The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing at an alarming rate. Elevated liver enzymes are a primary reason to refer patients for further... Show moreThe prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing at an alarming rate. Elevated liver enzymes are a primary reason to refer patients for further testing. However, liver enzymes within the normal range do not exclude the presence of MASLD. We examined the prevalence of MASLD in a middle-aged population with overweight and normal liver enzymes. In addition, we examined the accuracy of 4 sets of noninvasive proxies for MASLD.We included 1017 participants from the Netherlands epidemiology of obesity cohort study with body mass index ≥25 kg/m2 and liver enzymes (asparate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidase) within normal range. The diagnostic accuracy of biomarker scores (fatty liver index, liver fat score [LFS], STEATO-ELSA, and hepatic steatosis index) was determined against elevated hepatic triglyceride content measured by 1proton magnetic resonance spectroscopy.Participants (mean age 56 years, 49% women), had a median body mass index of 29.6 kg/m2 and a median hepatic triglyceride content of 4.4%. MASLD was present in 42% of participants and was more common in men than women, with respectively 47% and 36% being affected. The LFS showed the highest accuracy with an area under the curve of 0.72. We identified metabolic syndrome as the prime predictor for MASLD with an odds ratio of 2.95 (95% confidence interval 2.20–3.98).The prevalence of MASLD in middle-aged men and women with overweight and liver enzymes within the normal range is over 40%. LFS showed the highest accuracy to detect MASLD, but, overall, biomarker scores performed relatively poor. The presence of metabolic syndrome was the prime predictor of MASLD. Show less
Velde, J.H.P.M. van der; Boone, S.C.; Winters-van Eekelen, E.; Hesselink, M.K.C.; Schrauwen-Hinderling, V.B.; Schrauwen, P.; ... ; Mutsert, R. de 2022
Aims/hypothesis We hypothesised that the insulin-sensitising effect of physical activity depends on the timing of the activity. Here, we examined cross-sectional associations of breaks in sedentary... Show moreAims/hypothesis We hypothesised that the insulin-sensitising effect of physical activity depends on the timing of the activity. Here, we examined cross-sectional associations of breaks in sedentary time and timing of physical activity with liver fat content and insulin resistance in a Dutch cohort.Methods In 775 participants of the Netherlands Epidemiology of Obesity (NEO) study, we assessed sedentary time, breaks in sedentary time and different intensities of physical activity using activity sensors, and liver fat content by magnetic resonance spectroscopy (n=256). Participants were categorised as being most active in the morning (06:00-12:00 hours), afternoon (12:0018:00 hours) or evening (18:00-00:00 hours) or as engaging in moderate-to-vigorous-physical activity (MVPA) evenly distributed throughout the day. Most active in a certain time block was defined as spending the majority (%) of total daily MVPA in that block. We examined associations between sedentary time, breaks and timing of MVPA with liver fat content and HOMA-IR using linear regression analyses. adjusted for demographic and lifestyle factors including total body fat. Associations of timing of MVPA were additionally adjusted for total MVPA.Results The participants (42% men) had a mean (SD) age of 56 (4) years and a mean (SD) BMI of 26.2 (4.1) kg/m(2). Total sedentary time was not associated with liver fat content or insulin resistance, whereas the amount of breaks in sedentary time was associated with higher liver fat content. Total MVPA (-5%/h [95% CI -10%/h, 0%/h]) and timing of MVPA were associated with reduced insulin resistance but not with liver fat content. Compared with participants who had an even distribution of MVPA throughout the day. insulin resistance was similar (-3% [95% CI -25%, 16%]) in those most active in morning, whereas it was reduced in participants who were most active in the afternoon (-18% [95% CI -33%, -2%]) or evening (-25% [95% CI -49%, -4%]).Conclusions/interpretation The number of daily breaks in sedentary time was not associated with lower liver fat content or reduced insulin resistance. Moderate-to-vigorous activity in the afternoon or evening was associated with a reduction of up to 25% in insulin resistance. Further studies should assess whether timing of physical activity is also important for the occurrence of type 2 diabetes. Show less
Boone, S.C.; Smeden, M. van; Rosendaal, F.R.; Cessie, S. le; Groenwold, R.H.H.; Jukema, J.W.; ... ; Mutsert, R. de 2022
Visceral adipose tissue (VAT) is a strong prognostic factor for cardiovascular disease and a potential target for cardiovascular risk stratification. Because VAT is difficult to measure in clinical... Show moreVisceral adipose tissue (VAT) is a strong prognostic factor for cardiovascular disease and a potential target for cardiovascular risk stratification. Because VAT is difficult to measure in clinical practice, we estimated prediction models with predictors routinely measured in general practice and VAT as outcome using ridge regression in 2,501 middle-aged participants from the Netherlands Epidemiology of Obesity study, 2008-2012. Adding waist circumference and other anthropometric measurements on top of the routinely measured variables improved the optimism-adjusted R-2 from 0.50 to 0.58 with a decrease in the root-mean-square error (RMSE) from 45.6 to 41.5 cm(2) and with overall good calibration. Further addition of predominantly lipoprotein-related metabolites from the Nightingale platform did not improve the optimism-corrected R-2 and RMSE. The models were externally validated in 370 participants from the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS, 2006-2009) and 1,901 participants from the Multi-Ethnic Study of Atherosclerosis (MESA, 2000-2007). Performance was comparable to the development setting in PIVUS (R-2 = 0.63, RMSE = 42.4 cm(2), calibration slope = 0.94) but lower in MESA (R-2 = 0.44, RMSE = 60.7 cm(2), calibration slope = 0.75). Our findings indicate that the estimation of VAT with routine clinical measurements can be substantially improved by incorporating waist circumference but not by metabolite measurements. Show less
Winters-Van Eekelen, E.; Velde, J.H.P.M. van der; Boone, S.C.; Westgate, K.; Brage, S.; Lamb, H.J.; ... ; Mutsert, R. de 2021
Purpose: It remains unclear to what extent habitual physical activity and sedentary time (ST) are associated with visceral fat and liver fat. We studied the substitution of ST with time spent... Show morePurpose: It remains unclear to what extent habitual physical activity and sedentary time (ST) are associated with visceral fat and liver fat. We studied the substitution of ST with time spent physically active and total body fat (TBF), visceral adipose tissue (VAT), and hepatic triglyceride content (HTGC) in middle-age men and women. Design: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study, physical activity was assessed in 228 participants using a combined accelerometer and heart rate monitor. TBF was assessed by the Tanita bioelectrical impedance, VAT by magnetic resonance imaging, and HTGC by proton-MR spectroscopy. Behavioral intensity distribution was categorized as ST, time spent in light physical activity (LPA), and moderate to vigorous physical activity (MVPA). To estimate the effect of replacing 30 min.d(-1) of ST with 30 min.d(-1) LPA or MVPA, we performed isotemporal substitution analyses, adjusted for sex, age, ethnicity, education, the Dutch Healthy Diet index, and smoking. Results: Included participants (41% men) had a mean +/- SD age of 56 +/- 6 yr and spent 88 +/- 56 min in MVPA and 9.0 +/- 2.1 h of ST. Replacing 30 min.d(-1) of ST with 30 min of MVPA was associated with 1.3% less TBF (95% confidence interval = -2.0 to -0.7), 7.8 cm(2) less VAT (-11.6 to -4.0), and 0.89 times HTGC (0.82-0.97). Replacement with LPA was not associated with TBF (-0.03%; -0.5 to 0.4), VAT (-1.7 cm(2); -4.4 to 0.9), or HTGC (0.98 times; 0.92-1.04). Conclusions: Reallocation of time spent sedentarywith time spent inMVPA, but not LPA, was associated with less TBF, visceral fat, and liver fat. These findings contribute to the development of more specified guidelines on ST and physical activity. Show less
Pulse wave velocity (PWV) assessed by magnetic resonance imaging (MRI) is a prognostic marker for cardiovascular events. Prediction modelling could enable indirect PWV assessment based on clinical... Show morePulse wave velocity (PWV) assessed by magnetic resonance imaging (MRI) is a prognostic marker for cardiovascular events. Prediction modelling could enable indirect PWV assessment based on clinical and anthropometric data. The aim was to calculate estimated-PWV (ePWV) based on clinical and anthropometric measures using linear ridge regression as well as a Deep Neural Network (DNN) and to determine the cut-off which provides optimal discriminative performance between lower and higher PWV values. In total 2254 participants from the Netherlands Epidemiology of Obesity study were included (age 45-65 years, 51% male). Both a basic and expanded prediction model were developed. PWV was estimated using linear ridge regression and DNN. External validation was performed in 114 participants (age 30-70 years, 54% female). Performance was compared between models and estimation accuracy was evaluated by ROC-curves. A cut-off for optimal discriminative performance was determined using Youden's index. The basic ridge regression model provided an adjusted R-2 of 0.33 and bias of < 0.001, the expanded model did not add predictive performance. Basic and expanded DNN models showed similar model performance. Optimal discriminative performance was found for PWV < 6.7 m/s. In external validation expanded ridge regression provided the best performance of the four models (adjusted R-2: 0.29). All models showed good discriminative performance for PWV < 6.7 m/s (AUC range 0.81-0.89). ePWV showed good discriminative performance with regard to differentiating individuals with lower PWV values (< 6.7 m/s) from those with higher values, and could function as gatekeeper in selecting patients who benefit from further MRI-based PWV assessment. Show less
Vanweert, F.; Boone, S.C.; Brouwers, B.; Mook-Kanamori, D.O.; Mutsert, R. de; Rosendaal, F.R.; ... ; Phielix, E. 2021
Aims To evaluate whether the association between plasma branched-chain amino acids (BCAA) and intrahepatic lipid (IHL) was affected by physical activity level. Furthermore, to investigate if a... Show moreAims To evaluate whether the association between plasma branched-chain amino acids (BCAA) and intrahepatic lipid (IHL) was affected by physical activity level. Furthermore, to investigate if a conventional exercise training program, a subcategory of physical activity, could lower plasma BCAA along with alterations in IHL content in patients with type 2 diabetes (T2DM) and people with nonalcoholic fatty liver (NAFL).Methods To investigate the effect of physical activity on the association between plasma BCAA and IHL content, linear regression analyses were performed in 1983 individuals from the Netherlands Epidemiology of Obesity (NEO) stratified by physical activity frequency. Furthermore, the effect of a 12-week supervised combined aerobic resistance-exercise program on plasma BCAA, insulin sensitivity (hyperinsulinemic-euglycemic clamp), and IHL (proton-magnetic resonance spectroscopy (H-1-MRS)) was investigated in seven patients with T2DM, seven individuals with NAFL and seven BMI-matched control participants (CON).Results We observed positive associations between plasma valine, isoleucine and leucine level, and IHL content (1.29 (95% CI: 1.21, 1.38), 1.52 (95% CI: 1.43, 1.61), and 1.54 (95% CI: 1.44, 1.64) times IHL, respectively, per standard deviation of plasma amino acid level). Similar associations were observed in less active versus more active individuals. Exercise training did not change plasma BCAA levels among groups, but reduced IHL content in NAFL (from 11.6 +/- 3.0% pre-exercise to 8.1 +/- 2.0% post exercise, p < 0.05) and CON (from 2.4 +/- 0.6% pre-exercise to 1.6 +/- 1.4% post exercise, p < 0.05), and improved peripheral insulin sensitivity in NAFL as well by similar to 23% (p < 0.05).Conclusions The association between plasma BCAA levels and IHL is not affected by physical activity level. Exercise training reduced IHL without affecting plasma BCAA levels in individuals with NAFL and CON. We conclude that exercise training-induced reduction in IHL content is not related to changes in plasma BCAA levels. Show less
Neeland, I.J.; Boone, S.C.; Mook-Kanamori, D.O.; Ayers, C.; Smit, R.A.J.; Tzoulaki, I.; ... ; Mutsert, R. de 2019
Background-Identifying associations between serum metabolites and visceral adipose tissue (VAT) could provide novel biomarkers of VAT and insights into the pathogenesis of obesity-related diseases.... Show moreBackground-Identifying associations between serum metabolites and visceral adipose tissue (VAT) could provide novel biomarkers of VAT and insights into the pathogenesis of obesity-related diseases. We aimed to discover and replicate metabolites reflecting pathways related to VAT.Methods and Results-Associations between fasting serum metabolites and VAT area (by computed tomography or magnetic resonance imaging) were assessed with cross-sectional linear regression of individual-level data from participants in MESA (Multi-Ethnic Study of Atherosclerosis; discovery, N=1103) and the NEO (Netherlands Epidemiology of Obesity) study (replication, N=2537). Untargeted H-1 nuclear magnetic resonance metabolomics profiling of serum was performed in MESA, and metabolites were replicated in the NEO study using targeted H-1 nuclear magnetic resonance spectroscopy. A total of 30 590 metabolomic spectral variables were evaluated. After adjustment for age, sex, race/ethnicity, socioeconomic status, smoking, physical activity, glucose/lipid-lowering medication, and body mass index, 2104 variables representing 24 nonlipid and 49 lipid/lipoprotein subclass metabolites remained significantly associated with VAT (P=4.88 x 10(-20)-1.16 x 10(-3)). These included conventional metabolites, amino acids, acetylglycoproteins, intermediates of glucose and hepatic metabolism, organic acids, and subclasses of apolipoproteins, cholesterol, phospholipids, and triglycerides. Metabolites mapped to 31 biochemical pathways, including amino acid substrate use/metabolism and glycolysis/gluconeogenesis. In the replication cohort, acetylglycoproteins, branched-chain amino acids, lactate, glutamine (inversely), and atherogenic lipids remained associated with VAT (P=1.90 x 10(-35)-8.46 x 10(-7)), with most associations remaining after additional adjustment for surrogates of VAT (glucose level, waist circumference, and serum triglycerides), reflecting novel independent associations.Conclusions-We identified and replicated a metabolite panel associated with VAT in 2 community-based cohorts. These findings persisted after adjustment for body mass index and appear to define a metabolic signature of visceral adiposity. Show less
Boone, S.C.; Cessie, S. le; Dijk, K.W. van; Mutsert, R. de; Mook-Kanamori, D.O. 2019
