Epidemiology and Causes of Anemia in Older

The incidence and prevalence of anemia increase with age. The NHANES III study (6) found that the prevalence of anemia was approximately 9.5% in individuals aged 65 and older, increased with age, and it was higher for African-Americans, when compared with Caucasians, non black Hispanic and Asian-Americans. Anemia was more common in older man than in older women, a finding that needs qualification. The NHANES III adopted the definition of anemia of the World Health Organization (WHO), that normal hemoglobin values are >12 gm/dl for women and >13.0 gm/dl for man. The accuracy of these values has been questioned since the publications of the Woman Health and Aging studies (WHAS), demonstrating that in women 65 and older hemoglobin levels <13.5 gm/dl were associated with increased risk of mortality (30) and of functional impairment (31). If there is no reason to expect that the average hemoglobin levels should be lower in older women than in older men, as suggested by the WHAS, the prevalence of anemia in the NHANES III is similar for both sexes.

The NHANES III data are consistent with the studies of Olmstead county that demonstrated an age-related increase in incidence and prevalence of anemia. The prevalence of anemia was somehow higher in Olmsted county, as this was a survey of the full population, including the sickest and oldest individuals (8). The data are also consistent with the Italian cross-sectional study that showed a prevalence of anemia of 9.2% for individuals aged 65 and over (32). The Italian study showed that the average hemoglobin levels did not change with age, whereas the prevalence of anemia increased with age, suggesting that anemia, even mild anemia, is not a consequence of age by itself. This suggestion has been challenged by a Japanese cohort study, showing that in the absence of any disease or impairment the values of hemoglobin decreased by 0.036 gm/dl/year for women and by 0.04 gm/dl for men between age 70 and 80 (33). Irrespective of whether there is a modest drop in average hemoglobin levels with age, this appears negligible and unable to explain the increased incidence of anemia in the elderly.

The most common causes of anemia in older individuals in the NHANES III and the Olmstead county study are shown in Table 2.2. It is possible that with more investigations a specific cause might have been found for the so called anemias of unknown causes, including early myelodysplasia, and anemia of renal insufficiency, as the GFR declines with age in the majority of cases, and this decline has not been associated with increase in the concentration of serum creatinine (12). A number of studies indicated that the secretion of erythropoietin by the kidney may decrease when the GFR drops below 60 ml/dl (34).

Recent findings are germane to the discussion of the causes of anemia in older individuals:

• Incidence and prevalence of B12 deficiency increase with age (35, 36). The most common cause of B12 deficiency is the inability to digest food B12 due to decreased gastric secretion of hydrochloric acid and of pepsin, and may be responsive to oral crystalline B12. In addition to anemia, B12 deficiency may be a cause of neurologic disorders including dementia, and posterior column lesions.

• Seemingly, the main cause of iron deficiency is chronic bleeding, from cancer, diverticuli, or angiodysplasia. In older age iron deficiency may have other causes, including decreased absorption of iron, due to gastric achylia, and to increased circulating concentrations of hepcidin. Hepcidin prevents the absorption of iron from the duodenum, and is a protein synthesized in the liver, whose production is stimulated by IL-6 (37) A recently recognized cause of iron deficiency is H Pylori gastritis (38).

• In some older individuals the secretion of erythropoietin and the ery-thropoietic response to erythropoietin may be impaired, as a result of increased circulating concentrations of IL-6 and other inflammatory cytokines (39, 40). In elderly patients from Chianti, Ferrucci et al. demonstrated that increased concentration of inflammatory cytokines in the circulation is associated with increased concentrations of erythropoi-etin initially, followed by reduced response of erythropoietin to anemia

(Fig. 2.3) (39). Similar findings were reported in a sample of patients from the Baltimore Longitudinal Study by Ershler et al. (40). These studies suggest a biphasic response of erythropoietin to inflammatory cytokines: an initial increased production of erythropoietin even for normal hemoglobin levels, followed by a reduced response of erythropoietin to the drop of hemoglobin concentration. This condition of relative ery-thropoietin deficiency, similar to relative insulin deficiency in type II diabetes, is exacerbated by increased resistance of erythropoietic progenitors to erythropoietin, also mediated by IL-6, and increased circulating levels of hepcidine, that prevent mobilization of iron from iron stores. Is there a difference between anemia of aging and anemia of chronic inflammation (ACI) (41)? Certainly there is almost complete overlap in the patho-genesis of the two forms of anemia, and aging may be considered a chronic progressive inflammation. At present there is not good reason to distinguish the two entities.

• In the INCHIANTI study Ferrucci et al. found that anemia was associated with low testosterone levels both in men and women and that low testosterone levels predicted the development of anemia in non anemic


Hemoglobin (g/dL) Fig. 2.3. Recommended diagnostic investigations of anemia

Hemoglobin (g/dL) Fig. 2.3. Recommended diagnostic investigations of anemia

individuals over the next 3 years (42). The role of hypogonadism in the development of anemia deserves further exploration especially in view of the current trend to treat older men with testosterone replacement.

• Recent studies show that lenalidomide may induce a complete cytogenetic response in patients with refractory anemia and q (-) cytogenetic abnormalities (43) and may prolong the survival of these patients. Thus, work up for myelodysplasia in older individuals with mild anemia of unknown causes may avert to some extent the mortality and morbidity from this condition. This hypothesis should be tested in randomized controlled studies.

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