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Anemia and adverse outcomes in the elderly: a detrimental inflammatory loop?
Domenico Girelli and Fabiana Busti
Department of Medicine, Section of Internal Medicine, University of Verona, EuroBloodNet Referral Center for Iron Metabolism Disorders, Azienda Ospedaliera Universitaria Integrata Verona, Italy.
E-mail: DOMENICO GIRELLI - domenico.girelli@univr.it doi:10.3324/haematol.2018.208066
Anemia is one of the easiest diagnoses in clinical prac- tice, being based on a widely available and cheap lab- oratory parameter: hemoglobin concentration. In the near future, this diagnosis could become even simpler through a smartphone app.1 Nonetheless, anemia is fre- quently overlooked, particularly when it is mild (e.g. hemo- globin values >10 g/dL but <12 g/dL or <13 g/dL in females and males, respectively) and no obvious symptoms are apparently associated. This typically occurs in the elderly, in whom other co-morbidities are often present, distracting the attention of physicians and caregivers.2 Indeed, the preva- lence of anemia in people aged >65 years is high, ranging from nearly 12% in those living in the community to more than 45% in institutionalized nursing-home residents.2 While a mild anemia has been traditionally considered as a “physiological” consequence of aging, more recent studies have shown that the decline in hemoglobin is minimal, if any, in the “wellderly”, namely people aging well without significant comorbidities.3 Moreover, growing evidence sug- gests that anemia in the elderly is not an innocent bystander, being strongly and independently associated with a number of adverse outcomes, including cognitive decline, reduced physical performance, increased risk of falls and fractures, and even increased mortality.2 In this issue of Haematologica, Wouters and colleagues report the results of the large Lifelines Cohort Study, confirming that anemia in the elderly is negatively associated with either quality of life or survival.4 A key point of anemia in the elderly lies in the dif- ficulty of establishing the etiology, which in turn should drive its management. While anemia in young people is gen- erally due to a single cause (e.g. iron deficiency in pre- menopausal women with heavy menstrual bleeding), ane- mia in the elderly is often multifactorial, reflecting the typi- cal multimorbidity of aged people.5 This frequently makes it hard to dissect out the main mechanism leading to anemia in a given elderly individual. For example, iron deficiency in the elderly can be due to a mixture of malnutrition, malabsorp- tion and bleeding, often aggravated by multiple medication use.6 Such difficulty is even more pronounced in large epi- demiological surveys, such as the Lifelines Study, in which only three general subcategories of anemia can be distin- guished, based on a few available laboratory parameters: nutritional deficiencies, anemia of inflammation (also named anemia of chronic diseases), and “unexplained” anemia,7 each of them accounting roughly for one third of cases. Notwithstanding these inherent limitations, the study by Wouters and colleagues points out anemia of inflammation as the most detrimental subcategory in the elderly, because of the strongest association with quality of life and mortali- ty. This is somewhat at variance with the findings of other studies, in which subjects with anemia due to nutritional deficiency showed the worst prognosis.8 Such a discrepancy reflects the uncertainty in the correct etiological classifica-
tion of anemia in the elderly, as well as our limited knowl- edge in the field. The broad category of “unexplained ane- mia” well illustrates this gap, although it likely represents a heterogeneous group of conditions that cannot be adequate- ly addressed by large epidemiological surveys because of the need for second level laboratory tests. Such conditions include androgen deficiency, vitamin D deficiency, unrecog- nized iron deficiency with apparently normal traditional biomarkers, impaired bone marrow response to erythropoi- etin, clonal hematopoiesis, and “inflammaging”.2 Of note, recent advances suggest that the last two conditions may share a relevant role in the pathophysiology of anemia in the elderly, both by inducing a low-grade chronic inflamma- tory status (Figure 1). Clonal hematopoiesis refers to age- related acquisition of somatic mutations in certain driver genes (e.g. TET2, DNMT3A, and JAK2) in hematopoietic stem cells, conferring them a competitive advantage and hence giving rise to a clonal progeny in the peripheral blood, at variance with normal polyclonal hematopoiesis.9 Clonal hematopoiesis is detectable through next-generation sequencing studies in nearly 10% of 70-year old individuals without abnormalities of peripheral blood cell counts and, in these people, is a risk factor for subsequent development of myeloid neoplasms. This is generally associated with accumulation of multiple mutations, but the rate of progres- sion appears as low as 0.5% per year. Such a condition has been termed clonal hematopoiesis of indeterminate poten- tial (CHIP), since, in fact, most carriers of clonal hematopoiesis will never develop myeloid neoplasms. Nevertheless, individuals with CHIP have been found at increased risk of mortality due to cardiovascular events, rather than to hematologic complications.10 Mounting evi- dence suggests that accelerated atherosclerosis in CHIP is associated with a systemic pro-inflammatory status driven by abnormal clonal leukocytes deriving from mutated hematopoietic stem cells.11 On the other hand, “inflammag- ing” also contributes to a chronic upregulation of pro- inflammatory cytokines in the elderly. This phenomenon is thought to be the result of activation of the nuclear factor- κB/inflammasome pathway driven by the so-called dam- aged-associated molecular pattern, i.e., endogenous altered molecules and reactive oxygen species that accumulate with aging.12,13 Reciprocal influences between CHIP and “inflam- maging” are likely, for example considering that reactive oxygen species can also cause genomic instability, and that subclinical inflammation by itself can prime a detrimental vicious circle in tumorigenesis.14 The exact proportions by which CHIP and “inflammaging” actually contribute to unexplained anemia in the elderly deserve further studies. Similarly, whether or not chronic subclinical inflammation, which is difficult to detect using classical biomarkers such as C-reactive protein, contributes to anemia through the same mechanisms as those associated with overt inflamma-
haematologica | 2019; 104(3)
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