IGF-1 as screening tool for acromegaly and adult-onset growth hormone deficiency in the Netherlands.

OBJECTIVE: Insulin-like growth factor 1 (IGF-1) measurements play a central role in the diagnosis and follow-up of acromegaly and growth hormone deficiency. However, improving health care outcomes for these patients involves an intricate process of laboratory diagnostics and skilled health care professionals. The integrated effects of IGF-1 reports on diagnosis and treatment decisions are yet unknown. DESIGN, PATIENTS AND MEASUREMENTS: Extended quality assessment, distributing the description of five (real) patient cases with accompanying blood samples. Patients suspected or during follow up for acromegaly or adult onset of growth hormone deficiency were included. Laboratory specialists and endocrinologists in the same centre were asked to interpret their centre-specific IGF-1 results by using a laboratory and medical questionnaire. This way, insight could be obtained into the combined effects of different assays, assay harmonisation, reference value sets, and individual physician interpretation in relation to guidelines, thus reviewing the entire diagnostic and management process. RESULTS: Limited variation (CV 13.8 ± 2.8) was found in IGF-1 concentrations despite different use of the harmonization sample and factor among laboratories. This interlaboratory variation increased upon conversion to SD scores (CV 15.7 ± 40.7) as a consequence of the use of different reference value sets. Furthermore, there was a lack of adherence to international guidelines among endocrinologists. CONCLUSIONS: Highly variable diagnostic and treatment outcomes in acromegaly and AGHD in the Netherlands can be attributed to increased variability of IGF-1 upon conversion to SD scores and low adherence to clinical guidelines.

Hypothyroidism, comorbidity and health-related quality of life: a population-based study.

Hypothyroidism is associated with a decreased health-related quality of life (HRQoL). We hypothesized that individuals with hypothyroidism (defined as use of thyroid hormone (TH)) and especially those having an impaired HRQoL are characterized by a high prevalence of comorbid disorders and that the impact of hypothyroidism and comorbidity on HRQoL is synergistic. Presence of comorbidity was based on data obtained using structured questionnaires, physical examination, biochemical measurements and verified medication use. Single morbidities were clustered into 14 different disease domains. HRQoL was measured using the RAND-36. Logistic regression analyses were used to determine the effect of TH use on the odds of having an affected disease domain and a lower score than an age- and sex-specific reference value for HRQoL. TH was used by 4537/14,7201 participants of the population-based Lifelines cohort with a mean (± s.d.) age of 51.0 ± 12.8 years (88% females). Eighty-five percent of the TH users had ≥1 affected disease domain in contrast to 71% of nonusers. TH use was associated with a higher odds of 13 out of 14 affected disease domains independent of age and sex. In a multivariable model, TH use was associated with a decreased HRQoL across six out of eight dimensions. No significant interactions between TH use and affected disease domains were observed. TH users with an impaired HRQoL had significantly more comorbidity than those not having an impaired HRQoL. In this large, population-based study, we demonstrated that TH users had more comorbidity than individuals not using TH. The coexistence of other chronic medical conditions in subjects with TH use led to further lowering of HRQoL in an additive manner.

Differences in lipid and blood pressure measurements between individuals with type 1 diabetes and the general population: a cross-sectional study.

OBJECTIVES: Cardiovascular disease (CVD) is a precarious complication of type 1 diabetes (T1D). Alongside glycaemic control, lipid and blood pressure (BP) management are essential for the prevention of CVD. However, age-specific differences in lipid and BP between individuals with T1D and the general population are relatively unknown. DESIGN: Cross-sectional study. SETTING: Six diabetes outpatient clinics and individuals from the Lifelines cohort, a multigenerational cohort from the Northern Netherlands. PARTICIPANTS: 2178 adults with T1D and 146 22 individuals without diabetes from the general population. PRIMARY AND SECONDARY OUTCOME MEASURES: Total cholesterol, low-density lipoprotein cholesterol (LDL-cholesterol), systolic BP (SBP) and diastolic BP (DBP), stratified by age group, glycated haemoglobin category, medication use and sex. RESULTS: In total, 2178 individuals with T1D and 146 822 without diabetes were included in this study. Total cholesterol and LDL-cholesterol were lower and SBP and DBP were higher in individuals with T1D in comparison to the background population. When stratified by age and medication use, total cholesterol and LDL-cholesterol were lower and SBP and DBP were higher in the T1D population. Men with T1D achieved lower LDL-cholesterol levels both with and without medication in older age groups in comparison to women. Women with T1D had up to 8 mm Hg higher SBP compared with the background population, this difference was not present in men. CONCLUSIONS: Lipid and BP measurements are not comparable between individuals with T1D and the general population and are particularly unfavourable for BP in the T1D group. There are potential sex differences in the management of LDL-cholesterol and BP.

Type 1 diabetes management: Room for improvement.

AIMS/HYPOTHESIS: Optimal diabetes care and risk factor management are important to delay micro- and macrovascular complications in individuals with type 1 diabetes (T1D). Ongoing improvement of management strategies requires the evaluation of target achievement and identification of risk factors in individuals who do (or do not) achieve these targets. METHODS: Cross-sectional data were collected from adults with T1D visiting six diabetes centers in the Netherlands in 2018. Targets were defined as glycated hemoglobin (HbA1c) <53 mmol/mol, low-density lipoprotein-cholesterol (LDL-c) <2.6 mmoL/L (no cardiovascular disease [CVD] present) or <1.8 mmoL/L (CVD present), or blood pressure (BP) <140/90 mm Hg. Target achievement was compared for individuals with and without CVD. RESULTS: Data from 1737 individuals were included. Mean HbA1c was 63 mmol/mol (7.9%), LDL-c was 2.67 mmoL/L, and BP 131/76 mm Hg. In individuals with CVD, 24%, 33%, and 46% achieved HbA1c, LDL-c, and BP targets respectively. In individuals without CVD these percentages were 29%, 54%, and 77%, respectively. Individuals with CVD did not have any significant risk factors for HbA1c, LDL-c, and BP target achievement. In comparison, individuals without CVD were more likely to achieve glycemic targets if they were men and insulin pump users. Smoking, microvascular complications, and the prescription of lipid-lowering and antihypertensive medication were negatively associated with glycemic target achievement. No characteristics were associated with LDL-c target achievement. Microvascular complications and antihypertensive medication prescription were negatively associated with BP target attainment. CONCLUSION: Opportunities for improvement of diabetes management exist for the achievement of glycemic, lipid, and BP targets but may differ between individuals with and without CVD.

Genome-wide association study identifies novel loci associated with skin autofluorescence in individuals without diabetes.

BACKGROUND: Skin autofluorescence (SAF) is a non-invasive measure reflecting accumulation of advanced glycation endproducts (AGEs) in the skin. Higher SAF levels are associated with an increased risk of developing type 2 diabetes and cardiovascular disease. An earlier genome-wide association study (GWAS) revealed a strong association between NAT2 variants and SAF. The aim of this study was to calculate SAF heritability and to identify additional genetic variants associated with SAF through genome-wide association studies (GWAS). RESULTS: In 27,534 participants without diabetes the heritability estimate of lnSAF was 33% ± 2.0% (SE) in a model adjusted for covariates. In meta-GWAS for lnSAF five SNPs, on chromosomes 8, 11, 15 and 16 were associated with lnSAF (P < 5 × 10-8): 1. rs2846707 (Chr11:102,576,358,C > T), which results in a Met30Val missense variant in MMP27 exon 1 (NM_022122.3); 2. rs2470893 (Chr15:75,019,449,C > T), in intergenic region between CYP1A1 and CYP1A2; with attenuation of the SNP-effect when coffee consumption was included as a covariate; 3. rs12931267 (Chr16:89,818,732,C > G) in intron 30 of FANCA and near MC1R; and following conditional analysis 4. rs3764257 (Chr16:89,800,887,C > G) an intronic variant in ZNF276, 17.8 kb upstream from rs12931267; finally, 30 kb downstream from NAT2 5. rs576201050 (Chr8:18,288,053,G > A). CONCLUSIONS: This large meta-GWAS revealed five SNPs at four loci associated with SAF in the non-diabetes population. Further unravelling of the genetic architecture of SAF will help in improving its utility as a tool for screening and early detection of diseases and disease complications.

A non-invasive risk score including skin autofluorescence predicts diabetes risk in the general population.

Increased skin autofluorescence (SAF) predicts the development of diabetes-related complications and cardiovascular disease. We assessed the performance of a simple model which includes SAF to identify individuals at high risk for undiagnosed and incident type 2 diabetes, in 58,377 participants in the Lifelines Cohort Study without known diabetes. Newly-diagnosed diabetes was defined as fasting blood glucose ≥ 7.0 mmol/l and/or HbA1c ≥ 6.5% (≥ 48 mmol/mol) or self-reported diabetes at follow-up. We constructed predictive models based on age, body mass index (BMI), SAF, and parental history of diabetes, and compared to results with the concise FINDRISC model. At 2nd visit to Lifelines, 1113 (1.9%) participants were identified with undiagnosed diabetes and 1033 (1.8%) participants developed diabetes during follow-up. A model comprising age, BMI and SAF yielded an AUC of 0.783 and was non-inferior to the concise FINDRISC model, which had an AUC of 0.797 to predict new diabetes. At a score of 5.8, sensitivity was 78% and specificity of 66%. Model 2 which also incorporated parental diabetes history, had an AUC of 0.792, and a sensitivity of 74% and specificity of 70% at a score of 6.5. Net reclassification index (NRI) did not improve significantly (NRI 1.43% (- 0.50-3.37 p = 0.15). The combination of an easy to perform SAF measurement with age and BMI is a good alternative screening tool suitable for medical and non-medical settings. Parental history of diabetes did not significantly improve model performance in this homogeneous cohort.

Plasma carnitine concentrations in Medium-chain acyl-CoA dehydrogenase deficiency: lessons from an observational cohort study.

Our aim was to study the effect of secondary carnitine deficiency (SCD) and carnitine supplementation on important outcome measures for persons with medium-chain Acyl-CoA dehydrogenase deficiency (MCADD). We performed a large retrospective observational study using all recorded visits of persons with MCADD in the University Medical Center Groningen, the Netherlands, between October 1994 and October 2019. Frequency and duration of acute unscheduled preventive hospital visits, exercise tolerance, fatigue, and muscle pain were considered important clinical outcomes and were studied in relation to (acyl)carnitine profile and carnitine supplementation status. The study encompassed 1228 visits of 93 persons with MCADD. >60% had SCD during follow-up. This included only persons with severe MCADD. Carnitine supplementation and SCD were unrelated to the frequency and duration of the acute unscheduled preventive hospital visits (P > 0.05). The relative risk for fatigue, muscle ache, or exercise intolerance was equal between persons with and without SCD (RR 1.6, 95% CI 0.48-5.10, P = 0.4662). No episodes of metabolic crisis were recorded in non-carnitine-supplemented persons with MCADD and SCD. In some persons with MCADD, SCD resolved without carnitine supplementation. There is absence of real-world evidence in favor of routine carnitine analysis and carnitine supplementation in the follow-up of persons with MCADD.

Cardiovascular risk management in people with type 1 diabetes: performance using three guidelines.

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of mortality in individuals with type 1 diabetes mellitus (T1DM). Cardiovascular risk management is therefore essential in the management of individuals with T1DM. This study describes the performance of lipid and blood pressure management in individuals with T1DM using three guidelines. RESEARCH DESIGN AND METHODS: Individuals ≥18 years with T1DM, treated with insulin for ≥1 year, visiting Diabeter or the University Medical Center Groningen between January 1, 2018 and December 31, 2018, were included. Lipid and blood pressure management were examined using the Dutch, American Diabetes Association (ADA) and National Institute for Health and Care Excellence (NICE) guidelines. Concordance of recommended and prescribed lipid-lowering (LLM) or antihypertensive medication (AHM) was assessed per guideline and 10-year age groups. Achievement of treatment targets was assessed for those prescribed medication. RESULTS: A total of 1855 individuals with T1DM were included. LLM and AHM was prescribed in 19% and 17%, respectively. In individuals recommended LLM, this was prescribed in 22%-46% according to Dutch, ADA or NICE guideline recommendations. For individuals recommended AHM, this was prescribed in 52%-75%. Recommended and actual prescription of LLM and AHM increased over age for all three guidelines. However, discordance between treatment recommendation and medication prescribed was higher in younger, compared with older, age groups. Low-density lipoprotein-cholesterol targets were achieved by 50% (without CVD) and 31% (with CVD) of those prescribed LLM. The blood pressure target was achieved by 46% of those prescribed AHM. CONCLUSION: This study suggests that there is undertreatment of lipid and blood pressure according to guideline recommendations, particularly in younger age groups. Treatment targets are not met by most individuals prescribed medication, while guidelines recommendations differ considerably. We recommend to investigate the factors influencing undertreatment of lipid and blood pressure management in individuals with T1DM.

Decreased haemoglobin levels are associated with lower muscle mass and strength in kidney transplant recipients.

BACKGROUND: Post-transplant anaemia and reduced muscle mass and strength are highly prevalent in kidney transplant recipients (KTRs). Decreased haemoglobin levels, a marker of anaemia, could adversely affect muscle mass and strength through multiple mechanisms, among others, through diminished tissue oxygenation. We aimed to investigate the association between haemoglobin levels with muscle mass and strength in KTRs. METHODS: We included stable KTRs from the TransplantLines Biobank and Cohort study with a functional graft ≥1 year post-transplantation. Muscle mass was assessed using 24 h urinary creatinine excretion rate (CER) and bioelectrical impedance analysis (BIA). Muscle strength was assessed with a handgrip strength test using a dynamometer and, in a subgroup (n = 290), with the five-times sit-to-stand (FTSTS) test. We used multivariable linear and logistic regression analyses to investigate the associations of haemoglobin levels with muscle mass and strength. RESULTS: In 871 included KTRs [median age 58 (interquartile range (IQR), 48-66)] years; 60% men; eGFR 51 ± 18 mL/min/1.73 m2 ) who were 3.5 (1.0-10.2) years post-transplantation, the mean serum haemoglobin level was 13.9 ± 1.8 g/dL in men and 12.8 ± 1.5 g/dL in women. Lower haemoglobin levels were independently associated with a lower CER (std. ß = 0.07, P = 0.01), BIA-derived skeletal muscle mass (std. ß = 0.22, P < 0.001), handgrip strength (std. ß = 0.15, P < 0.001), and worse FTSTS test scores (std. ß = -0.17, P = 0.02). KTRs in the lowest age-specific and sex-specific quartile of haemoglobin levels had an increased risk of being in the worst age-specific and sex-specific quartile of CER (fully adjusted OR, 2.09; 95% CI 1.15-3.77; P = 0.02), handgrip strength (fully adjusted OR, 3.30; 95% CI 1.95-5.59; P < 0.001), and FTSTS test score (fully adjusted OR, 7.21; 95% CI 2.59-20.05; P < 0.001). CONCLUSIONS: Low haemoglobin levels are strongly associated with decreased muscle mass and strength in KTRs. Future investigation will need to investigate whether maintaining higher haemoglobin levels may improve muscle mass and strength in KTRs.

Monocytosis and its association with clonal hematopoiesis in community-dwelling individuals.

Monocytosis may occur in numerous inflammatory conditions but is also the defining feature of chronic myelomonocytic leukemia (CMML). Clonal somatic mutations detectable in CMML may occur with aging in otherwise healthy individuals, so-called "clonal hematopoiesis" (CH). We investigated whether the combination of CH and monocytosis would represent an early developmental stage of CMML. We studied community-dwelling individuals with monocytosis (≥1 × 109/L and ≥10% of leukocytes) in the population-based Lifelines cohort (n = 144 676 adults). The prevalence and spectrum of CH were evaluated for individuals ≥60 years with monocytosis (n = 167 [0.8%]), and control subjects 1:3 matched for age and sex (n = 501). Diagnoses of hematological malignancies were retrieved by linkage to the Netherlands Cancer Registry (NCR). Monocyte counts and the prevalence of monocytosis increased with advancing age. Older individuals with monocytosis more frequently carried CH (50.9% vs 35.5%; P < .001). Monocytosis is associated with enrichment of multiple gene mutations (P = .006) and spliceosome mutations (P = .007) but not isolated mutated DNMT3A, TET2, or ASXL1. Persistent monocytosis over 4 years was observed in 30/102 evaluable individuals and associated with a higher prevalence of CH (63%). Myeloid malignancies, including 1 case of CMML, developed in 4 individuals with monocytosis who all carried CH. In conclusion, monocytosis and CH both occur at an older age and do not necessarily reflect clonal monocytic proliferation. In a fraction of older subjects with monocytosis, CH might constitute early clonal dominance in developing malignant myelomonocytic disease. Mutational spectra deviating from age-related CH require attention.

The PRolaCT studies - a study protocol for a combined randomised clinical trial and observational cohort study design in prolactinoma.

BACKGROUND: First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal remission rates are approximately 34%. Therefore, many patients require prolonged DA treatment, while side effects negatively impact health-related quality of life (HRQoL). Endoscopic transsphenoidal resection is reserved for patients with severe side effects, or with DA-resistant prolactinoma. Surgery has a good safety profile and high probability of remission and may thus deserve a more prominent place in prolactinoma treatment. The hypothesis for this study is that early or upfront surgical resection is superior to DA treatment both in terms of HRQoL and remission rate in patients with a non-invasive prolactinoma of limited size. METHODS: We present a combined randomised clinical trial and observational cohort study design, which comprises three unblinded randomised controlled trials (RCTs; PRolaCT-1, PRolaCT-2, PRolaCT-3), and an observational study arm (PRolaCT-O) that compare neurosurgical counselling, and potential subsequent endoscopic transsphenoidal adenoma resection, with current standard care. Patients with a non-invasive prolactinoma (< 25 mm) will be eligible for one of three RCTs based on the duration of pre-treatment with DAs: PRolaCT-1: newly diagnosed, treatment-naïve patients; PRolaCT-2: patients with limited duration of DA treatment (4-6 months); and PRolaCT-3: patients with persisting prolactinoma after DA treatment for > 2 years. PRolaCT-O will include patients who decline randomisation, due to e.g. a clear treatment preference. Primary outcomes are disease remission after 36 months and HRQoL after 12 months. DISCUSSION: Early or upfront surgical resection for patients with a limited-sized prolactinoma may be a reasonable alternative to the current standard practice of DA treatment, which we will investigate in three RCTs and an observational cohort study. Within the three RCTs, patients will be randomised between neurosurgical counselling and standard care. The observational study arm will recruit patients who refuse randomisation and have a pronounced treatment preference. PRolaCT will collect randomised and observational data, which may facilitate a more individually tailored practice of evidence-based medicine. TRIAL REGISTRATION: US National Library of Medicine registry (ClinicalTrials.gov) NCT04107480 . Registered on 27 September 2019, registered retrospectively (by 2 months).

The anemia-independent impact of myelodysplastic syndromes on health-related quality of life.

Myelodysplastic syndromes (MDS) are in the majority of cases characterized by anemia. Both anemia and MDS per se may directly contribute to impairments in health-related quality of life (HRQoL). In this study, we aimed to investigate the anemia-independent impact of MDS on HRQoL. We evaluated participants (≥ 50 years) from the large population-based Lifelines cohort (N = 44,694, mean age 59.0 ± 7.4 years, 43.6% male) and the European MDS Registry (EUMDS) (N = 1538, mean age 73.4 ± 9.0 years, 63.0% male), which comprises a cohort of lower-risk MDS patients. To enable comparison concerning HRQoL, SF-36 scores measured in Lifelines were converted to EQ-5D-3L index (range 0-1) and dimension scores. Lower-risk MDS patients had significantly lower HRQoL than those from the Lifelines cohort, as illustrated in both the index score and in the five different dimensions. Multivariable linear regression analysis demonstrated that MDS had an adjusted total impact on the EQ-5D index score (B = - 0.12, p < 0.001) and an anemia-independent "direct" impact (B = - 0.10, p < 0.001). Multivariable logistic regression analysis revealed an anemia-independent impact of MDS in the dimension mobility, self-care, usual activities, and anxiety/depression (all except pain/discomfort). This study demonstrates that the major part of the negative impact of lower-risk MDS on HRQoL is not mediated via anemia. Thus, the therapeutic focus should include treatment strategies directed at underlying pathogenic mechanisms to improve HRQoL, rather than aiming predominantly at increasing hemoglobin levels.

Peripheral blood cytopenias in the aging general population and risk of incident hematological disease and mortality.

Peripheral blood cytopenias may precede the development of hematological malignancies and frequently pose clinical challenges in the older population. The natural course of (mild) cytopenias during aging and their association with hematological disorders in community-dwelling individuals are not well studied. Within the population-based Lifelines cohort (n = 167729), we studied changes in peripheral blood counts, occurrence of cytopenias, and associated hematological outcomes in the context of aging. Development of hematological malignancies and (cause-specific) mortality were evaluated by linkage to nationwide registries. Anemia and thrombocytopenia emerged with older age, in line with a general age-related decline in these blood counts. For neutropenia, no increase in prevalence with older age was observed. Using standard reference limits to define cytopenias, anemia (hazard ratio [HR], 1.84; 95% confidence interval [CI], 1.59-2.12), thrombocytopenia (HR, 1.58; 95% CI, 1.32-1.89), and, especially the concomitant presence of anemia and thrombocytopenia (HR, 4.75; 95% CI, 2.98-7.55) were associated with inferior overall survival. Only a minor proportion of deaths was explained by diagnosed hematological malignancies, with the majority attributable to other causes. Neutropenia, either isolated (HR, 0.88; 95% CI, 0.73-1.06) or combined with another cytopenia, did not affect overall survival. For individuals aged ≥60 years, 5-year cumulative incidence of hematological malignancies was 0.60% (95% CI, 0.50-0.70), with higher incidences among those with anemia (P < .001) or thrombocytopenia (P < .001) but not neutropenia (P = .201). Highest cumulative incidences of diagnoses and mortality from hematological malignancies were observed in individuals with >1 cytopenia. We conclude that anemia and thrombocytopenia, but not neutropenia, are associated with inferior overall survival of community-dwelling individuals. Hematological malignancies develop in a small fraction of these cases.

A retrospective in-depth analysis of continuous glucose monitoring datasets for patients with hepatic glycogen storage disease: Recommended outcome parameters for glucose management.

Continuous glucose monitoring (CGM) systems have great potential for real-time assessment of glycemic variation in patients with hepatic glycogen storage disease (GSD). However, detailed descriptions and in-depth analysis of CGM data from hepatic GSD patients during interventions are scarce. This is a retrospective in-depth analysis of CGM parameters, acquired in a continuous, real-time fashion describing glucose management in 15 individual GSD patients. CGM subsets are obtained both in-hospital and at home, upon nocturnal dietary intervention (n = 1), starch loads (n = 11) and treatment of GSD Ib patients with empagliflozin (n = 3). Descriptive CGM parameters, and parameters reflecting glycemic variation and glycemic control are considered useful CGM outcome parameters. Furthermore, the combination of first and second order derivatives, cumulative sum and Fourier analysis identified both subtle and sudden changes in glucose management; hence, aiding assessment of dietary and medical interventions. CGM data interpolation for nocturnal intervals reduced confounding by physical activity and diet. Based on these analyses, we conclude that in-depth CGM analysis can be a powerful tool to assess glucose management and optimize treatment in individual hepatic GSD patients.

Skin autofluorescence predicts new cardiovascular disease and mortality in people with type 2 diabetes.

BACKGROUND: Skin autofluorescence (SAF) is a non-invasive marker of tissue accumulation of advanced glycation endproducts (AGE). Recently, we demonstrated in the general population that elevated SAF levels predict the development of type 2 diabetes (T2D), cardiovascular disease (CVD) and mortality. We evaluated whether elevated SAF may predict the development of CVD and mortality in individuals with T2D. METHODS: We included 2349 people with T2D, available baseline SAF measurements (measured with the AGE reader) and follow-up data from the Lifelines Cohort Study. Of them, 2071 had no clinical CVD at baseline. 60% were already diagnosed with diabetes (median duration 5, IQR 2-9 years), while 40% were detected during the baseline examination by elevated fasting blood glucose ≥7.0 mmol/l) and/or HbA1c ≥6.5% (48 mmol/mol). RESULTS: Mean (±SD) age was 57 ± 12 yrs., BMI 30.2 ± 5.4 kg/m2. 11% of participants with known T2D were treated with diet, the others used oral glucose-lowering medication, with or without insulin; 6% was using insulin alone. Participants with known T2D had higher SAF than those with newly-detected T2D (SAF Z-score 0.56 ± 0.99 vs 0.34 ± 0.89 AU, p < 0.001), which reflects a longer duration of hyperglycaemia in the former group. Participants with existing CVD and T2D had the highest SAF Z-score: 0.78 ± 1.25 AU. During a median follow-up of 3.7 yrs., 195 (7.6%) developed an atherosclerotic CVD event, while 137 (5.4%) died. SAF was strongly associated with the combined outcome of a new CVD event or mortality (OR 2.59, 95% CI 2.10-3.20, p < 0.001), as well as incidence of CVD (OR 2.05, 95% CI 1.61-2.61, p < 0.001) and death (OR 2.98, 2.25-3.94, p < 0.001) as a single outcome. In multivariable analysis for the combined endpoint, SAF retained its significance when sex, systolic blood pressure, HbA1c, total cholesterol, eGFR, as well as antihypertensive and statin medication were included. In a similar multivariable model, SAF was independently associated with mortality as a single outcome, but not with incident CVD. CONCLUSIONS: Measuring SAF can assist in prediction of incident cardiovascular disease and mortality in individuals with T2D. SAF showed a stronger association with future CVD events and mortality than cholesterol or blood pressure levels.

Association Between Peripheral Blood Cell Count Abnormalities and Health-Related Quality of Life in the General Population.

Complete blood cell counts, including differentials, are widely available and change on aging. Peripheral blood cell counts outside the normal range have previously been associated with increased mortality rates and a number of comorbid conditions. However, data about the association between blood cell count abnormalities, other than anemia, and health-related quality of life (HRQoL) are scarce. We investigated the association between abnormalities in (differential) blood cell counts and HRQoL in 143 191 community-dwelling individuals from the prospective population-based Lifelines cohort. HRQoL was measured using the RAND 36-Item Health Survey. Logistic regression analyses were used to determine the effect of blood cell count abnormalities on the odds of having a lower score than an age- and sex-specific reference value for each domain. Leukocytosis, neutrophilia, and a high neutrophil to lymphocyte ratio were associated with impaired HRQoL across multiple domains, both for younger and older (≥60 years) individuals. Using multivariable models, we confirmed that these associations were independent of the potential confounding factors obesity, smoking, alcohol use, number of medications (as a measure of comorbidity), anemia, and mean corpuscular volume. The impact on HRQoL was most pronounced for high neutrophil levels. Further, high white blood cell counts proved to be a better marker for inferior HRQoL as compared to elevated high-sensitivity C-reactive protein levels. Decreased HRQoL in several domains was also observed for individuals with monocytosis, lymphocytosis, and thrombocytosis. Taken together, the present study demonstrates an association between inflammatory and myeloid-skewed blood cell counts and inferior HRQoL in community-dwelling individuals.

Erythrocytosis in the general population: clinical characteristics and association with clonal hematopoiesis.

Erythrocytosis is a common reason for referral to hematology services and is usually secondary in origin. The aim of this study was to assess clinical characteristics and clonal hematopoiesis (CH) in individuals with erythrocytosis in the population-based Lifelines cohort (n = 147 167). Erythrocytosis was defined using strict (World Health Organization [WHO] 2008/British Committee for Standards in Hematology) and wide (WHO 2016) criteria. Individuals with erythrocytosis (strict criteria) and concurrent leukocytosis and/or thrombocytosis were 1:2 matched with individuals with isolated erythrocytosis and analyzed for somatic mutations indicative of CH (≥5% variant allele frequency). One hundred eighty five males (0.3%) and 223 females (0.3%) met the strict criteria, whereas 4868 males (7.6%) and 309 females (0.4%) met the wide criteria. Erythrocytosis, only when defined using strict criteria, was associated with cardiovascular morbidity (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.6), cardiovascular mortality (hazard ratio [HR], 2.2; 95% CI, 1.0-4.6), and all-cause mortality (HR, 1.7; 95% CI, 1.2-2.6), independent of conventional risk factors. Mutations were detected in 51 of 133 (38%) evaluable individuals, with comparable frequencies between individuals with and without concurrent cytosis. The JAK2 V617F mutation was observed in 7 of 133 (5.3%) individuals, all having concurrent cytosis. The prevalence of mutations in BCOR/BCORL1 (16%) was high, suggesting aberrant epigenetic regulation. Erythrocytosis with CH was associated with cardiovascular morbidity (OR, 9.1; 95% CI, 1.2-68.4) in a multivariable model. Our data indicate that only when defined using strict criteria erythrocytosis is associated with cardiovascular morbidity (especially in the presence of CH), cardiovascular mortality, and all-cause mortality.

Epidemiology of thyroid disorders in the Lifelines Cohort Study (the Netherlands).

BACKGROUND: Thyroid hormone plays a pivotal role in human metabolism. In epidemiologic studies, adequate registration of thyroid disorders is warranted. We examined the prevalence of thyroid disorders, reported thyroid medication use, thyroid hormone levels, and validity of thyroid data obtained from questionnaires in the Lifelines Cohort Study. METHODS: We evaluated baseline data of all 152180 subjects (aged 18-93 years) of the Lifelines Cohort Study. At baseline, participants were asked about previous thyroid surgery and current and previous thyroid hormone use. At follow-up (n = 136776, after median 43 months), incident thyroid disorders could be reported in an open, non-structured question. Data on baseline thyroid hormone measurements (TSH, FT4 and FT3) were available in a subset of 39935 participants. RESULTS: Of the 152180 participants, mean (±SD) age was 44.6±13.1 years and 58.5% were female. Thyroid medication was used by 4790 participants (3.1%); the majority (98.2%) used levothyroxine, and 88% were females. 59.3% of levothyroxine users had normal TSH levels. The prevalence of abnormal TSH levels in those not using thyroid medication was 10.8%; 9.4% had a mildly elevated (4.01-10.0 mIU/L), 0.7% had suppressed (<0.40 mIU/L), while 0.7% had elevated (>10.0 mIU/L) TSH levels. Over 98% of subjects with TSH between 4 and 10 mIU/L had normal FT4. Open text questions allowing to report previous thyroid surgery and incident thyroid disorders proved not to be reliable and severely underestimated the true incidence and prevalence of thyroid disorders. CONCLUSIONS: Undetected thyroid disorders were prevalent in the general population, whereas the prevalence of thyroid medication use was 3.1%. Less than 60% of individuals using levothyroxine had a normal TSH level. The large group of individuals with subclinical hypothyroidism (9.4%) offers an excellent possibility to prospectively follow the natural course of this disorder. Both structured questions as well as linking to G.P.'s and pharmacists' data are necessary to improve the completeness and reliability of Lifelines' data on thyroid disorders.