Iron Deficiency in Elderly: Investigating Prevalence and Consequences - Research Paper

Introduction

Iron deficiency (ID) is relatively common among the elderly population, contributing substantially to the high prevalence of anemia observed in the last decades of life, which in turn has important implications both on quality of life and on survival. In elderly subjects, ID is often multifactorial, i.e., due to multiple concurring causes, including inadequate dietary intake or absorption, occult bleeding, medications. Moreover, because of the typical multimorbidity of aged people, other conditions leading to anemia frequently coexist and make diagnosis of ID particularly challenging. Treatment of ID is also problematic in elderly, since response to oral iron is often slow, with a substantial fraction of patients showing refractoriness and requiring cumbersome intravenous administration. In the last decade, the discovery of the iron regulatory hormone hepcidin has revolutionized our understanding of iron pathophysiology. In this review, we revisit ID among elderly people in the light of the impressive recent advances on knowledge of iron regulation, and discuss how hepcidin may help in diagnosis and treatment of this common clinical condition.

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Anemia in Elderly, Prevalence, and Definition

Anemia is a common, multi-factorial condition in elderly. Indeed, the prevalence of anemia increases with age, representing an important health problem among older individuals. Large studies on community-dwelling older adults from the United States and Europe have reported prevalence rates for anemia ranging from 8 to 25% (Patel, 2008). One of the largest population survey, i.e., the third US National Health and Nutrition Examination Survey (NHANES III), indicated that 10.2% of women and 11% of men >65 years of age were anemic (Guralnik et al., 2004). These fractions rose to 26.1 and to 20.1% in subjects older than 85 years old, in males and females, respectively (Guralnik et al., 2004).

There is some debate on which hemoglobin (Hb) threshold should be used to define anemia in the general population and particularly in elderly individuals (Beutler and Waalen, 2006). In many studies, anemia has been defined according to the World Health Organization (WHO) criteria (Blanc et al., 1968) as a Hb level <13 g/dL in men and <12 g/dL in women, respectively. However, these criteria have been criticized since they were based on statistical distributions (i.e., equivalent to two standard deviations below the mean) in reference samples that did not include individuals >65 years of age, making unfeasible their application to older individuals (Mindell et al., 2013). Since Hb values in apparently healthy elderly individuals are generally lower than those in younger adults and the differences between males and females tend to disappear with aging (Patel, 2008), a Hb value < 12 g/dL is now commonly considered indicative of anemia in elderly of both sexes (Izaks et al., 1999; Andres et al., 2013).

Anemia in elderly is typically hyporegenerative and relatively mild, with Hb levels near 10-11 g/dL in most subjects (Guralnik et al., 2004). Nevertheless, it is associated with a variety of adverse outcomes, including longer hospitalization, disability, and increased mortality risk (Chaves et al., 2004; Zakai et al., 2005; Culleton et al., 2006; Denny et al., 2006; Penninx et al., 2006; den Elzen et al., 2009; Price et al., 2011). Moreover, it also significantly impacts on the quality of life, being associated with fatigue, cognitive dysfunction, depression, decreased muscle strength, falls, and "frailty," even when Hb levels are merely low-normal (Woodman et al., 2005; Eisenstaedt et al., 2006).

Approximately, one-third of the cases of anemia in elderly can be ascribed to a chronic disease (inflammation and chronic kidney diseases), and one-third is due to nutrient deficiencies (folate, B12, and iron). Iron deficiency (ID), alone or in combination with deficiency of other nutrients, accounts for more than one-half of this group. The last third remains "unexplained" (Guralnik et al., 2004). Noteworthy, a significant proportion of elderly anemic patients (30-50%) is presumed to have multiple causes of anemia (Petrosyan et al., 2012). Since elderly patients are typically affected by several different pathologic conditions (multimorbidity), and are commonly taking a long list of medications, the precise etiology of anemia is often difficult to determine in a given individual (Andres et al., 2013), and sometimes remains "unexplained" despite extensive investigation (Guralnik et al., 2004). Thinking in terms of multimorbidity is a key to understanding, diagnosis, and treatment of anemia in the elderly.

Iron Deficiency in Elderly

According to the WHO, ID is by far the most common and widespread nutritional disorder worldwide (http://www.who.int/nutrition/topics/ida/en/), with estimated one billion people affected, thus constituting a public health condition of epidemic proportions. Besides the large number of children and young women affected in developing countries, ID is the only nutrient deficiency that is also significantly prevalent in industrialized countries [World Health Organization (WHO), 2001; Hershko and Camaschella, 2013], where an additional category at risk is represented by elderly people (Guyatt et al., 1990).

Iron deficiency syndromes include a range of different conditions (Goodnough, 2012). "Absolute" ID is defined by the lack of storage iron (Cook, 2005; Fairweather-Tait et al., 2013). In physiological conditions, the total body iron amount (near 3-4 g) is maintained by a fine balance between three distinct factors: body requirements, iron supply (depending on dietary iron intake and duodenal absorption), and blood losses. While an increased iron demand is the main cause of ID in children and fertile females, insufficient dietary iron intake, gastrointestinal (GI) malabsorption and/or increased blood losses are the most common causes of ID in older individuals (see below).

At variance with "absolute" ID, many disorders are characterized by the so-called "functional" or "relative" ID, defined as the occurrence of iron-restricted erythropoiesis in presence of normal or even increased amounts of body iron stores. This phenomenon is often related to an impaired iron trafficking (i.e., block of iron release from macrophages and hepatocytes, typically during inflammatory diseases) or to increased/ineffective/stimulated erythropoiesis, with iron demand exceeding the supply (i.e., during hemoglobinopathies, chronic hemolytic anemias or treatment with erythropoiesis stimulating agents). Since the focus of this article is on etiology, diagnosis, and management of the absolute ID in elderly, the readers are referred to others excellent reviews for details on the functional ID syndromes (Goodnough et al., 2010, Goodnough, 2012; Auerbach et al., 2013a).

Whatever the mechanism, both absolute and functional ID reduce iron availability to erythroid precursors, with the development of an iron-restricted erythropoiesis, and finally of anemia. In particular, two ID stages can be distinguished: (a) initial, characterized by reduced transferrin saturation but without anemia; and (b) advanced, when microcytic, hypochromic iron-deficiency anemia (IDA) becomes evident.

In elderly, ID and IDA are nearly always due to chronic GI diseases, which in turn lead to iron loss and malabsorption not infrequently occurring in combination at individual level (Figure 1). Indeed, the most frequent cause is represented by chronic upper and lower GI blood losses, because of esophagitis, gastritis, peptic ulcer, colon cancer or pre-malignant polyps, inflammatory bowel disease, or angiodysplasia (Eisenstaedt et al., 2006). The prevalence of most of these conditions increases with age, which is particularly true for neoplastic lesions (Eddy, 1990) and angiodysplasia (Sami et al., 2014). Remarkably, GI bleeding is typically increased by concomitant assumption of medications for conditions highly prevalent in elderly individuals, such as non-steroidal anti-inflammatory drugs for osteoarthritis, and antithrombotic therapies for cardiovascular disease, especially for atrial fibrillation.

FIGURE 1

FIGURE 1. Gastrointestinal diseases representing the most frequent causes of ID and IDA in elderly patients. Of note, more than one of these conditions not infrequently coexist in a given individual. Bleeding is often favored by antithrombotic drugs for treatment of cardiovascular diseases that are highly prevalent in this age group. Suggested diagnostic tools are reported on the right side. AAG, autoimmune atrophic gastritis; CD, celiac disease; GI, gastrointestinal; HP, Helicobacter pylori; IBD, inflammatory bowel disease; PPI, proton pump inhibitors; VCE, video capsule endoscopy.

Iron malabsorption is also relatively frequent in the elderly. Indeed, further conditions whose prevalence typically increases with age are represented by Helicobacter pylori (HP) infection (Pounder and Ng, 1995) and atrophic gastritis. Of note, although, for a long time, celiac disease (CD) has been primarily considered an enteropathy of childhood and young adults, a number of epidemiological studies have reported an increased detection rate in older subjects, with up to one third of newly diagnosed patients being older than 65 years (Patel et al., 2005; Rashtak and Murray, 2009; Vilppula et al., 2009). In this age group, multifactorial anemia is the most frequent clinical presentation (Harper et al., 2007), with micronutrients deficiency (particularly ID) being the leading cause. For poorly understood reasons, the classical triad of malabsorptive symptoms including diarrhea, weight loss and abdominal pain is less common in elderly (Freeman, 2008), making the diagnosis frequently overlooked in this age category. Another factor that could theoretically contribute to iron malabsorption in elderly patients is represented by the frequent long-term use of proton pump inhibitors (PPI), being gastric acid essential for optimal intestinal absorption of the element (Ganz, 2013). However, only few reports have specifically addressed this issue, which remains controversial (Reimer, 2013).

Typically, all the above-mentioned conditions impairing iron absorption share a clinical phenotype of refractoriness to oral iron therapy, recently named "acquired IRIDA" (iron refractory ID anemia; for a review see Hershko and Camaschella, 2013). These conditions should be always considered in elderly subjects with IDA and no evidence of GI blood loss.

Finally, malnutrition is an obvious contributing factor to ID in elderly. However, since iron requirement (1-2 mg/day) only corresponds to near 10% of the average daily iron intake, malnutrition is rarely sufficient per se to cause IDA, at least in industrialized countries. Nevertheless, evaluation of the patient's nutritional status plays an important role in the diagnostic approach to anemia in the older adult.

Hepcidin, the Key Regulator of Iron Homeostasis

Hepcidin, a defensin-like hormone synthesized mainly by the liver, has been discovered in 2001 and recognized as the master regulator of iron metabolism (Ganz and Nemeth, 2011). The active form of hepcidin is a 25-amino acid peptide derived from an 84 amino acid precursor, but at least two others isoforms truncated at the N-terminus, i.e., hepcidin-20 and hepcidin-22, have been also identified in biological fluids (Castagna et al., 2010). The biological meaning of these isoforms is s...