Anemia is a significant health problem in the elderly because
of both a high prevalence and significant associated morbidity
(Table 93-1).1 Although there is a long-established perspective that anemia in the elderly is of little consequence, studies have shown that even mild decreases in hemoglobin levels are associated with reduced quality of life, clinical depression, falls, functional impairment, slower walking speed, reduced grip strength, loss of mobility, worsening comorbidities, and mortality and have called for a greater focus on this problem.2 Currently, screening for anemia is not generally practiced, and thus it is typically discovered during a workup for other conditions, at a time when many of its deleterious effects may have already occurred. The World Health Organization (WHO) defines anemia as a hemoglobin level of less than 13g/dL in adult males and less than 12g/dL in adult females.3 In older men and women, anemia by this definition is associated with an increase in mortality.49 It has been pointed out the WHO criteria do not take into account inherent racial variations, particularly with respect to African Americans who may have lower levels of hemoglobin without significant adverse outcomes.10,11 In a study that analyzed 1018 black and 1583 white adults aged 71 to 82 years, anemia was associated with increased mortality in whites but not blacks.10,11 The issue of defining criteria for the diagnosis of anemia is quite relevant in the context of age as well. Older women, for example, have better physical performance and function at hemoglobin values between 13 and 15 g/dL than between 12 and 12.9 g/ dL,12 suggesting perhaps that a cutoff level of 12 g/dL is too low. Nevertheless, the WHO definition remains the current standard utilized in most current epidemiologic surveys and many clinical laboratories. Prevalence of Anemia Guralnik and colleagues examined the third National Health and Nutrition Examination Survey (NHANES III) database, a nationally representative sample of community-dwelling persons and determined age- and sex-specific prevalence rates of anemia in the total U.S. population.13 For those over the age of 65 years, by WHO criteria, approximately 11% were anemic (see Table 93-1). The prevalence of anemia was lowest (1.5%) among males between 17 and 49 years of age and highest (26.1%) in males over 85 years. Among those 65 years and older, the prevalence rate was notably higher in African Americans as compared to whites and Hispanics. Prevalence rates of anemia in the elderly vary in communitydwelling and institutionalized populations. It is also quite
clear that anemia is more common among frail elderly. In the nursing home, for example, anemia prevalence approaches 50% or higher.1417
Pathogenesis
In younger adults with anemia, the cause is usually readily
apparent. In older patients, however, discerning the cause of anemia can oftentimes be challenging (Table 93-2). Inflammation, nutritional deficiencies, and renal insufficiency are commonly observed, but for as many as one third of elderly anemic individuals (and almost 50% for those residing in nursing homes), the anemia cannot be attributed to conventional causes, a condition now termed unexplained anemia.18 ANEMIA OF INFLAMMATION
Chronic diseases, such as atherosclerosis, diabetes, arthritis,
infection, and malignancy, increase in prevalence with age and each is characterized by inflammatory processes. Although there are several ways in which inflammation can negatively influence erythropoiesis, disordered iron kinetics is a common feature.19 During inflammation, there is reduced iron absorption from the gastrointestinal tract and defective reutilization of iron sequestered in reticuloendothelial cells. Hepcidin, a 25 amino acid polypeptide produced in the liver in response to inflammatory stimuli, down-regulates intestinal iron absorption as well as macrophage and monocyte iron release, thereby creating functional iron deficiency and resultant hypoproliferative anemia.2024 Reduced secretion of erythropoietin due to the action of inflammatory cytokines is also known to play a role in the anemia of chronic inflammation. 25
IRON DEFICIENCY ANEMIA
The prevalence of iron deficiency in the elderly may range
from 2.5% to as high as 30% in some studies. Iron deficiency is usually secondary to iron loss rather than inadequate intake and is important to identify because it may be a manifestation of an occult malignancy. For example, in one study, of 114 outpatients referred to a gastroenterologist for investigation of iron deficiency, 45 had upper gastrointestinal and 18 had colonic sources of bleeding.26 In an older study of 100 patients in whom the site of bleeding could not be established by any means other than laparotomy, a malignancy was found to be the cause in 10%.27 In a survey of 1388 patients over 65 years of age, 25% were anemic and approximately one third were iron deficient. Of those with iron deficiency, gastrointestinal endoscopy found 57% to have an upper gastrointestinal lesion and 27% to have colonic lesions. In total, gastrointestinal malignancy was found in 15% of those with iron deficiency anemia. 28 Iron deficiency may be the result of gastrointestinal malabsorption, particularly in patients who have had bowel resection, inflammatory bowel disease, or who are on chronic antacid therapy. Furthermore, malabsorption of iron may be an early manifestation of celiac disease.29,30 For patients who present with anemia and microcytic red
blood cell indices, serum levels of iron, ferritin, and transferrin
saturation are typically low and total iron-binding capacity is elevated. The coexistence of chronic inflammatory disease may complicate analysis. To determine whether patients with chronic inflammation and anemia are iron deficient, measurement of the soluble transferrin receptor is frequently useful. Under conditions of iron deficiency, transferrin receptor is upregulated and increased levels are found in the serum. An index, derived by dividing the serum level of soluble transferrin receptor by the log of the ferritin level, has been shown to be helpful.31 A ratio of less than 2 denotes anemia of chronic inflammation, whereas values greater than 2 identify patients with either uncomplicated iron deficiency anemia or a combination of both iron deficiency and inflammation. B12 AND FOLATE
Since the implementation of the Food and Drug Administrations
policy of folic acid fortification of cereal grain products in 1998, there has been a dramatic reduction in measurable folate deficiency. Just 2 years after implementation, examination of the NHANES cohort IV (19992000) compared with cohort III (19881994) revealed the prevalence of low-serum folate concentrations (<6.8 nmol/L) decreased from 16% before to 0.5% after fortification.32 Thus, folic acid deficiency is currently an uncommon cause of anemia. Vitamin B12 deficiency, however, remains a problem, particularly in geriatric populations. 33 The great majority of B12 deficiency in the elderly is due to food cobalamin malabsorption with true dietary deficiency or pernicious anemia being significantly less common. An age-associated atrophic gastritis with or without antacid therapy is a frequent antecedent. Macrocytic indices, the hallmark of B12 deficiency, may not be apparent because of concomitant inflammatory disease or iron deficiency. In addition to red cell changes, patients with B12 deficiency may also present with a myriad of hematologic abnormalities including leukcopenia, thrombocytopenia, and pancytopenia occasionally requiring the diagnosis of myelodysplasia or aplastic anemia. B12 deficiency is usually suspected by the finding of an elevated mean corpuscular volume (MCV) either on routine screening or for evaluation of the cause for anemia. However, other causes for macrocytosis are more common, and these include excessive alcohol intake, drug intake (particularly antineoplastic agents), reticulocytosis, myelodysplasia, and hypothyroidism. Levels of B12 below 200 pg/mL quite reliably indicate vitamin B12 deficiency; however, measurement of methylmalonic acid levels and homocysteine (which are elevated) may be necessary to establish the diagnosis for those with higher serum B12 levels. Treatment with both intramuscular B12 and crystalline oral B12 are effective in the elderly, even in patients with cobalamin food malabsorption Increasingly, it has become recognized that approximately one third of older adults with anemia do not have an obviously discernible cause upon routine evaluation (Table 93-3). Typically, this anemia is generally mild (hemoglobin concentration
in the 10 to 12 g/dL range), normocytic, and
hypoproliferative (low reticulocyte count). It has been postulated that the cause relates to a number of factors including testosterone,40 occult inflammation,41 reduced hematopoietic reserve with advancing age,42 inappropriately low-serum erythropoietin level,43 and myelodysplastic syndromes (discussed later). It is clear that this anemia is associated with a low-serum erythropoietin level for the degree of anemia. The EPO level usually falls within the normal reference range. However, this is abnormal because serum EPO should rise with falling hemoglobin concentration. The diagnosis of unexplained anemia assumes the clinician has excluded Hemoglobin 10.5 to 12 g/dL Reticulocyte index Low MCV 80 to 95 fL Serum iron Mildly low normal TIBC Normal % Iron saturation Mildly low normal B12, folate, ESR, TSH Normal Platelet and white blood counts Normal Creatinine clearance <90 to >30 mL/min
serious causes. The threshold to pursue a bone marrow
examination to exclude myelodysplastic syndromes remains unknown. However, we advocate considering a bone marrow examination in all patients requiring red cell transfusion who otherwise have an unexplained anemia. Macrocytosis, thrombocytopenia, neutropenia, splenomegaly or unexplained constitutional symptoms of fever, chills, early satiety, bone pain, or weight loss should prompt consideration of a bone marrow examination.