The anemia of ageing is not associated with increased plasma hepcidin levels
Introduction
Numerous studies show that there is a distinct decline in the hemoglobin levels with increasing age. In many elderly patients anemia is a consequence of diseases such as cancer, chronic inflammatory disorders, bleeding from benign lesions, or vitamin B12 or folate deficiency. However, even excluding such patients, the hemoglobin levels of the elderly are lower, particularly in males [1], [2], [3], [4].
The modest decline in hemoglobin levels that occurs during ageing has gained potential clinical importance with the publication of a number of studies indicating that the outcomes of a variety of disorders, including heart failure [5], percutaneous coronary intervention [6], and acute myocardial infarction [7], [8] are related to hemoglobin levels, even when confounding factors are taken into account. A prospective study of 5888 community-dwelling individuals with median 11.2 year follow-up (53,866 person years) led to the conclusion that overall mortality was increased in persons with lower hemoglobin levels, even when adjustments were made for comorbidities [9]. A “reverse J-shaped” relationship was found between hemoglobin levels and mortality [9], a pattern that has also been noted in patients with the acute coronary syndromes.
The cause(s) of the anemia of ageing are not known. It has been suggested that increased levels of interleukin-6 that have been reported to occur in the course of ageing may stimulate hepcidin production. The consequent dysregulation of iron homeostasis could result in decreased erythropoiesis and anemia [4]. Accurate measurement of plasma hepcidin levels has proven to be technically difficult. They have been measured previously only using a mass spectroscopy-based technique [10], [11] which has a fairly large coefficient of variation [10], and one immunoassay [12], which has not been generally validated. A more reproducible immunoassay [13] has recently become commercially available, which has made it possible for us to measure plasma hepcidin levels in a group of patients with the anemia of ageing. Plasma levels of hepcidin in a few patients with the anemia of chronic inflammation were also determined, to validate the technique, since it is well known that chronic inflammation increases hepcidin levels.
Section snippets
Materials and methods
To study the anemia of ageing 20 white patients from the Scripps/Kaiser study [14], aged 63–83 years of age were selected for study. Ten patients were anemic, with hemoglobin levels < 12.4 g/dl for males and < 11.4 g/dl for females. None of these patients had a known cause of anemia, although, as noted below, 2 patients were subsequently found not to meet the criteria of the anemia of ageing, and were removed from the analysis, one because the mean corpuscular volume (MCV) was increased to
Results
The results of the hepcidin assays of elderly patients with anemia are summarized in Fig. 1. The hepcidin levels of the anemic patients were actually lower, albeit not statistically significantly so, than the levels in the controls. Pooling the data from the eight anemic patients and 10 controls the mean hepcidin level (± 1 S.D.) was 165.8 ± 119.7 ng/ml and 195.6 ± 141.3 ng/ml, respectively. The corresponding median values were 146.4 and 164.7. There was no relationship between hemoglobin levels and
Discussion
It has been proposed that the anemia of ageing might be due to increased IL-6 levels leading to increased secretion of hepcidin [4]. The current studies fail to show such an effect. Although the number of patients studied was very small, the fact that both the mean and median hepcidin level was lower in the anemic patients rather than higher, the hypothesis that was being examined, it is unlikely that statistically significant higher values for plasma hepcidin concentrations would have been
Acknowledgments
This is manuscript 19606-MEM from The Scripps Research Institute. This work was supported by grants from the National Institutes of Health grant AG029135–02 and the Stein Endowment Fund.
References (18)
- et al.
The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration?
Blood
(2006) - et al.
Anemia in the elderly: current understanding and emerging concepts
Blood Rev.
(2006) - et al.
Anemia as a risk factor and therapeutic target in heart failure
J. Am. Coll. Cardiol.
(2004) - et al.
Anemia is an independent predictor of mortality after percutaneous coronary intervention
J. Am. Coll. Cardiol.
(2004) - et al.
Impact of anemia in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention — analysis from the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial
J. Am. Coll. Cardiol.
(2004) - et al.
Quantitation of hepcidin from human and mouse serum using liquid chromatography tandem mass spectrometry
Blood
(2007) - et al.
Penetrance of the 845G–>A (C282Y) HFE hereditary haemochromatosis mutation in the USA
Lancet
(2002) - et al.
Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein
Blood
(2003) - et al.
Hepcidin is decreased in TFR2 hemochromatosis
Blood
(2005)
Cited by (17)
Heat stress stimulates hepcidin mRNA expression and C/EBPα protein expression in aged rodent liver
2014, Archives of Gerontology and GeriatricsCitation Excerpt :Currently, little is known about the effects of aging on hepcidin expression in the liver. The few studies that do exist on hepcidin and aging have evaluated either urinary hepcidin (Ferrucci et al., 2010) or plasma hepcidin concentrations (Lee, Gelbart, Waalen, & Beutler, 2008) in older humans (ages 63–89), without including reference groups of young individuals. Thus, there is a need to evaluate hepcidin directly in the livers of young and old animals.
Anemia in older persons: Etiology and evaluation
2011, Blood Cells, Molecules, and DiseasesCitation Excerpt :These differences, however, were clinically minor, and might be explained by underlying co-morbid disease. In two prior studies, older participants with unexplained anemia did not have an increase in inflammatory markers or hepcidin levels compared to controls or older participants with non-inflammatory anemia [9,24]. We further found that as unexplained anemia worsened, erythropoietin levels remained relatively low compared to those participants who were suspicious for MDS.
Decline of the Red Blood Cell Count in Patients Receiving Androgen Deprivation Therapy for Localized Prostate Cancer: Impact of ADT on Insulin-like Growth Factor-1 and Erythropoiesis
2010, UrologyCitation Excerpt :Yet, we did not find any difference in the erythropoietin level between before and after ADT or association between this hormone and IGF-1. Also, IL-6, of which elevation in the serum is relevant to anemia, was not changed by ADT.21 Thus, the discordance in the GH/IGF-1 axis may be more influential than erythropoietin for hematopoiesis during ADT.
Proinflammatory state, hepcidin, and anemia in older persons
2010, BloodCitation Excerpt :Our findings are consistent with those reported by Lee et al, who studied 8 subjects with anemia of aging. However, our findings are more robust because of larger and representative samples and detailed measures of cytokine levels.20 IL-6 has been directly implicated in the up-regulation of hepcidin, and in preclinical studies the evidence for such regulation is overwhelming.3
The anemia of inflammation/chronic disease and the unexplained anemia of the elderly
2018, Anemia in the Young and Old: Diagnosis and Management