acidosis regulate Ca2+signaling in glomus cells, we studied the effects of small changes in extracellular pH (pHo) on the kinetics of Ca2+oscillations and the roles of Cav, ASIC and TASK. A decrease in pHo from 7.4 to 7.3 (mild acidosis) and 7.2 (moderate acidosis) produced significant increases in the frequency and amplitude of Ca2+ oscillations without affecting the resting basal [Ca2+]c. These effects on Ca2+ oscillations were not blocked by 0.1 mM amiloride (an ASIC inhibitor) that blocked Na‐H exchange in glomus cells. Mild acidosis was associated with a small but significant inhibition of TASK current and cell depolarization. The increase in Ca2+oscillations produced by mild acidosis was strongly inhibited by nifedipine (1 µM; L‐type Cav inhibitor), as well as by TTA‐P2 (20 µM; T‐type Cav inhibitor). Mild acidosis (0.1 pH unit decrease) and mild hypoxia (~5% O2) produced similar levels of change in the kinetics of Ca2+oscillations and produced an additive effect on Ca2+oscillations. Our study shows that mild to moderate levels of acidosis inhibit TASK to increase Ca2+ influx via both L‐ and T‐type Cav, resulting in increased frequency and amplitude of Ca2+ oscillations. Our study also indicate that ASICs are not involved in the stimulatory effects of mild acidosis on Ca2+oscillations. [ABSTRACT FROM AUTHOR]

Background and Aim Gallbladder polyps ( GBPs) appear to be strongly associated with obesity and metabolic disease. To date, the relationship between GBPs and fatty liver has not been adequately evaluated. The aim of the present study was to investigate whether GBPs are associated with fatty liver, which is an ectopic regional fat deposit, independent of visceral adipose tissue ( VAT). Methods A cross-sectional study using 2643 health checkup subjects (961 patients with GBP and 1682 age- and sex-matched healthy controls) was conducted. The subjects underwent various laboratory tests, abdominal fat computed tomography ( CT), and hepatic ultrasonography. Results The mean age of the subjects was 51.4 ± 8.3 years, and 74.1% were male. GBPs were significantly associated with fatty liver. Multivariate regression analysis revealed that GBPs were significantly associated with the presence of fatty liver (odds ratio [ OR] 1.23, 95% confidence interval [ CI]: 1.02-1.48), and adjusting for the homeostatic metabolic assessment index had little effect on this association ( OR 1.23, 95% CI: 1.02-1.48). Additionally, GBPs remained significantly associated with the presence of fatty liver after adjustments for CT-measured VAT and subcutaneous adipose tissue ( OR 1.24, 95% CI: 1.03-1.50). The degree of fatty liver showed an independent ( OR 1.37 95% CI: 1.03-1.80) and dose-dependent relationship (moderate-severe fatty liver: OR 1.55 95% CI: 1.07-2.23, P for trend = 0.014) with large GBPs (≥ 5 mm). Conclusion Fatty liver, an ectopic regional fat deposit, was found to be closely associated with GBPs independent of known metabolic risk factors, insulin resistance, and CT-measured VAT, confirming a relevant clinical relationship between the two diseases. [ABSTRACT FROM AUTHOR]

Background & Aims Limited evidence supports a role for physical activity ( PA) in nonalcoholic fatty liver disease ( NAFLD) independent of visceral obesity or/and insulin resistance. We investigated the association between PA and NAFLD while considering visceral adipose tissue ( VAT) and insulin resistance in a large general population. Methods Nonalcoholic fatty liver disease was diagnosed based on typical ultrasonographic findings. A detailed PA questionnaire included type, frequency, duration and length of time that the subject engaged in PA. PA was determined by a metabolic equivalent. VAT was evaluated by computed tomography taken at the umbilicus level. Results A total of 3718 subjects were enrolled in the analysis. After adjusting for age, gender, body mass index, smoking, hypertension, diabetes, soft drink and coffee consumption, the total PA was inversely associated with NAFLD [4th quartile (highest activities), odds ratio ( OR) 0.68, 95% confidence interval ( CI) 0.54-0.85; 3rd quartile, OR 0.74, 95% CI 0.59-0.93 vs. 1st quartile (lowest activities), P for trend <0.001]. After further adjusting for VAT or insulin resistance or both ( P for trend = 0.027, 0.001 and 0.040 respectively), this relationship was slightly attenuated but remained statistically significant. The leisure-time PA and weighted PA also had inverse associations with NAFLD independent of the VAT or insulin resistance or both. Conclusions This study showed an inverse association between various types of PA and the prevalence of NAFLD in a dose-dependent manner that was independent of visceral obesity and insulin resistance. This finding suggests a beneficial association between PA and NAFLD. [ABSTRACT FROM AUTHOR]

The author discusses the potential endocytosis as another pathway in receptor Gq-TASK signalling. He cites a study which indicates that muscarine can cause a rapid, clathrin-mediated endocytosis which was dependent on protein kinase C (PKC). The author explains the outcome of the study and suggests the need for investigators to repeat studies using more than one cell type to show pathways in receptor-Gq-TASK signalling and indeed cell type specific.

Highlights from the article: Keywords: energy-storage electrodes; flexible electrodes; layer-by-layer assembly; room-temperature metallic fusion; tetraoctylammonium thiosulfate-stabilized silver nanoparticles In article number 1806584, Seung Woo Lee, Jinhan Cho, and co-workers report a room-temperature metallic fusion-induced layer-by-layer assembly that can produce highly flexible paper electrodes with bulk-metal like electrical conductivity. Energy-storage electrodes, flexible electrodes, layer-by-layer assembly, room-temperature metallic fusion, tetraoctylammonium thiosulfate-stabilized silver nanoparticles.

To fabricate flexible electrodes, conventional silver (Ag) nanomaterials have been deposited onto flexible substrates, but the formed electrodes display limited electrical conductivity due to residual bulky organic ligands, and thus postsintering processes are required to improve the electrical conductivity. Herein, an entirely different approach is introduced to produce highly flexible electrodes with bulk metal–like electrical conductivity: the room‐temperature metallic fusion of multilayered silver nanoparticles (NPs). Synthesized tetraoctylammonium thiosulfate (TOAS)‐stabilized Ag NPs are deposited onto flexible substrates by layer‐by‐layer assembly involving a perfect ligand‐exchange reaction between bulky TOAS ligands and small tris(2‐aminoethyl)amine linkers. The introduced small linkers substantially reduce the separation distance between neighboring Ag NPs. This shortened interparticle distance, combined with the low cohesive energy of Ag NPs, strongly induces metallic fusion between the close‐packed Ag NPs at room temperature without additional treatments, resulting in a high electrical conductivity of ≈1.60 × 105 S cm−1 (bulk Ag: ≈6.30 × 105 S cm−1). Furthermore, depositing the TOAS–Ag NPs onto cellulose papers through this approach can convert the insulating substrates into highly flexible and conductive papers that can be used as 3D current collectors for energy‐storage devices. [ABSTRACT FROM AUTHOR]

Depending on the amount of AgSbF6 used, this hydroarylation of alkynes yields either E- or Z-triarylalkenes. [ABSTRACT FROM AUTHOR]

Background/aims: Lacunar infarct, a small subcortical ischaemic lesion, is a known risk factor for future cognitive impairment, dementia and stroke. We evaluated the relationship between fatty liver disease (FLD) and lacunar infarct in a healthy general population., Methods: Subjects who underwent brain magnetic resonance imaging (MRI) and abdominal ultrasonography (US) during health check-ups from 2007 to 2009 were included. FLD was diagnosed by US. Subjects with a history of cerebrovascular disease, radiological findings consistent with cerebrovascular stenosis or cerebral small vessel disease were excluded., Results: Of the 1277 subjects, 54 (4.2%) exhibited lacunar infarct, and 514 (40.3%) had FLD. Subjects with lacunar infarct had a higher prevalence of FLD (59.3% vs 39.4%, P = .004). There was significant interaction between obesity (BMI < 25 kg/m 2 vs ≥ 25 kg/m 2 ) and FLD for lacunar infarct (P for interaction = .024). Subgroup analysis revealed that non-obese FLD was more common in the subjects with lacunar infarct than those without (51.7% vs 23.5%, P = .001). However, there was no significant difference in the obese FLD prevalence between these 2 groups. In multivariate models adjusted by age, sex, smoking, alcohol, hypertension and diabetes, FLD was significantly associated with lacunar infarct (odds ratio [OR] 1.97; 95% confidence interval [CI] 1.08-3.58; P = .027). Non-obese FLD was associated with lacunar infarct (OR 3.58; 95% CI 1.63-7.89; P = .002); however, this association remained insignificant in obese FLD. Instead, ageing and hypertension were independent risk factors for lacunar infarct in the obese population., Conclusions: FLD is significantly associated with lacunar infarct, independent of traditional risk factors. This association was prominent in the non-obese population., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)