Markers of iron status and cardiometabolic disease risk: an exploration of the association based on cross-sectional and prospective studies in multiple populations

The aim of this thesis is to contribute to the understanding of iron metabolism, as a factor associated with cardiometabolic risk, by undertaking secondary data analyses. The objectives were to identify gaps in existing knowledge in terms of populations studied and alternative iron markers, and to attempt to fill the gaps with additional analyses and interpretation. Serum ferritin was the most widely available measure of iron status but the role of serum transferrin and soluble transferrin receptor (sTfR) levels was considered where available. I have taken a life-course approach with analyses in childhood and adulthood, and have included both intermediate factors such as the metabolic syndrome (MetS), and disease diagnoses of diabetes and cardiovascular disease as outcomes. Chapter one presents a review of empirical research literature on the relationship between iron metabolism and cardiometabolic risk, concepts surrounding iron markers and the study outcomes. This chapter also describes the gaps in understanding the iron-cardiometabolic risk relationship, which are subsequently explored in chapters two to six. Chapter two explores the link between serum ferritin and transferrin and MetS in cross-sectional and prospective studies of 725 Spanish children and 567 Chilean adolescents. I found associations between both ends of the ferritin distribution and MetS or glucose metabolism markers in different paediatric populations. For instance, whereas in the Spanish children there was a decrease of 0.02 SD units in the change of MetS score over time for every SD unit increase in ferritin, in the Chilean male adolescents being in the highest tertile of ferritin (v. the lowest) was associated with an increase of 0.25 SD units of MetS score. Furthermore, sustained high ferritin levels at various time points and gradual increase of ferritin during childhood were associated with higher MetS score in adolescence. The third chapter describes the association between serum ferritin status and MetS in adults in two cross-sectional studies of Scottish populations (2,047 individuals from Shetland Islands and 8,563 subjects from the Scottish Health Surveys (SHeS) 1995- 1998). I also examined the overall association between ferritin, MetS and each MetS component in adults, by conducting a meta-analysis and investigating potential relevant sources of heterogeneity for the association. Interestingly, ferritin levels were positively associated with MetS in the Scottish populations, but the association was not independent of the effect of covariates, mainly body mass index (BMI) and transaminase levels [Men Odds ratio (OR) 95% confidence interval (CI) 1.43(0.83- 2.46); Postmenopausal women OR (95%CI) 1.09(0.62-1.90); Premenopausal women OR (95%CI) 1.02(0.42-2.46), P>0.05]. The meta-analysis supported this finding by describing hepatic injury markers and BMI as the major attenuating factors of the ferritin-MetS association. Chapter four investigates the association between sTfR or ferritin, and MetS in 725 Croatian adults in a cross-sectional study. There was no evidence of an association between sTfR and MetS [Men OR (95%CI) 1.35(0.90-2.02); Postmenopausal women OR (95%CI) 0.73(0.47-1.15); Premenopausal women OR (95%CI) 0.87(0.66-1.17), P>0.05]. In contrast serum ferritin, was positively and independently associated with MetS in men and postmenopausal women (P<0.05) [Men OR (95%CI) 1.78(1.31- 2.42); Postmenopausal women OR (95%CI) 1.71(1.12-2.62); Premenopausal women OR (95%CI) 1.24(0.85-1.80)]. These contrasting results suggest that different iron markers reflect different physiological processes other than iron metabolism. Chapter five evaluates the longitudinal association between serum ferritin and several cardiometabolic disease outcomes (CMDs) in the nationally representative SHeS 1995 and 1998 (n = 6,497). I found an independent positive longitudinal association between ferritin and cerebrovascular disease (CEVD), which was strengthened by using higher cut-points for increased ferritin [higher v. lowest sextile fully adjusted Hazard ratio(HR) 95%CI 2.08 (1.09-3.94), P=0.024], and a not significant association with coronary heart disease (CHD) after adjustment for covariates. My analyses confirmed the widely established association with type 2 diabetes (T2D) [whole sample fully adjusted HR 95% CI 1.59(1.10-2.34), P=0.006], even with serum ferritin within the normal range. The above set of observations confirm ferritin as biomarker mainly related to the development of T2D and identifies the need to investigate the association between ferritin and CEVD in other populations. Chapter six investigates whether ferritin is associated with risk for cardiovascular complications among people with T2D using cross-sectional study designs in two populations with differing baseline cardiovascular risk (Spanish study SIDIAP n=38,617) and (Edinburgh Type 2 Diabetes Study (ET2DS) n= 821) with additional analysis of follow-up data for ET2DS. Interestingly, ferritin levels were negatively associated with prevalence of cardiovascular disease, mainly CHD, in people with T2D in both studies [ET2DS OR (95%CI): 0.80(0.67-0.96), P=0.020; SIDIAP study: 0.85(0.83-0.88), P<0.001). Ferritin was also negatively associated with incident cardiovascular disease in ET2DS: HR 95% CI: 0.39(0.16-0.93), P=0.035. Therefore, the association between iron status and CMD risk in people with T2D appears to differ from that in general populations in which a positive association has been more commonly described. In conclusion, serum ferritin is associated with cardiometabolic risk in different ways in a variety of populations. Inconsistent associations for other iron markers suggest that iron biomarkers reflect factors other than iron homeostasis that influence cardiometabolic risk. The association between iron markers and MetS appears to differ between populations. This thesis illustrates the complex relationship between iron metabolism markers, MetS and CMD, and identifies the need for further research on the topic in order to extend knowledge about pathophysiology and the potential for measures of iron status as biomarkers for CMD

Ferritin levels throughout childhood and metabolic syndrome in adolescence

© 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II UniversityBackground and aim: Increased ferritin levels have been widely associated with cardiovascular risk in adults. Whether ferritin levels and their changes during childhood are related to metabolic syndrome (MetS) at adolescence is unknown. We aimed to evaluate these associations using levels of ferritin at 5, 10 and 16 years and their linear increases and patterns of sustained increased levels across childhood. Methods and results: There were four samples evaluated according to non-missing values for study variables at each stage (5 years: 562; 10 years: 381; and 16 years: 567 children; non-missing values at any stage: 379). MetS risk was evaluated as a continuous Z score. Patterns of sustained increased ferritin (highest tertile) and slope of the change of ferritin per year acro

Children’s and adolescents’ rising animal-source food intakes in 1990–2018 were impacted by age, region, parental education and urbanicity

Animal-source foods (ASF) provide nutrition for children and adolescents’ physical and cognitive development. Here, we use data from the Global Dietary Database and Bayesian hierarchical models to quantify global, regional and national ASF intakes between 1990 and 2018 by age group across 185 countries, representing 93% of the world’s child population. Mean ASF intake was 1.9 servings per day, representing 16% of children consuming at least three daily servings. Intake was similar between boys and girls, but higher among urban children with educated parents. Consumption varied by age from 0.6 at <1 year to 2.5 servings per day at 15–19 years. Between 1990 and 2018, mean ASF intake increased by 0.5 servings per week, with increases in all regions except sub-Saharan Africa. In 2018, total ASF consumption was highest in Russia, Brazil, Mexico and Turkey, and lowest in Uganda, India, Kenya and Bangladesh. These findings can inform policy to address malnutrition through targeted ASF consumption programmes.publishedVersio

Incident type 2 diabetes attributable to suboptimal diet in 184 countries

The global burden of diet-attributable type 2 diabetes (T2D) is not well established. This risk assessment model estimated T2D incidence among adults attributable to direct and body weight-mediated effects of 11 dietary factors in 184 countries in 1990 and 2018. In 2018, suboptimal intake of these dietary factors was estimated to be attributable to 14.1 million (95% uncertainty interval (UI), 13.8–14.4 million) incident T2D cases, representing 70.3% (68.8–71.8%) of new cases globally. Largest T2D burdens were attributable to insufficient whole-grain intake (26.1% (25.0–27.1%)), excess refined rice and wheat intake (24.6% (22.3–27.2%)) and excess processed meat intake (20.3% (18.3–23.5%)). Across regions, highest proportional burdens were in central and eastern Europe and central Asia (85.6% (83.4–87.7%)) and Latin America and the Caribbean (81.8% (80.1–83.4%)); and lowest proportional burdens were in South Asia (55.4% (52.1–60.7%)). Proportions of diet-attributable T2D were generally larger in men than in women and were inversely correlated with age. Diet-attributable T2D was generally larger among urban versus rural residents and higher versus lower educated individuals, except in high-income countries, central and eastern Europe and central Asia, where burdens were larger in rural residents and in lower educated individuals. Compared with 1990, global diet-attributable T2D increased by 2.6 absolute percentage points (8.6 million more cases) in 2018, with variation in these trends by world region and dietary factor. These findings inform nutritional priorities and clinical and public health planning to improve dietary quality and reduce T2D globally.publishedVersio

Patient safety incidents and adverse events in ambulatory dental care: A systematic scoping review

Background There have been efforts to understand the epidemiology of iatrogenic harm in hospitals and primary care and to improve the safety of care provision. There has in contrast been very limited progress in relation to the safety of ambulatory dental care. Objectives To provide a comprehensive overview of the range and frequencies of existing evidence on patient safety incidents and adverse events in ambulatory dentistry. Methods We searched MEDLINE and EMBASE for articles reporting events that could have or did result in unnecessary harm in ambulatory dental care. We extracted and synthesized data on the types and frequencies of patient safety incidents and adverse events. Results Forty articles were included. We found that the frequencies varied very widely between studies; this reflected differences in definitions, populations studied, and sampling strategies. The main 5 PSIs we identified were errors in diagnosis and examination, treatment planning, communication, procedural errors, and the accidental ingestion or inhalation of foreign objects. However, little attention was paid to wider organizational issues. Conclusions Patient safety research in dentistry is immature because current evidence cannot provide reliable estimates on the frequency of patient safety incidents in ambulatory dental care or the associated disease burden. Well-designed epidemiological investigations are needed that also investigate contributory factors

Patient Safety Incidents and Adverse Events in Ambulatory Dental Care:A Systematic Scoping Review

Background There have been efforts to understand the epidemiology of iatrogenic harm in hospitals and primary care and to improve the safety of care provision. There has in contrast been very limited progress in relation to the safety of ambulatory dental care. Objectives To provide a comprehensive overview of the range and frequencies of existing evidence on patient safety incidents and adverse events in ambulatory dentistry. Methods We searched MEDLINE and EMBASE for articles reporting events that could have or did result in unnecessary harm in ambulatory dental care. We extracted and synthesized data on the types and frequencies of patient safety incidents and adverse events. Results Forty articles were included. We found that the frequencies varied very widely between studies; this reflected differences in definitions, populations studied, and sampling strategies. The main 5 PSIs we identified were errors in diagnosis and examination, treatment planning, communication, procedural errors, and the accidental ingestion or inhalation of foreign objects. However, little attention was paid to wider organizational issues. Conclusions Patient safety research in dentistry is immature because current evidence cannot provide reliable estimates on the frequency of patient safety incidents in ambulatory dental care or the associated disease burden. Well-designed epidemiological investigations are needed that also investigate contributory factors

Global, regional, and national consumption of animal-source foods between 1990 and 2018: findings from the Global Dietary Database

International audienceBackground:Diet is a major modifiable risk factor for human health and overall consumption patterns affect planetary health. We aimed to quantify global, regional, and national consumption levels of animal-source foods (ASF) to inform intervention, surveillance, and policy priorities.Methods:Individual-level dietary surveys across 185 countries conducted between 1990 and 2018 were identified, obtained, standardised, and assessed among children and adults, jointly stratified by age, sex, education level, and rural versus urban residence. We included 499 discrete surveys (91·2% nationally or subnationally representative) with data for ASF (unprocessed red meat, processed meat, eggs, seafood, milk, cheese, and yoghurt), comprising 3·8 million individuals from 134 countries representing 95·2% of the world population in 2018. We used Bayesian hierarchical models to account for differences in survey methods and representativeness, time trends, and input data and modelling uncertainty, with five-fold cross-validation.Findings:In 2018, mean global intake per person of unprocessed red meat was 51 g/day (95% uncertainty interval [UI] 48–54; region-specific range 7–114 g/day); 17 countries (23·9% of the world's population) had mean intakes of at least one serving (100 g) per day. Global mean intake of processed meat was 17 g/day (95% UI 15–21 g/day; region-specific range 3–54 g/day); seafood, 28 g/day (27–30 g/day; 12–44 g/day); eggs, 21 g/day (18–24 g/day; 6–35 g/day); milk 88 g/day (84–93 g/day; 45–185 g/day); cheese, 8 g/day (8–10 g/day; 1–34 g/day); and yoghurt, 20 g/day (17–23 g/day; 7–84 g/day). Mean national intakes were at least one serving per day for processed meat (≥50 g/day) in countries representing 6·9% of the global population; for cheese (≥42 g/day) in 2·3%; for eggs (≥55 g/day) in 0·7%; for milk (≥245 g/day) in 0·3%; for seafood (≥100 g/day) in 0·8%; and for yoghurt (≥245 g/day) in less than 0·1%. Among the 25 most populous countries in 2018, total ASF intake was highest in Russia (5·8 servings per day), Germany (3·8 servings per day), and the UK (3·7 servings per day), and lowest in Tanzania (0·9 servings per day) and India (0·7 servings per day). Global and regional intakes of ASF were generally similar by sex. Compared with children, adults generally consumed more unprocessed red meat, seafood and cheese, and less milk; energy-adjusted intakes of other ASF were more similar. Globally, ASF intakes (servings per week) were higher among more-educated versus less-educated adults, with greatest global differences for milk (0·79), eggs (0·47), unprocessed red meat (0·42), cheese (0·28), seafood (0·28), yoghurt (0·22), and processed meat (0·21). This was also true for urban compared to rural areas, with largest global differences (servings per week) for unprocessed red meat (0·47), milk (0·38), and eggs (0·20). Between 1990 and 2018, global intakes (servings per week) increased for unprocessed red meat (1·20), eggs (1·18), milk (0·63), processed meat (0·50), seafood (0·44), and cheese (0·14).Interpretation:Our estimates of ASF consumption identify populations with both lower and higher than optimal intakes. These estimates can inform the targeting of intervention, surveillance, and policy priorities relevant to both human and planetary health