Blood eosinophil counts and the development of obstructive lung disease: the Kangbuk Samsung Health Study.

AIM: The impact of blood eosinophil counts on the development of chronic obstructive lung disease (COPD) is unknown. We investigated whether a higher blood eosinophil count was associated with the risk of developing obstructive lung disease (OLD) in a large cohort of men and women free from lung disease at baseline. METHODS: This was a cohort study of 359 456 Korean adults without a history of asthma and without OLD at baseline who participated in health screening examinations including spirometry. OLD was defined as pre-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.7 and FEV1 <80% predicted. RESULTS: After a median (interquartile range) follow-up of 5.6 (2.9-9.2) years, 5008 participants developed incident OLD (incidence rate 2.1 (95% CI 2.1-2.2) per 1000 person-years). In the fully adjusted model, the hazard ratios for incident OLD comparing eosinophil counts of 100- <200, 200- <300, 300- <500 and ≥500 versus <100 cells·µL-1 were 1.07 (95% CI 1.00-1.15), 1.30 (95% CI 1.20-1.42), 1.46 (95% CI 1.33-1.60) and 1.72 (95% CI 1.51-1.95), respectively (ptrend<0.001). These associations were consistent in clinically relevant subgroups, including never-, ex- and current smokers. CONCLUSION: In this large longitudinal cohort study, blood eosinophil counts were positively associated with the risk of developing of OLD. Our findings indicate a potential role of the eosinophil count as an independent risk factor for developing COPD.

Low Levels of Alcohol Consumption, Obesity, and Development of Fatty Liver With and Without Evidence of Advanced Fibrosis.

BACKGROUND AND AIMS: The effects of low-level alcohol consumption on fatty liver disease and the potential for effect modification by obesity is uncertain. We investigated associations among low-level alcohol consumption, obesity status, and the development of incident hepatic steatosis (HS), either with or without an increase in noninvasive liver fibrosis score category (from low to intermediate or high category). APPROACH AND RESULTS: A total of 190,048 adults without HS and a low probability of fibrosis with alcohol consumption less than 30 g/day (men) and less than 20 g/day (women) were followed for up to 15.7 years. Alcohol categories of no, light, and moderate consumption were defined as 0, 1-9.9, and 10-29.9 g/day (10-19.9 g/day for women), respectively. HS was diagnosed by ultrasonography, and the probability of fibrosis was estimated using the fibrosis-4 index (FIB-4). Parametric proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 43,466 participants developed HS, 2,983 of whom developed HS with an increase in FIB-4 index (to intermediate or high scores). Comparing light drinkers and moderate drinkers with nondrinkers, multivariable-adjusted HRs (95% CI) for incident HS were 0.93 (0.90-0.95) and 0.90 (0.87-0.92), respectively. In contrast, comparing light drinkers and moderate drinkers with nondrinkers, multivariable-adjusted HRs (95% CI) for developing HS plus intermediate/high FIB-4 were 1.15 (1.04-1.27) and 1.49 (1.33-1.66), respectively. The association between alcohol consumption categories and incident HS plus intermediate/high FIB-4 was observed in both nonobese and obese individuals, although the association was stronger in nonobese individuals (P for interaction by obesity = 0.017). CONCLUSIONS: Light/moderate alcohol consumption has differential effects on the development of different stages of fatty liver disease, which is modified by the presence of obesity.

Mammographic breast density, its changes, and breast cancer risk in premenopausal and postmenopausal women.

BACKGROUND: The risk of breast cancer related to changes in breast density over time, including its regression and persistence, remains controversial. The authors investigated the relationship between breast density and its changes over time with the development of breast cancer in premenopausal and postmenopausal women. METHODS: The current cohort study included 74,249 middle-aged Korean women (aged ≥35 years) who were free of breast cancer at baseline and who underwent repeated screening mammograms. Mammographic breast density was categorized according to the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS). A dense breast was defined as heterogeneously dense or extremely dense, and changes in dense breasts between baseline and subsequent follow-up were classified as none, developed, regressed, or persistent dense breast. RESULTS: During a median follow-up of 6.1 years (interquartile range, 4.1-8.8 years), a total of 803 incident breast cancers were identified. Baseline breast density was found to be positively associated with incident breast cancer in a dose-response manner, and this association did not significantly differ by menopausal status. The multivariable-adjusted hazard ratios (HRs) for breast cancer comparing "heterogeneously dense" and "extremely dense" categories with the nondense category were 1.96 (95% confidence interval [95% CI], 1.40-2.75) and 2.86 (95% CI, 2.04-4.01), respectively. With respect to changes in dense breasts over time, multivariable-adjusted HRs for breast cancer comparing persistent dense breast with none were 2.37 (95% CI, 1.34-4.21) in premenopausal women and 3.61 (95% CI, 1.78-7.30) in postmenopausal women. CONCLUSIONS: Both baseline dense breasts and their persistence over time were found to be strongly associated with an increased risk of incident breast cancer in premenopausal and postmenopausal women. LAY SUMMARY: Both baseline breast density and its changes over time were found to be independently associated with the risk of breast cancer in both premenopausal and postmenopausal women. The risk of incident breast cancer increased in women with persistent dense breasts, whereas the breast cancer risk decreased as dense breasts regressed. The findings of the current study support that both dense breasts at baseline and their persistence over time are independent risk factors for developing breast cancer.

Alcoholic and Nonalcoholic Fatty Liver Disease and Incident Hospitalization for Liver and Cardiovascular Diseases.

BACKGROUND & AIMS: We compared the associations of nonalcoholic fatty liver disease (NAFLD) and alcohol-associated fatty liver disease (AFLD) with risk of incident hospitalization for liver and cardiovascular diseases. METHODS: We collected data from the Kangbuk Samsung Health Study on 218,030 men and women in Korea who underwent a health examination from 2011 through 2016. Fatty liver disease (FLD) was detected by ultrasound during the initial examination. The Fibrosis-4 index was used to identify individuals with liver fibrosis. Participants were followed up for as long as 5.9 years and data on hospitalizations for liver and cardiovascular diseases were collected. RESULTS: The prevalence of NAFLD was 22.0% and the prevalence of AFLD was 6.4%. Over a median follow-up period of 4.2 years, we observed 51 and 1097 incident cases of liver disease- or cardiovascular disease-related hospitalizations, respectively. After adjustment for potential confounders, the multivariable-adjusted hazard ratios for liver disease-related hospitalization, comparing NAFLD and AFLD with the reference category (no excessive alcohol intake and no FLD), were 1.73 (95% CI, 0.76-3.96) and 5.00 (95% CI, 2.12-11.83), respectively. The corresponding hazard ratios for cardiovascular disease hospitalization were 1.20 (95% CI, 1.02-1.40) and 1.08 (95% CI, 0.86-1.34), respectively. Among participants with FLD, the risk of liver disease-related hospitalization increased with high Fibrosis-4 index scores, whereas the risk of incident cardiovascular disease did not. CONCLUSIONS: In a large cohort study, we found an increased risk of liver disease-related hospitalizations for patients with NAFLD or AFLD, especially among those with Fibrosis-4 index scores. An increased risk of cardiovascular disease-associated hospitalization was observed in patients with NAFLD but not AFLD.

Nonheavy Drinking and Worsening of Noninvasive Fibrosis Markers in Nonalcoholic Fatty Liver Disease: A Cohort Study.

The effect of modest alcohol consumption on fibrosis progression in the general population with nonalcoholic fatty liver disease (NAFLD) remains unclear. We examined the association of nonheavy alcohol consumption with worsening of noninvasive fibrosis indices in a large-scale, low-risk population with NAFLD. A cohort study was performed in 58,927 Korean adults with NAFLD and low fibrosis scores who were followed for a median of 4.9 years. Non-, light, and moderate drinkers were defined as 0 g/day, 1-9.9 g/day, and 10-29.9 g/day (10-19.9 g/day for women), respectively. Progression from low to intermediate or high probability of advanced fibrosis was assessed using noninvasive indices including NAFLD fibrosis score (NFS) and Fibrosis-4 Index (FIB-4). A parametric proportional hazards model was used to estimate the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). During 347,925.4 person-years of follow-up, 5,630 subjects with low FIB-4 progressed to intermediate or high FIB-4. The multivariable-adjusted HRs (95% CI) for worsening of FIB-4 comparing light and moderate drinkers with nondrinkers were 1.06 (0.98-1.16) and 1.29 (1.18-1.40), respectively. Similarly, using NFS, corresponding HRs (95% CI) comparing light and moderate drinkers with nondrinkers were 1.09 (1.02-1.16) and 1.31 (1.23-1.40), respectively. Furthermore, the association of moderate drinkers with worsening of either FIB-4 or NFS remained significant after introducing alcohol use and confounders treated as time-varying covariates. Conclusion: In this large-scale cohort of young and middle-aged individuals with NAFLD, nonheavy alcohol consumption, especially moderate alcohol consumption, was significantly and independently associated with worsening of noninvasive markers of fibrosis, indicating that even moderate alcohol consumption might be harmful.

Diabetes mellitus is associated with an increased risk of gastric cancer: a cohort study.

BACKGROUND: Diabetes mellitus (DM) has been considered a potential risk factor for gastric cancer, but the evidence is conflicting. We evaluated the association of DM with incident gastric cancer in a large cohort of men and women with endoscopic assessment at baseline and during follow-up. METHODS: We performed a retrospective cohort study of 195,312 adult men and women who underwent upper endoscopy at baseline and during follow-up between 2003 and 2014. DM was defined as fasting serum glucose ≥ 126 mg/dL, self-reported history of DM or current use of antidiabetic medications. Gastric cancer was confirmed histologically. RESULTS: The prevalence of DM at baseline was 3.0% (n = 5774). Over 865,511 person-years of follow-up, 198 participants developed gastric cancer. The fully adjusted hazard ratio (HR) for incident gastric cancer comparing participants with and without DM at baseline was 1.76 [95% confidence interval (CI) 1.04-2.97; P = 0.033). When we evaluated DM as a time-varying covariate, the fully adjusted HR was 1.66 (95% CI 1.04-2.68; P = 0.036). The association between DM and incident gastric cancer did not differ by the presence of intestinal metaplasia (P for interaction = 0.61). CONCLUSIONS: In this large cohort with endoscopic follow-up, DM was independently associated with increased gastric cancer incidence. The increased risk was independent of mucosal atrophy and intestinal metaplasia and was consistent in participants with newly developed DM during follow-up. Patients with DM may require more intensive endoscopic follow-up for gastric cancer screening.

Alcoholic and non-alcoholic fatty liver disease and associations with coronary artery calcification: evidence from the Kangbuk Samsung Health Study.

OBJECTIVE: Recent evidence suggests that alcoholic fatty liver disease (AFLD) and non-alcoholic fatty liver disease (NAFLD) may differentially affect risk of cardiovascular mortality. To investigate whether early liver disease due to AFLD or NAFLD have similar or dissimilar effects on risk of early coronary artery atherosclerosis, we have investigated the associations between AFLD and NAFLD and coronary artery calcium (CAC). DESIGN: A cross-sectional study was performed in 105 328 Korean adults who attended a health check-up programme. CAC score was assessed using CT, daily alcohol intake was recorded as grams/day and liver fat by ultrasound. Logistic regression model was used to calculate ORs with 95% CIs for prevalent CAC. RESULTS: Both NAFLD and AFLD were positively associated with CAC score. After adjusting for potential confounders, multivariable-adjusted OR (95% CIs) for CAC >0 comparing NAFLD and AFLD to the reference (absence of both excessive alcohol use and fatty liver disease) were 1.10 (95% CI 1.05 to 1.16) and 1.20 (95% CI 1.11 to 1.30), respectively. In post hoc analysis, OR (95% CI) for detectable CAC comparing AFLD to NAFLD was 1.09 (95% CI 1.01 to 1.17). Associations of NAFLD and AFLD with CAC scores were similar in both non-obese and obese individuals without significant interaction by obesity (p for interaction=0.088). After adjusting for homeostasis model assessment of insulin resistance and high-sensitivity C reactive protein, the associations between fatty liver disease and CAC scores remained statistically significant. CONCLUSION: In this large sample of young and middle-aged individuals, early liver disease due to NAFLD and AFLD were both significantly associated with the presence of coronary artery calcification.

Neutrophil-to-lymphocyte ratio and risk of lung cancer mortality in a low-risk population: A cohort study.

Neutrophil-to-lymphocyte ratio (NLR) is associated with poor prognosis in patients with lung cancer, but the predictive role of NLR on the risk of developing lung cancer is unknown. We investigated the association between NLR and lung cancer mortality in lung cancer-free adults. A cohort study was performed with 527,124 Korean adults who were free of lung cancer and were followed for up to 16 years. Vital status and lung cancer-related deaths were ascertained through national death records. Hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer mortality were estimated using a Cox proportional hazards model. During 4,567,495.8 person-years of follow-up, 574 lung cancer deaths were identified. A higher NLR was positively associated with lung cancer mortality. The multivariable-adjusted HR (95% CI) for lung cancer mortality comparing quintiles 2, 3, 4 and 5 of NLR to the lowest quintile were 1.26 (0.96-1.67), 1.23 (0.93-1.63), 1.33 (1.01-1.75) and 1.47 (1.13-1.92), respectively. The highest risk of lung cancer mortality was also observed in the highest NLR quintile among never-smokers and low-risk individuals after adjusting for lung function and other possible confounders. Platelet-to-lymphocyte ratio showed an inverse J-shaped association with lung cancer mortality in men but the trends in women, low-risk individuals or never-smokers were neither linear nor U-shaped. In this large cohort of young and middle-aged individuals, NLR was independently associated with increased risk of lung cancer mortality in low-risk individuals, indicating a role of systemic inflammation in lung cancer mortality in our study population.

Serum concentration of thyroid hormones in abnormal and euthyroid ranges and breast cancer risk: A cohort study.

The impact of variations in serum thyroid hormone concentration within the euthyroid range on breast cancer risk remains unclear. We investigated the effect of serum thyrotropin (TSH) and thyroid hormone concentration on breast cancer risk. This cohort study involved 62,546 Korean women, aged ≥40 years, who were free of breast cancer at baseline and underwent health examination with determination of free thyroxine (FT4) and TSH. A parametric proportional hazard model was used to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI). During a median follow-up of 4.8 years (interquartile range: 2.8-7.3 years), 834 incident breast cancers were identified. Compared to normal FT4 level, abnormally high serum FT4 level was associated with an increased risk of incident breast cancer with a corresponding multivariable aHR (95% CI) of 1.98 (1.02-3.83). This association tended to be stronger in postmenopausal women than in premenopausal women. Within the euthyroid range, the highest TSH tertile was associated with a lower risk of breast cancer than the lowest TSH tertile with a corresponding aHR (95% CI) of 0.68 (0.55-0.84). In contrast, highest FT4 tertile was associated with a higher risk of breast cancer than the lowest FT4 tertile. Abnormally high FT4 as well as higher FT4 within the euthyroid range were positively associated with breast cancer risk, while higher TSH concentration within the euthyroid range was negatively associated with breast cancer risk. Our findings indicate that thyroid function within both the abnormal and euthyroid ranges may contribute to the development of breast cancer.

Obesity and Weight Gain Are Associated With Progression of Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: The effects of weight change on the progression of liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) in the general population are unclear. We evaluated the association of weight change and baseline body mass index (BMI) with fibrosis progression, determined by non-invasive measurement of a marker, in young and middle-aged adults with NAFLD. METHODS: We performed a prospective cohort study of 40,700 adults with NAFLD in Korea who received regular health screening examinations and were followed for a median 6.0 years. Weight change was defined as the difference between weights measured at baseline and at a subsequent follow-up visit. The progression from a low to an intermediate or high probability of advanced fibrosis was assessed using the aspartate aminotransferase to platelet ratio index (APRI). RESULTS: During 275,421.5 person-years of follow-up, 5454 subjects with a low APRI progressed to an intermediate or high APRI. Multivariable-adjusted hazard ratios for APRI progression, determined by comparing the first and second weight change quintiles (the weight-loss group) and the fourth and fifth quintiles (weight-gain group) with the third quintile (weight-stable group, reference), were 0.68 (95% CI, 0.62-0.74), 0.86 (95% CI, 0.78-0.94), 1.17 (95% CI, 1.07-1.28), and 1.71 (95% CI, 1.58-1.85), respectively. The multivariable-adjusted hazard ratios for APRI progression were determined by comparing subjects with BMIs of 23-24.9, 25-29.9, and ≥30 with subjects with BMIs of 18.5-22.9 kg/m2 (reference); these ratios were 1.13 (95% CI, 1.02-1.26), 1.41 (95% CI, 1.28-1.55), and 2.09 (95% CI, 1.86-2.36), respectively. CONCLUSIONS: In a prospective cohort study of 40,700 adults with NAFLD, we found obesity and weight gain to be independently associated with increased risk of fibrosis progression, based on APRI. Maintaining a normal healthy weight and preventing weight gain may help reduce fibrosis progression in individuals with NAFLD.

Alcoholic and Nonalcoholic Fatty Liver Disease and Liver-Related Mortality: A Cohort Study.

OBJECTIVES: We compared liver-related mortality by fibrosis severity between 2 types of fatty liver disease (FLD), nonalcoholic FLD (NAFLD) and alcoholic FLD (AFLD), in a large cohort of nonobese and obese individuals. METHODS: A cohort study was performed with 437,828 Korean adults who were followed up for up to 14 years. Steatosis was diagnosed based on ultrasonography; fibrosis severity was determined by the fibrosis 4 (FIB-4) score. Vital status and liver-related deaths were ascertained through linkage to national death records. RESULTS: The prevalence of NAFLD and AFLD was 20.9% and 4.0%, respectively. During 3,145,541.1 person-years of follow-up, 109 liver-related deaths were identified (incidence rate of 3.5 per 10 person-years). When changes in fatty liver status, FIB-4 scores, and confounders during follow-up were updated as time-varying covariates, compared with the reference (absence of both excessive alcohol use and FLD), the multivariable-adjusted hazard ratios with 95% confidence intervals for liver-related mortality among those with low, intermediate, and high FIB-4 scores were 0.43 (0.19-0.94), 2.74 (1.23-6.06), and 84.66 (39.05-183.54), respectively, among patients with NAFLD, whereas among patients with AFLD, the corresponding hazard ratios (95% confidence intervals) were 0.67 (0.20-2.25), 5.44 (2.19-13.49), and 59.73 (27.99-127.46), respectively. The associations were more evident in nonobese individuals than in obese individuals (P for interaction = 0.004). DISCUSSION: In this large cohort of young and middle-aged individuals, NAFLD and AFLD with intermediate to high fibrosis scores were associated with an increased risk of liver-related mortality in a dose-dependent manner, especially among nonobese individuals.

Metabolically healthy versus unhealthy obesity and risk of fibrosis progression in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Little is known about the impact of metabolically healthy obesity on fibrosis progression in non-alcoholic fatty liver disease (NAFLD). We investigated the association of body mass index (BMI) category, body fat percentage and waist circumference with worsening of noninvasive fibrosis markers in metabolically healthy and unhealthy individuals with NAFLD. METHODS: A cohort study was performed on 59 957 Korean adults with NAFLD (13 285 metabolically healthy and 46 672 metabolically unhealthy individuals) who were followed for a median of 7.7 years. Being metabolically healthy was defined as not having any metabolic syndrome component and having a homoeostasis model assessment of insulin resistance <2.5. Progression from low to intermediate or high probability of advanced fibrosis was assessed using the NAFLD fibrosis score (NFS). RESULTS: During 339 253.1 person-years of follow-up, 9857 subjects with low NFS at baseline progressed to intermediate or high NFS. Among metabolically healthy individuals, the multivariable-adjusted HRs (95% CI) for NFS worsening comparing BMIs 23-24.9, 25-29.9 and ≥30 with a BMI of 18.5-22.9 kg/m2 were 1.19 (1.00-1.42), 1.79 (1.52-2.10) and 3.52 (2.64-4.69), respectively, whereas the corresponding HRs (95% CI) in metabolically unhealthy individuals were 1.37 (1.24-1.52), 2.18 (1.99-2.39) and 4.26 (3.83-4.75). A similar trend was observed in the analyses using body fat and waist circumference. CONCLUSION: In the large-scale cohort of young and middle-aged individuals with NAFLD, BMI was positively associated with worsening of noninvasive fibrosis marker regardless of metabolic health status. Excess adiposity per se, even without accompanying metabolic health status, may contribute to fibrosis progression in NAFLD.

Cigarette smoking and thyroid cancer risk: a cohort study.

BACKGROUND: We evaluated the association between smoking status and thyroid cancer risk and whether this association is mediated by body mass index (BMI) and thyroid-stimulating hormone (TSH). METHODS: We performed a cohort study of 96,855 Korean adults who were followed annually or biennially for a median of 5.9 years. RESULTS: During 511,052.9 person-years of follow-up, 1,250 participants developed thyroid cancer. In men, we observed a dose-dependent inverse association between current smoking, pack-years, and thyroid cancer. After adjustment for confounders, adjusted hazard ratios (95% confidence intervals) for thyroid cancer comparing current and former smokers to never smokers were 0.58 (0.45-0.75) and 0.93 (0.73-1.18), respectively. After further adjustment for BMI and TSH as potential mediators, this association was slightly attenuated, but remained significant. For women, current smokers tended to have a lower risk of thyroid cancer, but this association did not reach statistical significance. CONCLUSIONS: In this cohort study, current smoking was associated with a decreased risk of incident thyroid cancer in men but not in women and this association was observed even after adjusting for TSH and BMI levels as potential mediators. Further mechanistic studies are needed to elucidate the possible effect of smoking on the pathogenesis of thyroid cancer development.

Metabolically Healthy Obesity and Development of Chronic Kidney Disease: A Cohort Study.

BACKGROUND: The risk for chronic kidney disease (CKD) among obese persons without obesity-related metabolic abnormalities, called metabolically healthy obesity, is largely unexplored. OBJECTIVE: To investigate the risk for incident CKD across categories of body mass index in a large cohort of metabolically healthy men and women. DESIGN: Prospective cohort study. SETTING: Kangbuk Samsung Health Study, Kangbuk Samsung Hospital, Seoul, South Korea. PARTICIPANTS: 62 249 metabolically healthy, young and middle-aged men and women without CKD or proteinuria at baseline. MEASUREMENTS: Metabolic health was defined as a homeostasis model assessment of insulin resistance less than 2.5 and absence of any component of the metabolic syndrome. Underweight, normal weight, overweight, and obesity were defined as a body mass index less than 18.5 kg/m2, 18.5 to 22.9 kg/m2, 23 to 24.9 kg/m2, and 25 kg/m2 or greater, respectively. The outcome was incident CKD, defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m2. RESULTS: During 369 088 person-years of follow-up, 906 incident CKD cases were identified. The multivariable-adjusted differences in 5-year cumulative incidence of CKD in underweight, overweight, and obese participants compared with normal-weight participants were -4.0 (95% CI, -7.8 to -0.3), 3.5 (CI, 0.9 to 6.1), and 6.7 (CI, 3.0 to 10.4) cases per 1000 persons, respectively. These associations were consistently seen in all clinically relevant subgroups. LIMITATION: Chronic kidney disease was identified by a single measurement at each visit. CONCLUSION: Overweight and obesity are associated with an increased incidence of CKD in metabolically healthy young and middle-aged participants. These findings show that metabolically healthy obesity is not a harmless condition and that the obese phenotype, regardless of metabolic abnormalities, can adversely affect renal function. PRIMARY FUNDING SOURCE: None.

Metabolically Healthy Obesity and the Development of Nonalcoholic Fatty Liver Disease.

OBJECTIVES: The risk of nonalcoholic fatty liver disease (NAFLD) among obese individuals without obesity-related metabolic abnormalities, a condition referred to as metabolically healthy obese (MHO), is largely unexplored. Therefore, we examined the association between body mass index (BMI) categories and the development of NAFLD in a large cohort of metabolically healthy men and women. METHODS: A cohort study was conducted in 77,425 men and women free of NAFLD and metabolic abnormalities at baseline, who were followed-up annually or biennially for an average of 4.5 years. Being metabolically healthy was defined as not having any metabolic syndrome component and having a homeostasis model assessment of insulin resistance <2.5. The presence of fatty liver was determined using ultrasound. RESULTS: During 348,193.5 person-years of follow-up, 10,340 participants developed NAFLD (incidence rate, 29.7 per 1,000 person-years). The multivariable adjusted hazard ratios (95% confidence intervals) for incident NAFLD comparing overweight and obese with normal-weight participants were 2.15 (2.06-2.26) and 3.55 (3.37-3.74), respectively. In detailed dose-response analyses, increasing baseline BMI showed a strong and approximately linear relationship with the incidence of NAFLD, with no threshold at no risk. This association was present in both men and women, although it was stronger in women (P for interaction <0.001), and it was evident in all clinically relevant subgroups evaluated, including participants with low inflammation status. CONCLUSIONS: In a large cohort of strictly defined metabolically healthy men and women, overweight and obesity were strongly and progressively associated with an increased incidence of NAFLD, suggesting that the obese phenotype per se, regardless of metabolic abnormalities, can increase the risk of NAFLD.

Sugar-sweetened carbonated beverage consumption and coronary artery calcification in asymptomatic men and women.

BACKGROUND: Sugar-sweetened carbonated beverage consumption has been linked to obesity, metabolic syndrome, type 2 diabetes, and clinically manifest coronary heart disease, but its association with subclinical coronary heart disease remains unclear. We investigated the relationship between sugar-sweetened carbonated beverage consumption and coronary artery calcium (CAC) in a large study of asymptomatic men and women. METHODS: This was a cross-sectional study of 22,210 adult men and women who underwent a comprehensive health screening examination between 2011 and 2013 (median age 40 years). Sugar-sweetened carbonated beverage consumption was assessed using a validated food frequency questionnaire, and CAC was measured by cardiac computed tomography. Multivariable-adjusted CAC score ratios and 95% CIs were estimated from robust Tobit regression models for the natural logarithm (CAC score +1). RESULTS: The prevalence of detectable CAC (CAC score >0) was 11.7% (n = 2,604). After adjustment for age; sex; center; year of screening examination; education level; physical activity; smoking; alcohol intake; family history of cardiovascular disease; history of hypertension; history of hypercholesterolemia; and intake of total energy, fruits, vegetables, and red and processed meats, only the highest category of sugar-sweetened carbonated beverage consumption was associated with an increased CAC score compared with the lowest consumption category. The multivariable-adjusted CAC ratio comparing participants who consumed ≥5 sugar-sweetened carbonated beverages per week with nondrinkers was 1.70 (95% CI, 1.03-2.81). This association did not differ by clinical subgroup, including participants at low cardiovascular risk. CONCLUSION: Our findings suggest that high levels of sugar-sweetened carbonated beverage consumption are associated with a higher prevalence and degree of CAC in asymptomatic adults without a history of cardiovascular disease, cancer, or diabetes.

Sleep Duration, Sleep Quality, and Markers of Subclinical Arterial Disease in Healthy Men and Women.

OBJECTIVE: Short and long sleep duration are associated with increased risk of clinical cardiovascular events, but the association between sleep duration and subclinical cardiovascular disease is not well established. We examined the association between sleep duration and sleep quality with coronary artery calcification (CAC) and with brachial-ankle pulse wave velocity (PWV) in a large sample of young and middle-aged asymptomatic adults. APPROACH AND RESULTS: We conducted a cross-sectional study of adult men and women who underwent a health checkup examination, including assessment of sleep duration and quality and coupled with either CAC (n=29 203) or brachial-ankle PWV (n=18 106). The multivariate-adjusted CAC score ratios (95% confidence interval) comparing sleep durations of ≤5, 6, 8, and ≥9 hours with 7 hours of sleep were 1.50 (1.17-1.93), 1.34 (1.10-1.63), 1.37 (0.99-1.89), and 1.72 (0.90-3.28), respectively (P for quadratic trend=0.002). The corresponding average differences in brachial-ankle PWV were 6.7 (0.75-12.6), 2.9 (-1.7 to 7.4), 10.5 (4.5-16.5), and 9.6 (-0.7 to 19.8) cm/s, respectively (P for quadratic trend=0.019). Poor subjective sleep quality was associated with CAC in women but not in men, whereas the association between poor subjective sleep quality and brachial-ankle PWV was stronger in men than in women. CONCLUSIONS: In this large study of apparently healthy men and women, extreme sleep duration and poor subjective sleep quality were associated with increased prevalence of CAC and higher PWV. Our results underscore the importance of an adequate quantity and quality of sleep to maintain cardiovascular health.

Age at menarche and non-alcoholic fatty liver disease.

BACKGROUND & AIMS: The goal of this study was to examine the association between age at menarche and non-alcoholic fatty liver disease (NAFLD) in Korean women and to explore whether any observed associations were mediated by adult adiposity. METHODS: A cross-sectional study was performed for 95,183 Korean women, aged 30 or older, who underwent a regular health screening examination between March 2011 and April 2013. Information regarding age at menarche was collected using standardized, self-administered questionnaires. The presence of fatty liver was determined using ultrasonographic findings. Poisson regression models with robust variance were used to evaluate the association between age at menarche and NAFLD. RESULTS: Of the 76,415 women evaluated in this study, 9601 had NAFLD. Age at menarche was inversely associated with the prevalence of NAFLD. In a multivariable-adjusted model, the prevalence ratios (95% CIs) for NAFLD comparing menarche at <12, 12, 14, 15, and 16-18 years to menarche at 13 years were 1.31 (1.18-1.45), 1.05 (0.97-1.13), 0.93 (0.87-0.99), 0.87 (0.82-0.93), and 0.78 (0.73-0.84), respectively (p for trend <0.001). Adjusting for adult BMI or percent fat mass (%) substantially reduced these associations; however, they remained statistically significant. The association between age at menarche and NAFLD was modified by age. CONCLUSIONS: We identified an inverse association between age at menarche and NAFLD in a large sample of middle-aged women. This association was partially mediated by adiposity. The findings of this study suggest that obesity prevention strategies are needed in women who undergo early menarche to reduce the risk of NAFLD.

Metabolic syndrome, insulin resistance, and mammographic density in pre- and postmenopausal women.

Little is known about the association of metabolic syndrome (MetS) or insulin resistance (IR) with mammographic density, a strong risk factor for breast cancer. The goal of this study was to evaluate these associations in pre- and postmenopausal women. A cross-sectional study was performed in 73,974 adult women who underwent a comprehensive health screening examination that included a mammogram between 2011 and 2013 (mean age 42.6 years). MetS was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III. IR was assessed with the homeostasis model assessment-insulin resistance (HOMA-IR). Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for dense breast were estimated using logistic regression models after adjustment for potential confounders. In premenopausal women, MetS and all its components except waist circumference were associated with dense breast. After adjustment for potential confounders, the OR (95% CI) for dense breast in women with MetS compared with those without MetS was 1.22 (1.06-1.39). In postmenopausal women, however, there was positive but non-significant association between MetS and dense breast. In both pre- and postmenopausal women, high blood glucose and IR were positively associated with dense breast. The OR (95% CI) for dense breast between the highest and lowest quartiles of HOMA-IR was 1.29 (1.20-1.39) for premenopausal women and 1.44 (1.05-1.97) for postmenopausal women. In a large sample of Korean women, MetS and IR were associated with mammographic dense breast, demonstrating that IR, a potentially modifiable risk factor, may increase breast cancer risk, possibly through high mammographic density.

Dietary intake of calcium and phosphorus and serum concentration in relation to the risk of coronary artery calcification in asymptomatic adults.

OBJECTIVE: The current data regarding the association between calcium and phosphorus and cardiovascular disease are lacking. The aim of this study was to explore whether dietary calcium and phosphorus intake and their serum levels are associated with the prevalence of coronary artery calcification (CAC) using cardiac computed tomography in asymptomatic participants without a history of chronic kidney disease or cardiovascular disease. APPROACH AND RESULTS: A cross-sectional study was performed in 23 652 Korean participants (40.8±7.3 years, male 83.5%) without chronic kidney disease (estimated glomerular filtration rate≥60 mL/min per 1.73 m(2)) or clinically overt cardiovascular disease, who underwent cardiac computed tomographic estimation of CAC scores as part of a general health checkup in addition to completing a self-administered food frequency questionnaire. We assessed the relationship of dietary calcium and phosphorus intake and serum levels with CAC scores using both multivariate-adjusted Tobit models and multinomial logistic regression models. Neither dietary calcium nor phosphorus intake was consistently associated with CAC scores. However, the serum calcium, phosphorus, and calcium-phosphorus product levels were significantly associated with the CAC score ratios. In multivariable-adjusted models, the CAC score ratios (95% confidence intervals) comparing the highest quartiles of serum calcium, phosphorus, and calcium-phosphorus product levels to the lowest quartiles were 1.89 (1.36-2.64), 3.33 (2.55-4.35), and 3.98 (3.00-5.28), respectively (P for trend <0.001). CONCLUSIONS: Elevated serum levels of calcium, phosphorus, and calcium-phosphorus product, but not dietary consumption, are associated with increased CAC scores. Our findings should be explored in further research.