In older age the main cause of iron deficiency is blood loss, especially from the gastro-intestinal tract [21–24]. Even in the absence of symptoms, and in the face of negative hemoccult stool test the gastrointestinal tract should be evaluated with colonoscopy and gastroduedonoscopy [21]. If these exams fail to reveal a bleeding lesion a camera endoscopy of the small bowel is indicated. In 30–50 % of adult individuals a cause of blood loss may not identifiable. In these situations iron malabsorption from atrophic gastritis, H. Pylori infections, celiac disease or medications may be responsible for iron deficiency.

Incidence and prevalence of cobalamin deficiency increase with age [25, 26]. Inability to digest food B12 from decreased gastric production of hydrochloric acid and of pepsin, is the most common cause. As the production of intrinsic factor is not compromised cobalamin deficiency may be ameliorated with oral crystalline B12 [25, 26]. Drug induced B12 deficiency is becoming increasingly common [27], especially with the use of proton pump inhibitors and metformin In addition to anemia, B12 deficiency may be a cause of neurologic disorders including dementia, and posterior column lesions.

Some cases of anemia of unknown causes may be accounted for by early myelodysplasia or chronic renal insufficiency that become more prevalent with age. For a glomerular filtration rate (GFR) lower than 60 ml/min as many as 75 % of patients develop anemia [28, 29]. These GFR values are common at age 65 and older and are almost universal after age 80. Hypogonadism may account for some anemia of unknown causes [30]. In the INCHIANTI study Ferrucci et al. found low levels of circulating testosterone in three fourth of older men and women with anemia. Low testosterone levels in non-anemic subjects were predictive of anemia during the following 3 years. The role of testosterone in promoting erythropoiesis is well documented by a number of clinical observations. In men testosterone replacement therapy and in women testosterone –producing ovarian tumors are associated with erythocytosis [31, 32]. After aromatization to estrogen androgens stimulate the proliferation of hemopoietic stem cells through estrogen receptor alpha that activates the TET gene and leads to increased telomerase synthesis [33]. Consistent with these findings, androgen deprivation therapy of prostate cancer and aromatase inhibition therapy of breast cancer may be associated with anemia.

Nutrition may play an important role in anemia of unknown causes [34] In addition to protein/calorie malnutrition that becomes more common with aging, the lack of specific nutrients may be important. Recent studies identified deficiency of Vitamin D [35] and copper [36] as potential causes of anemia in older individuals.

Relative erythropoietin deficiency may represent an important mechanism of anemia of unknown causes in the elderly. Whereas in the presence of iron deficiency an inverse relation exists between the hemoglobin and erythropoietin levels, older individuals with anemia of unknown origin lose the ability to raise the levels of circulating erythropoietin when the hemoglobin levels decline [6]. Ferrucci et al. found that the levels of erythropoietin were more elevated in the presence of normal hemoglobin levels, but failed to increase appropriately when the hemoglobin levels dropped, in patients with increased concentrations of inflammatory cytokines in the circulation [37]. Inflammatory cytokines may both reduce the sensitivity of erythropoietic precursors to erythropoietin and inhibit erythropoietin secretion. In other words, most cases of anemia of unknown origin would represent a form of anemia of inflammation. This is reasonable as aging is seen as a form of chronic and progressive inflammation [38]. A recent study showing that no relation exists between the excretion of hepcidin in the urines of older individuals and their hemoglobin levels questions this hypothesis, however [39]. Another group of investigators also found decreased erythropoietin sensitivity in the absence of increased hepcidin levels in elderly individuals with anemia of unknown causes [40]. Hepcidin is an enzyme that shuts down the transport of iron from the gastrointestinal tract and from the storages to the bone marrow by destroying the iron transporting protein ferroportin [41]. The production of hepcidin occurs in the liver and is stimulated by inflammatory cytokines, and in particular interleukin 6. Increased levels of hepcidin are considered essential to anemia of inflammation. While it is clear that the sensitivity to and the production of erythropoietin decline with the concentration of inflammatory cytokines in the circulation, it may not be concluded that this form of anemia is a classical anemia of inflammation. In this, elevated levels of hepcidin play a critical role.

An area of controversy is whether anemia may develop in older individuals in absence of a specific disease from an exhaustion of hemopoietic reserves, which may include numeric as well as functional abnormalities of the hemopoietic stem cells and failure of the hemopoietic microenvironment to support the viability of these elements. In older mammals, including humans, the stem cells are primed to differentiate into the myeloid rather than the erythroid series [42]. Also, the accumulation of oxidative damage may reduce the ability of human stem cell self renewal [43]. It is not clear whether these changes are sufficient to cause anemia in the aged. In some cross-sectional studies the average hemoglobin levels appeared consistent in all age groups at least up to age 85, though the prevalence of anemia increased with age [3, 44–46] suggesting that anemia is not a necessary consequence of age. Two longitudinal studies, one from Japan [47] and the other from Sweden [48] revealed a small but progressive decline in hemoglobin concentration with age. Such findings suggest that a progressive erythropoietic exhaustion, of low degree may occur with aging. It may become significant in condition of erythropoietic stress, such as blood loss with a delayed and incomplete correction of anemia.

As anemia may have multiple causes in as many as 50 % of anemic elderly [5] the diagnosis of the causes of anemia in the older person involves some unique problems. Perhaps the most important diagnostic issue is the recognition of iron deficiency in the presence of anemia of inflammation (table 2.2). A foolproof diagnostic test does not exist, but elevated levels of soluble transferrin receptors and low circulating levels of hepcidin suggest some degree of iron deficiency. In this situation an improvement of anemia following iron treatment may confirm the diagnosis of iron deficiency [49–52]. The distinction is important not only for therapeutic reasons. A diagnosis of iron deficiency should trigger investigations for occult bleeding especially from the gastrointestinal tract [20].

Figure 2.1 illustrates a reasonable approach to the evaluation of anemia in the older aged person. High reticulocyte count indicates loss of read blood cells though acute hemorrhage or hemolysis, while low count reveals anemia due to decreased production, that is the most common form of chronic anemia in the elderly. The size of the red blood cells (Mean Cellular Volume of MCV) may suggest to the cause of anemia:

The MCV may not be very reliable in older individuals because multiple causes of anemia may have different effects on MCV. For example the combination of iron and B12 deficiency may lead to normocytosis [5, 50]. When the B12 levels are borderline (that is lower than 300 ug/dl), one should also check the methymalonic acid levels. An increased concentration of this substance suggest functional B12 deficiency.

Bone marrow examination is required when one suspects the diagnosis of myelodysplasia or of marrow occupying diseases (myelofibrosis, cancer, infections). If myelodysplasia or a neoplastic disorder of the marrow is suspected, cytogenetics and flow cytometry of the marrow should be obtained