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Background and purpose Prior studies reported conflicting findings regarding the association of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis with measures of brain health. We examined whether NAFLD and liver fibrosis are associated with structural brain imaging measures in middle‐ and old‐age adults. Methods In this cross‐sectional study among dementia‐ and stroke‐free individuals, data were pooled from the Offspring and Third Generation cohorts of the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Study of Health in Pomerania. NAFLD was assessed through abdominal imaging. Transient hepatic elastography (FibroScan) was used to assess liver fibrosis in FHS and RS. Linear regression models were used to explore the relation of NAFLD and liver fibrosis with brain volumes, including total brain, gray matter, hippocampus, and white matter hyperintensities, adjusting for potential confounders. Results were combined using fixed effects meta‐analysis. Results In total, 5660 and 3022 individuals were included for NAFLD and liver fibrosis analyses, respectively. NAFLD was associated with smaller volumes of total brain (β = −3.5, 95% confidence interval [CI] = −5.4 to −1.7), total gray matter (β = −1.9, 95% CI = −3.4 to −0.3), and total cortical gray matter (β = −1.9, 95% CI = −3.7 to −0.01). In addition, liver fibrosis (defined as liver stiffness measure ≥8.2 kPa) was related to smaller total brain volumes (β = −7.3, 95% CI = −11.1 to −3.5). Heterogeneity between studies was low. Conclusions NAFLD and liver fibrosis may be directly related to brain aging. Larger and prospective studies are warranted to validate these findings and identify liver‐related preventive strategies for neurodegeneration.

To establish age- and sex-specific distribution of the infrarenal abdominal aortic diameters (IAD) among non-aneurysmal elderly population and to investigate the associations between traditional cardiovascular risk factors and IAD in men and women. We included 4032 participants (mean age 67.2 years; 60.4% women) from the population-based Rotterdam Study, free of cardiovascular disease, who underwent IAD ultrasound assessment between 2009–2014. Linear regression analysis was used to identify determinants of IAD. The medians (inter-quartile range) of absolute IAD and body surface area (BSA)-adjusted IAD were 17.0 (15.0–18.0) mm and 9.3 (8.5–10.2) mm for women and 19.0 (18.0–21.0) mm and 9.4 (8.6–10.3) mm for men, respectively. There was a non-linear relationship between age and IAD. IAD increased steeply with advancing age and up to 70 years. After around 75 years of age, the diameter values reached a plateau. Waist circumference and diastolic blood pressure were associated with larger diameters in both sexes. Body mass index [Effect estimate (95% CI): 0.04 (0.00 to 0.08)], systolic blood pressure [− 0.01(− 0.02 to 0.00)], current smoking [0.35 (0.06 to 0.65)], total cholesterol levels [− 0.21 (− 0.31 to − 0.11)], and lipid-lowering medication [− 0.43 (− 0.67 to − 0.19)] were significantly associated with IAD in women. Sex differences in IAD values diminished after taking BSA into account. The increase in diameters was attenuated after 70 years. Differences were observed in the associations of several cardiovascular risk factors with IAD among men and women.

The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the city of Rotterdam, The Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. The study focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1700 research articles and reports. This article provides an update on the rationale and design of the study. It also presents a summary of the major findings from the preceding 3 years and outlines developments for the coming period.

The disease burden of nonalcoholic fatty liver disease (NAFLD) increases rapidly, in line with the obesity pandemic. Physical activity has been linked to a lower risk of NAFLD. However, the impact of different intensities of activity and sedentary behavior and whether their effects on NAFLD are explained by metabolic health remain unclear. We performed cross-sectional analyses within the population-based Rotterdam Study cohort. Abdominal ultrasound and accelerometry data were collected between 2009 and 2014. NAFLD was defined as hepatic steatosis diagnosed by ultrasound, in the absence of secondary causes for steatosis: viral hepatitis, steatogenic drugs, and excessive alcohol. We categorized accelerometry data into sedentary time and light, moderate, and vigorous physical activities. We included 667 participants (aged 63.3 ± 6.3 years, 53% female individuals), and 34.3% had NAFLD. Total physical activity was associated with lower NAFLD prevalence adjusted for demographic, lifestyle, and socioeconomic factors (odds ratio: 0.958 per 10 min/d, 95% confidence interval [CI]: 0.929-0.986). More intensive physical activity was more strongly associated with lower NAFLD prevalence: odds ratios for light, moderate, and vigorous physical activities were 0.931 (95% CI: 0.882-0.982), 0.891 (95% CI: 0.820-0.967), and 0.740 (95% CI: 0.600-0.906) per 10 min/d, respectively. These associations were explained by metabolic health, particularly homeostatic model assessment of insulin resistance (proportion mediated: 0.59, P < 0.001) and waist circumference (proportion mediated: 1.08, P < 0.001). Beyond this indirect effect, no direct effect could be demonstrated (P = 0.282-0.827). Physical activity at each intensity is inversely associated with NAFLD prevalence, with larger effects for higher intensities of physical activity. This association is mediated by better metabolic health, mainly lower insulin resistance and waist circumference. Physical activity should therefore be incorporated into NAFLD disease management and prevention programs.

Background. Chronic hepatitis C virus (HCV) infection is a global health problem, resulting in liver failure, hepatocellular carcinoma, and liver-related death. Natural killer (NK) cells are innate immune cells, and their activity is known to correlate to viral treatment response of HCV. In this study, we investigate the immune effects of viral load decline with direct-acting antivirals (DAAs) in blood. Methods. Twelve patients with chronic HCV were treated with asunaprevir and daclatasvir, and peripheral blood was analyzed at various time points during therapy. Results. In line with previous studies, we confirmed restoration of HCV-specific T-cell frequency upon viral load decline. In addition, we show that serum interferon (IFN)-γ inducible-protein 10, interleukin (IL)–12p40, and IL-18 levels decreased early after start of therapy. Surface expression of activation receptors NKp30, NKp46, and inhibitory receptor NKG2A on blood NK cells reduced during therapy. In addition, the expression of TRAIL on NK cells was reduced during IFN-free therapy, suggesting a decrease in TRAIL-mediated killing by NK cells. Conclusions. We show that viral load decline as a consequence of treatment with novel DAAs in chronic HCV patients reduces serum levels of NK cell–stimulating cytokines and causes correction of the altered NK cell phenotype observed in chronic HCV patients. Clinical Trials Registration. NCT02282709.

Accumulating evidence shows that NAFLD might play a role in the etiology and progression of CVD, but little is known on the association of NAFLD and CVD mortality in patients with a history of a myocardial infarction (MI). Therefore, we studied the relationship of Fatty Liver Index (FLI), as indicator for non-alcoholic fatty liver disease (NAFLD), with 12-year risk of cardiovascular disease (CVD) and all-cause mortality in post-MI patients. We included 4165 Dutch patients from the Alpha Omega Cohort aged 60–80 years who had an MI ≤10 years prior to study enrolment. NAFLD was defined as FLI ≥60. Patients were followed for cause-specific mortality from enrolment (2002–2006) through December 2018. Hazard ratios for CVD and all-cause mortality were obtained by multivariable Cox regression using FLI <30 (indicating absence of NAFLD) as the reference. Baseline FLI as a continuous measure was studied with mortality using restricted cubic splines analyses. The median (IQR) FLI was 68 (48–84). Sixty percent of the patients had FLI ≥60, who were more likely to be male and more often had diabetes, high blood pressure, and high serum cholesterol levels. During 12 years of follow-up, 2042 deaths occurred of which 846 from CVD. Patients with NAFLD were at increased risk of CVD mortality (HR: 1.55 [1.19, 2.03]) and all-cause mortality (HR: 1.21 [1.03; 1.41]) compared to patients without NAFLD. Results remained consistent after excluding patients with obesity and diabetes. To conclude, the adverse association of FLI with CVD mortality was stronger in female than in male patients with conventional cut-off points. FLI ≥60, indicating NAFLD, was a predictor for CVD and all-cause mortality in post-MI patients, independent of other cardiometabolic risk factors. However, cut-off points might differ between male and female patients for predicting CVD mortality.

Thrombocytopenia (platelet count <150 × 10 9 /L) often complicates chronic liver disease, impeding optimal management of these patients. The prevalence of this manifestation ranges from 6 % among non-cirrhotic patients with chronic liver disease to 70 % among patients with liver cirrhosis. It has also been shown that the severity of liver disease is associated with both prevalence and level of thrombocytopenia. Its development is often multifactorial, although thrombopoietin is thought to be a major factor. The discovery of and ability to clone thrombopoietin led to new treatment opportunities for this clinical manifestation. This review discusses data on the three most important thrombopoietin receptor agonists: eltrombopag, avatrombopag, and romiplostim. Currently, only eltrombopag is approved for usage among patients with thrombocytopenia and chronic hepatitis C virus infection in order to initiate and maintain interferon-based antiviral treatment. Nevertheless, the optimal management of hematologic abnormalities among patients with chronic liver disease, and its risk for bleeding complications, is still a matter of discussion. Thrombocytopenia definitely contributes to hemostatic defects but is often counterbalanced by the enhanced presence of procoagulant factors. Therefore, a thorough assessment of the patient’s risk for thrombotic events is essential when the use of thrombopoietin receptor agonists is considered among patients with chronic liver disease and thrombocytopenia.

Dietary lifestyle intervention is key in treating non-alcoholic fatty liver disease (NAFLD). We aimed to examine the longitudinal relation between well-established dietary patterns as well as population-specific dietary patterns and NAFLD. Participants from two subsequent visits of the Rotterdam Study were included. All underwent serial abdominal ultrasonography (median follow-up: 4.4 years) and filled in a food frequency questionnaire. Secondary causes of steatosis were excluded. Dietary data from 389 items were collapsed into 28 food groups and a posteriori dietary patterns were identified using factor analysis. Additionally, we scored three a priori dietary patterns (Mediterranean Diet Score, Dutch Dietary Guidelines and WHO-score). Logistic mixed regression models were used to examine the relation between dietary patterns and NAFLD. Analyses were adjusted for demographic, lifestyle and metabolic factors. We included 963 participants of whom 343 had NAFLD. Follow-up data was available in 737 participants. Incident NAFLD was 5% and regressed NAFLD was 30%. We identified five a posteriori dietary patterns (cumulative explained variation [R 2 ] = 20%). The patterns were characterised as: vegetable and fish , red meat and alcohol , traditional , salty snacks and sauces , high fat dairy & refined grains pattern . Adherence to the traditional pattern (i.e. high intake of vegetable oils/stanols, margarines/butters, potatoes, whole grains and sweets/desserts) was associated with regression of NAFLD per SD increase in Z-score (0.40, 95% CI 0.15–1.00). Adherence to the three a priori patterns all showed regression of NAFLD, but only the WHO-score showed a distinct association (0.73, 95% CI 0.53–1.00). Hence, in this large elderly population, adherence to a plant-based, high-fibre and low-fat diet was related to regression of NAFLD.

Mucosal-associated invariant T (MAIT) cells comprise a subpopulation of T cells that can be activated by bacterial products and cytokines to produce IFN-γ. Since little is known on MAIT cells during HCV infection, we compared their phenotype and function in comparison to HIV and HCV/HIV co-infected patients, and determined the effect of IFN-α-based and direct-acting antiviral therapy on MAIT cells of HCV patients. Blood samples from patients with chronic HCV (CHCV), virologically suppressed HIV, acute HCV/HIV co-infection (AHCV/HIV) and healthy individuals were examined by flowcytometry for phenotype and function of MAIT and NK cells. Compared to healthy individuals, the frequency of CD161+Vα7.2+ MAIT cells was significantly decreased in patients with CHCV, HIV and AHCV/HIV co-infection. CD38 expression on MAIT cells was increased in AHCV/HIV patients. MAIT cells were responsive to IFN-α in vitro as evidenced by enhanced frequencies of IFN-γ producing cells. IFN-α-based therapy for CHCV decreased the frequency of IFN-γ+ MAIT cells, which was still observed 24 weeks after successful therapy. Importantly, even after successful IFN-α-based as well as IFN-α-free therapy for CHCV, decreased frequencies of MAIT cells persisted. We show that the frequencies of MAIT cells are reduced in blood of patients with CHCV, HIV and in AHCV/HIV co-infection compared to healthy individuals. Successful therapy for CHCV did not normalize MAIT cell frequencies at 24 weeks follow up. The impact of HIV and HCV infection on the numbers and function of MAIT cells warrant further studies on the impact of viral infections and the antimicrobial function of MAIT cells.

Treatment of hepatitis C virus infections (HCV) with direct acting antivirals (DAA) can prevent new infections since cured individuals cannot transmit HCV. However, as DAAs are expensive, many countries defer treatment to advances stages of fibrosis, which results in ongoing transmission. We assessed the epidemiological impact and cost-effectiveness of treatment initiation in different stages of infection in the Netherlands where the epidemic is mainly concentrated among HIV-infected MSMs. We calibrated a deterministic mathematical model to the Dutch HCV epidemic among HIV-infected MSM to compare three different DAA treatment scenarios: 1) immediate treatment, 2) treatment delayed to chronic infection allowing spontaneous clearance to occur, 3) treatment delayed until F2 fibrosis stage. All scenarios are simulated from 2015 onwards. Total costs, quality adjusted life years (QALY), incremental cost-effectiveness ratios (ICERs), and epidemiological impact were calculated from a providers perspective over a lifetime horizon. We used a DAA price of €35,000 and 3% discounting rates for cost and QALYs. Immediate DAA treatment lowers the incidence from 1.2/100 person-years to 0.2/100 person-years (interquartile range 0.1-0.2) and the prevalence from 5.0/100 person-years to 0.5/100 person-years (0.4-0.6) after 20 years. Delayed treatment awaiting spontaneous clearance will result in a similar reduction. However, further delayed treatment to F2 will increases the incidence and prevalence. Earlier treatment will cost society €68.3 and €75.1 million over a lifetime for immediate and awaiting until the chronic stage, respectively. The cost will increase if treatment is further delayed until F2 to €98.4 million. Immediate treatment will prevent 7070 new infections and gains 3419 (3019-3854) QALYs compared to F2 treatment resulting in a cost saving ICER. Treatment in the chronic stage is however dominated. Early DAA treatment for HIV-infected MSM is an excellent and sustainable tool to meet the WHO goal of eliminating HCV in 2030.