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Anemia, survival and health-related quality of life
Introduction
Anemia, according to the World Health Organization (WHO) criteria, is defined as a hemoglobin concentration <13.0 g/dL (8.0 mmol/L) in adult men and <12.0 g/dL (7.5 mmol/L) in adult, non-pregnant women. Anemia affects nearly 25% of the world population.1,2 In developed coun- tries, anemia is one of the most frequent conditions in older individuals, with a presumed prevalence of over 10% indi- viduals who are 65 years or older in selected populations.3,4 More than half of anemic older individuals can be diagnosed with nutritional deficiencies or have anemia of chronic inflammation (ACI). The etiology of anemia remains unknown in about one-third of the older population.4 In older individuals the presence of anemia, even mild anemia, is associated with an increased risk of falls,5 decreased phys- ical performance,6 longer and more frequent stays in hospi- tal,7-9 and increased mortality.7,9,10 Suggestions to raise the hemoglobin thresholds for the definition of anemia in older individuals have been made in several studies.11,12
The impact of anemia on health-related quality of life (HRQoL) has been studied in different populations of patients, including patients with chronic kidney dis- ease,13 chronic obstructive pulmonary disease,14 cancer15 and heart failure.16 In these studies, anemia was reported to be associated with a reduced HRQoL. However, little research has been done on this potential association in community-dwelling populations. Better understanding of the impact of anemia on HRQoL in a community- dwelling general population is therefore essential and could provide critical entry points for interventions that affect anemia, especially in older individuals.
In this study, we investigated the association between anemia and survival, and between anemia and HRQoL. In addition, we used this association to evaluate the def- inition of anemia, considering the impact of age and gen- der on this association in the large community-dwelling population from the Lifelines cohort.17
Methods
Subjects
In this study we used data from 138670 subjects participating in the Lifelines cohort study. Data from quality of life questionnaires and on hemoglobin concentration were available for these sub- jects. Lifelines is a multidisciplinary, prospective, population-based cohort study examining, in a unique three-generation design, the health and health-related behaviors of persons living in the north of the Netherlands. It has been shown that the Lifelines cohort is representative of the population of the northern part of the Netherlands.18 The local ethics committee approved the research protocol and informed consent was signed by every participant.
Health-related quality of life
HRQoL was measured using the RAND 36-Item Health Survey.19 Since HRQoL scores are not normally distributed, for each subscale we defined a sex-specific and age-specific cut-off point at the 25th percentile of the non-anemic Lifelines population. Participants with a score lower than 25th percentile were consid- ered to have an abnormally low score for that specific subscale.
Survival
All participants were followed from the moment of their inclusion in the Lifelines cohort until death or up to May 2018
(maximum follow-up 138 months, median 79 months). Information on participants’ deaths was obtained from the municipal personal records database.
Definition of anemia and classification into subtypes of anemia
In accordance with the WHO criteria, anemia was defined as a hemoglobin concentration <13.0 g/dL (8.0 mmol/L) in adult men and <12.0 g/dL (7.5 mmol/L) in adult, non-pregnant women.20 In anemic subjects older than 60 years of age addi- tional biochemical tests were performed, using stored plasma, to determine the type of anemia: anemia due to nutritional defi- ciency, ACI or unexplained anemia. There is no worldwide accepted classification into subtypes of anemia. Reference val- ues were taken from the University Medical Center Groningen or from published literature, as indicated. Iron deficiency was considered present if the participant had two or three of the fol- lowing criteria: serum ferritin concentration <30 mg/L, transfer- rin saturation rate <16% or hepcidin concentration <0.5 nmol/L.21-23 Transferrin saturation was calculated by dividing serum iron by total iron-binding capacity [transferrin (g/L)x25]. Folate deficiency was defined as a serum folate level <9.8 nmol/L. Vitamin B12 deficiency was defined as a serum methyl- malonic acid concentration >340 nmol/L, if the estimated glomerular filtration was >30 mL/min (because methylmalonic acid levels may be elevated in people with severely impaired renal function24). If there was no evidence of nutrient deficiency, subjects with anemia were evaluated for other causes. Subjects were classified as having anemia related to chronic renal disease if the estimated glomerular filtration rate was <30 mL/min. The Chronic Kidney Disease-Epidemiology Collaboration (CDK- EPI) formula was used to calculate the estimated glomerular fil- tration rate. ACI was defined as present if the participant had (i) a C-reactive protein concentration >5.0 mg/L or an absolute number of leukocytes >10x109/L and (ii) two or more of the fol- lowing criteria: transferrin saturation rate <16%, serum ferritin concentration >100 mg/L, serum iron <10 mmol/L and hepcidin >14.7 nmol/L in men or hepcidin>15.6 nmol/L in women.25,26 If subjects with anemia could not be classified into any of these categories, they were considered, by exclusion, to have unex- plained anemia.
Details of the Lifelines cohort, clinical examination, biochem- ical measurements, RAND 36-Item Health Survey and data description and statistical analysis are provided in the Online Supplementary Data.
Results
Relevant baseline characteristics are shown in Table 1 for anemic and non-anemic participants from the popu- lation-based Lifelines cohort. In total 551 men and 4959 women met the WHO criteria for anemia. The overall prevalence of anemia was 4.0% (Figure 1A). The preva- lence of anemia in women was highest (about 8%) in the age cohort 40-49 years and showed a second peak of about 4% at an older age (older than 70 years). In con- trast, the prevalence of anemia in men gradually increased with age, with a peak of about 5% in older age (older than 70 years). In the population of individuals 60 years of age and older the overall prevalence of anemia was 2.8%, with a prevalence of 2.7% in men and 3.0% in women. The distribution of the hemoglobin concen- tration according to age is shown in Online Supplementary Figure S2A,C. In men, unlike in women, the mean hemo-
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