Anemia in Elderly Persons

A decline in the hemoglobin level was long considered a natural and expected consequence of aging. The frequently-used phrase “anemia of the elderly” to describe this phenomenon implied that it is unnecessary to conduct a thorough workup to identify a treatable underlying cause. However, emerging data show that anemia in this age group does reflect poor health status and results in adverse outcomes. Consequently, the phrase “anemia in the elderly” has come into use, indicating that anemia in an elderly patient mandates a workup to identify correctable causes of anemia, so that treatment can prevent the resulting morbidity and mortality.

The importance of this condition is set to increase significantly in the coming years. The World Health Organization (WHO) estimates that between 2015 and 2050, the percentage of the world's population over age 60 years will nearly double, from 12% to 22% (rising from 900 million in 2015 to 2 billion in 2050). ^[1]

Go to Anemia, Iron Deficiency Anemia, and Chronic Anemia for complete information on these topics.

For patient education information, see Anemia.

Currently the only universally used definition of anemia in adults is the one proposed by WHO in 1968 as hemoglobin less than 13 g/dL in men and less than 12 g/dL in women. ^[2] This definition has since been used in population studies for anemia in elderly groups as well, though it is not an “elderly specific” definition.

Some investigators have questioned this definition, based on the National Health and Nutrition Survey (NHANES) and the Scripps-Kaiser database and outcome studies. ^{[3, 4, 5, 6]} The limitation of those population studies is that they included both healthy elderly persons with few or no comorbidities as well as those with various comorbidities. However, studies on small cohorts of elderly patients without any significant chronic medical condition have shown that the hemoglobin decline during aging tends to be minimal or insignificant, even in very older individuals. ^{[7, 8, 9]} Therefore, the1968 WHO definition of anemia has remained the standard and universally used by researchers. ^[10]

In addition to the varying thresholds for anemia, the highly heterogeneous nature of the elderly population has led to multiple estimates of anemia prevalence in the elderly. An analysis of NHANES data from 2001-2016 cycles found that in the United States population aged 65 years and older, the overall anemia prevalence was 14.1% in men (95% confidence interval [CI] 11.8–16.7%) and 10.2% in women (95% CI 8.5–12.1%). ^[12] An increase in the prevalence of anemia with increasing age was noted in all survey cycles for men and all but one survey cycle for women. In 2013–2016, for example, anemia prevalence by age was as follows:

• Age 65-74 y - Men, 7.4%; women, 7.6%
• Age 75–84 y - Men, 21.5% women, 11.0%
• Age ≥ 85 y - Men, 39.5%; women, 21.9%

Rates of anemia in the elderly may have been increasing. The NHANES data from 2001–2004 to 2013–2016 showed a statistically insignificant trend toward increased prevalence of anemia in men aged 75 to 84 years, and a significant increase (from 24.2% to 39.5%) in men aged 85 and older. The prevalence of anemia in elderly US women also increased over that period, although for the most part the trends were not significant. ^[12] Even if rates of anemia in the elderly were to remain stable, however, the number of elderly patients with anemia is likely to increase dramatically in the coming years because of the aging population globally. ^{[1, 13, 14]}

It should be noted that NHANES estimates are representative of the general noninstitutionalized US population. They do not include institutionalized persons, a population with higher rates of anemia. ^[15] A study of homebound older adults found that the rate of anemia was 4 times as high as that reported from NHANES III data. ^[16]

Studies from Europe, Japan, China, and Ecuador indicate a fairly similar prevalence of anemia in elderly adults in those parts of the world as in the United States. ^[17] A systematic review of 34 studies showed that, in Europeans older than 65 years, the prevalence of anemia was 12% in community-dwelling persons, 40% in hospitalized persons, and 47% in nursing home residents. ^[18] In this study overall, an estimated 17% of those older than 65 years (nearly 15 million elderly persons living in the European Union) were found to have anemia.

Similarly, in Japan the prevalence of anemia has been reported to be 17.1% in individuals older than 65 years ^[19] and 22.3% in those 69–91 years. ^[20] In rural China the prevalence of anemia in those older than 60 years has been reported as 12.9%. ^[21]

Racial and sexual demographics

Anemia is approximately 3 times more prevalent in elderly Blacks than in non-Hispanic Whites, with the median hemoglobin (Hb) concentration for elderly Blacks being approximately 0.8 g/dL lower than for Whites. ^[22] In older Mexican Americans, the prevalence of anemia is fairly similar to that of elderly whites, The reason for the higher prevalence of anemia in Blacks has not been established. However, some of the disparity is likely related to biologic differences. Whether anemia has different adverse consequences in Blacks is unclear.

In elderly persons, anemia is more common in men than in women. Some of the difference stems from employing a lower Hb threshold for women than for men (12 versus 13 g/dL, respectively). Hb levels decline slightly and anemia prevalence rises with advancing age in both men and women, but the change is more pronounced in men. ^[22]

Hematopoiesis—the production of blood elements—occurs in an orderly, hierarchical fashion. Blood cell production requires stem cells, a functioning bone marrow microenvironment, nutrients, and cytokines. A pluripotent hematopoietic stem cell gives rise to committed progenitors of myeloid, erythroid, and megakaryocytic lineages.

Erythropoiesis is the arm of hematopoiesis that generates erythrocytes. In adults, normal erythropoiesis occurs exclusively in the bone marrow and is generally restricted to the pelvis, vertebrae, sternum, ribs, and proximal femurs. The earliest committed erythroid lineage progenitors include the burst-forming unit-erythroid (BFU-E), which later gives rise to the colony-forming unit-erythroid (CFU-E).

The reticulocyte, an early red blood cell (RBC) that has lost the nucleus but retained the polyribosomal reticular network, eventually emerges into the blood. After 1-4 days, reticulocytes lose this ribosomal network and mature into RBCs. Mature RBCS have an average lifespan in the blood of 100-120 days. Macrophages engulf senescent RBCs in the spleen, liver, and marrow. Iron extracted from RBCs in this process is recycled back to bone marrow to maintain erythropoiesis.

Multiple conditions can lead to anemia in elderly persons. Moreover, the anemia may be multifactorial. The most common causes are iron deficiency (with or without blood loss), chronic disease/inflammation, and chronic kidney disease. ^[11] Other etiologies of anemia in the elderly include the following:

• Deficiencies of folate or vitamin B12
• Diseases of the bone marrow (eg, myelodysplastic syndromes (MDS),  aplastic anemia, myeloproliferative syndromes, acute or chronic leukemia, lymphoma)
• Hypothyroidism
• Hypersplenism
• Hemolytic anemia

See the table below.

Table 1. Prevalence of Various Etiologies of Anemia in Elderly Persons ^[23] (Open Table in a new window)

Up to 35-40% of anemia in older adults is “unexplained”. ^[23] In some of these cases, however, additional studies, including a bone marrow biopsy and next-generation sequencing, may identify the anemia as part of one of the following potential pre-MDS conditions ^[11] :

• Idiopathic cytopenia of undetermined significance (ICUS)
• Clonal cytopenia of undetermined significance (CCUS)
• Idiopathic dysplasia of undetermined potential (IDUS)
• Clonal hematopoiesis of indeterminate potential (CHIP)

Nutrient deficiencies

Iron deficiency anemia represents 12-32.4% of cases of anemia among the elderly. ^[23] The RBCs serve as the largest storage compartment of iron in the body, and RBC loss often leads to iron deficiency. Identifying iron deficiency anemia in elderly persons is essential, as the condition can be corrected. More importantly, iron deficiency, particularly in elderly persons, often points to an underlying gastrointestinal pathology, including malignancy. ^[24]

Folic acid, vitamin B12, zinc, and copper are essential macronutrients that directly affect hematopoiesis. To the extent that such reversible micronutrient deficiencies suggest other conditions (eg, pernicious anemia or hemolysis), they remain important to identify. Low vitamin B12 levels in elderly persons is common. ^[25] Folate deficiency is considered uncommon, in part because of mandatory fortification of grain products in the US and many other countries, but may occur at higher rates in certain populations. ^[26]

Copper deficiency appears to be becoming more common. ^[27] Copper deficiency can cause not only anemia (typically macrocytic) but also other cytopenias, such as neutropenia and thrombocytopenia. ^[28] Malnutrition, malabsorption, small bowel surgeries requiring total parenteral nutrition or jejunal feeding, and bariatric surgery increase the risk of copper deficiency in the elderly.

Zinc deficiency can be acquired or inherited. Acquired deficiency can result from decreased intake, impaired absorption, increased metabolic demand, or excessive loss. ^[29] In developing countries, acquired zinc deficiency is common and is attributable to malnutrition and high dietary phytate; in developed countries it is associated with aging and many chronic illnesses.

Anemia of chronic disease and inflammation

Anemia of chronic disease appears to be primarily related to inflammation, thus leading to the term anemia of chronic inflammation (ACI). ACI is a hypoproliferative anemia characterized by low serum iron without evidence of low iron stores. Inflammatory markers implicated in ACI include interleukin-6 (IL-6), interleukin-1 beta (IL-1β), Stat3, C/EBP alpha, and p53. ^[30] Conditions associated with ACI include cancer, chronic infection, and autoimmune diseases. ^[31]

Other chronic diseases (eg, osteoarthritis, hypertension) often contribute indirectly to anemia. Use of nonsteroidal anti-inflammatory drugs for treatment of osteoarthritis may lead to gastrointestinal bleeding and iron deficiency, whereas hypertension may contribute to anemia by causing chronic kidney disease (CKD). Emerging evidence suggests that conditions such as CKD, diabetes mellitus, obesity, liver disease, heart failure, and pulmonary hypertension can be classified as inflammatory conditions. 

Inflammation inhibits erythropoiesis through a variety of mechanisms. The discovery of hepcidin has considerably clarified the pathophysiology of ACI. Hepcidin, synthesized by the liver, is a 25–amino acid peptide that serves as a primary regulator of iron homeostasis. Inflammation, particularly with IL-6, increases hepcidin expression. Hepcidin directly inhibits ferroportin, a protein that transports iron out of cells that store it. ^[32] This leads to reduced enteral iron resorption and trapping of iron in reticuloendothelial cells, resulting in functional iron deficiency. ^[33] ACI and the disordered iron homeostasis that is typically found with it is explained by increased hepcidin expression. ^{[34, 35]} Impaired erythropoietin (EPO) production and activity and EPO receptor responsiveness have also been observed.

Kidney insufficiency

Various hematopoietic growth factors support stem cell proliferation, differentiation, and survival. EPO, a glycoprotein that is a hematopoietic growth factor, serves as a primary regulator of RBC production. Synthesis and regulation of EPO occurs primarily in the kidney, with a smaller contribution by liver hepatocytes. ^{[36, 37, 38, 39]} Reduced tissue oxygenation (rather than diminished RBC production), typically from anemia or hypoxia, potently stimulates a logarithmic enhancement of EPO synthesis. ^[40]

CKD is an important cause of anemia in elderly persons, especially considering that kidney function declines with aging. ^[41] In one study of older residents in a skilled nursing facility, 43% had CKD (defined as a creatinine clearance of less than 60 mL/min), and the residents with CKD were more likely to have anemia. ^[42]

Reduced renal EPO production is the primary factor leading to anemia in CKD. The precise degree of kidney dysfunction sufficient to cause anemia remains controversial. Serum EPO levels have been shown to be low at a creatinine clearance of less than 40 mL/min. However, mild anemia in adults may be detected at a creatinine clearance of 40-60 mL/min. ^{[43, 44, 45]} The InCHIANTI study, which was performed among community-dwelling elderly persons, suggested that anemia and low EPO levels are independent of age and other factors at a creatinine clearance of less than 30 mL/min. ^[46]

Endocrinopathies

Endocrine dysfunctions that result in anemia include the following:

• Relative EPO deficiency
• Thyroid disease
• Low testosterone

Relative EPO deficiency

In the prototypical model of complete kidney failure, inadequate endogenous EPO secretion rather than a primary marrow problem leads to anemia. ^[47] Even in kidney disorders without overt glomerular filtration abnormalities, endocrine function as measured by the endogenous EPO response to anemia may be impaired. For example, children with nephritic syndrome, before significant renal clearance impairment, have a blunted endogenous EPO response to anemia. ^[48] A decline in kidney function may be a feature of aging ^[49] that is accentuated by hypertension and diabetes. ^[50] Thus, a relative EPO deficiency, potentially from early and undiagnosed kidney damage, likely contributes to unexplained anemia. ^{[46, 51]}

Thyroid disease

Anemia has been recognized as a complication of thyroid dysfunction. ^[52] Hypothyroidism and hyperthyroidism may be associated with pernicious anemia and both conditions may also lead to a correctable anemia, but most patients with thyroid abnormalities are not anemic. ^[53] Hypothyroidism reduces RBC mass and may lead to a normocytic anemia. ^[54] Occasionally, hypothyroidism may lead to macrocytosis without anemia. ^[55]

The degree of thyroid dysfunction leading to anemia remains unknown. Generally, the more severe the thyroid dysfunction, the more likely anemia will occur. Kim et al found that a low-normal level of serum free T4 was associated with a lower serum Hb level and a higher risk of anemia in euthyroid adults, especially in younger participants. ^[54] A therapeutic trial correcting the thyroid abnormalities may be necessary to definitively determine their role in causing lower Hb concentration.

Low testosterone

A large epidemiologic study showed that men with lower testosterone levels were more likely to have anemia. ^[56] The general Hb difference between men and women relates in large part to the erythropoietic effects of testosterone, which can be illustrated by the fact that after orchiectomy ^[57] or androgen deprivation therapy for prostate cancer, ^[58] Hb falls by 1.2 to 1.5 g/dL on average. Testosterone levels decline with aging in men. ^[59] The greater rate of Hb decline in men than in women with advancing age raises the suspicion that falling testosterone may cause the “unexplained" anemia in this population. Further, testosterone replacement raises Hb in older men. ^[60] Whether testosterone replacement improves quality of life is yet to be systematically studied. ^[61]

Primary hematologic disorders

A variety of primary hematologic disorders have anemia as a manifestation. Thrombotic thrombocytopenic purpura (TTP), although rare, should be considered in every patient with anemia, as this a medical emergency requiring prompt intervention. Often (but not always), patients with TTP will have other cardinal features of the disorder, including thrombocytopenia, altered mental status, and kidney insufficiency.

Patients with myeloproliferative diseases often have an elevated white blood cell (WBC) count. However, elderly patients with acute leukemia can have a more smoldering disease course than younger patients. These patients may present with a low, high, or even normal WBC count, although in most individuals the WBC differential is abnormal. This fact emphasizes the importance of performing a manual differential in all patients with an abnormal complete blood cell count (CBC). ^[62]

Chronic lymphocytic leukemia (CLL) is common in elderly persons. Although most patients will have either an elevated WBC count or lymphadenopathy at presentation, some patients will present with autoimmune hemolytic anemia. ^[63]

Plasma cell disorders should always be considered, particularly in patients with elevated globulin levels.

Patients with aplastic anemia may or may not have a low WBC and/or platelet count. However, some patients with myelofibrosis will have anemia as the prominent abnormality. Myelodysplastic syndromes represent a heterogeneous group of disorders characterized by clonal hematopoiesis and peripheral blood cytopenias. They are more common in older adults and initially may present as an isolated anemia. In the elderly, anemia in conjunction with macrocytosis, thrombocytopenia, or neutropenia in the absence of another cause raises the suspicion of myelodysplastic syndrome. ^[64] When evaluating mean corpuscular volume (MCV), the clinician must be cognizant that recent RBC transfusions will alter the values. Thus, determining hematology values before a transfusion is critical.

Finally, anemia can be a sign of bone marrow infiltration from lymphoma and leukemia or metastatic solid tumors. Not uncommonly, the patient will not have palpable lymphadenopathy, but computed tomography (CT) scans could reveal extensive internal lymphadenopathy. In these patients, measurement of a lactate dehydrogenase (LDH) level is essential.

Although anemia in elderly population is a prevalent condition, it is underrecognized and undertreated. ^[65] Multiple epidemiologic studies show an association between anemia, or even mildly low hemoglobin (Hb) above the WHO threshold for anemia (ie, < 14 g/dL), and adverse health and economic outcomes. ^{[66, 67]} Anemia impairs quality of life and increases frailty; an increase of 1 g/dL in Hb is associated with a 14% reduction in risk of being frail (odds ratio [OR] 0.86, 95% CI 0.79–0.94). ^{[68, 69]} A Dutch study of 562 elderly persons aged 85 years, with a 5-year annual follow-up, found that the 26.7% of study participants who had anemia at baseline had more disability in instrumental activities of daily living than did the other participants. ^[70]

Fall and fracture risk rises as Hb level decreases, but importantly, even individuals with the mildest anemia (Hb 12–12.9 g/ dl) are at significantly greater risk of the following:

• Falls ^{[71, 72]}
• Poor cardiovascular disease outcome ^{[73, 74, 75, 75]}
• Dementia ^[76]
• Depression ^[77]
• Insomnia ^[78]
• Reduced executive function and physical performance ^{[79, 80, 81]}

Anemia also adversely affects the outcome of various procedures in elderly, from spinal procedures to carotid endarterectomy and knee arthroscopy. ^{[82, 83, 84, 85]} Overall, anemia in the elderly is associated with increased mortality and hospitalization. ^{[79, 86, 87, 88]} Older patients with anemia have longer hospital stays—from 4 to 10 days longer, depending on severity of anemia. ^{[89, 90, 91]}

Therefore, medical costs are more than twice as high as patients without anemia matched for age, sex, comorbidities, and insurance status. ^[92] Anemia also increases the medical cost associated with various comorbidities. ^{[93, 94, 95]} Additionally, the increased risk of injurious falls and fractures contributes to increased cost of care for this patient population. ^{[96, 97, 98]}

Medical history

Obtaining a detailed medical history can be extremely valuable in the diagnosis of anemia and its cause. Inquiries should include the following:

• Previous blood counts – These represent one of the most underused and invaluable tools to help clinicians determine the acuity of the anemia. Elderly persons have frequently had previous blood counts that are easily retrievable. The causes for an acute fall in Hb are narrow (eg, bleeding, hemolysis), as opposed to the more common slow decline over time.
• Previous RBC transfusions – This indicates a chronic problem.
• Recent hospitalization – Hospitalization often results in anemia, particularly in elderly persons. The anemia is often the consequence of multiple phlebotomies, as well as the acute illness itself. Thus, the prehospitalization Hb can be invaluable.
• Recent surgery – This suggests blood loss and necessitates comparison to preoperative Hb values. When surgery requires RBC transfusion, the patient has often had a low Hb before the surgery, had another condition preventing an appropriate response to blood loss, or both.

Diseases that frequently cause anemia should be noted, including the following:

• Myelodysplasia
• Cancer (and cancer chemotherapy, especially myelosuppressive chemotherapy)
• Chronic kidney disease
• End-stage kidney disease
• Rheumatologic disorders

Conditions that are associated with specific types of anemia should be clearly identified. Lymphoproliferative and autoimmune disease may cause autoimmune hemolytic anemia. Previous chemotherapy or radiotherapy raises the possibility of therapy-related myelodysplastic syndrome. Alcohol overuse may go unrecognized in the elderly and can lead to deficiencies of vitamin B12 and folate, as well as marrow hypoproliferation and gastrointestinal bleeding.

Family history and racial background

Family history can be useful for suggesting a coexistent thalassemia trait, hemoglobinopathies, and other inherited anemias. Racial ancestry should be considered, with recognition that Hb concentrations may be approximately 0.8 g/dL lower in Blacks than in Whites.

Signs and symptoms

Most symptoms of anemia are nonspecific (eg, fatigue, shortness of breath, tinnitus). Nevertheless, a detailed history often identifies the presence of anemia-related symptoms. Obvious blood loss should be directly inquired about (eg, melena, hematuria, hemoptysis, hematemesis, abnormal vaginal bleeding). A temporal relation between falling Hb and symptom exacerbation is very useful. Symptoms relate to the rapidity of the development of anemia, the depth of the Hb fall, and concomitant medical conditions. 

Inquiries about specific tasks, such as walking upstairs, can provide useful objective information. Fatigability was found to be a predictor of subclinical and clinical anemia in a longitudinal analysis of 905 well-functioning men and women aged 60-89 years who were followed for 1-5 years from the Baltimore Longitudinal Study of Aging conducted at the National Institute of Aging. ^[99]

Special attention should be paid to elements that indicate a cause for the anemia (eg, presence or symptoms of cancer, gastrointestinal blood loss, infection, arthritis) and symptoms related to anemia. Patients may mistakenly attribute decreased energy to aging or medications.

General signs and symptoms include the following:

• Fatigue
• Weakness
• Dyspnea on exertion
• Presyncope
• Palpitations
• Headache
• Poor concentration

Signs and symptoms of iron deficiency may include the following:

• Blood loss (tarry stools, red blood in the stools, hematuria)
• Pica (desire to consume unusual substances, such as ice or dirt)
• Koilonychia (spoon-shaped changes in the nail beds)
• Dysphagia (from esophageal webs)
• Mouth and tongue soreness (from atrophy)
• Hair loss

Signs and symptoms of vitamin B12 deficiency may include the following:

• Neuropathy
• Ataxia
• Dementia

Signs and symptoms of hemolysis may include the following:

• Jaundice
• Dark urine (if intravascular hemolysis)

Physical examination

The physical examination may uncover an anemia etiology, signs related to the anemia, or both. Thus, the examination must be comprehensive. Special attention should be paid to the following:

• Pallor
• Icterus
• Lymphadenopathy
• Tachycardia
• Cardiac murmurs
• Hepatomegaly
• Splenomegaly
• Edema

An abdominal ultrasonogram can be helpful if the patient's body habitus makes examination for hepatosplenomegaly difficult.

The differential diagnosis of anemia in the elderly should include the following:

• Anemia of chronic inflammation/anemia of chronic disease from infection, malignancy, or rheumatologic disease
• Anemia of chronic kidney disease
• Bone marrow failure
• Blood loss
• Coombs negative and positive hemolytic anemias
• Endocrinopathies
• Medications
• Paraneoplastic
• Malignancies (hematologic and nonhematologic)
• Nutritional deficiencies
• Pernicious anemia
• Splenomegaly
• Inherited anemias
• Microangiopathic anemias

Initiate an evaluation under the following conditions:

• Hb below the WHO threshold (Hb < 13 g/dL for men; < 12 g/dL for women)
• Hb that has fallen more than 2 g/dL over any period without an adequate explanation (eg, major surgery)
• Hb that does not recover to baseline after an acute event

Numerous algorithms have been proposed for the evaluation of anemia and anemia in elderly persons. They are often based on kinetic measures made by first assessing the reticulocyte count, RBC size (using mean corpuscular volume [MCV]), or peripheral smear (see the image below). Such an investigation must account for the unique epidemiology in this population.

The following commonalities guide the evaluation:

• Anemia can be multifactorial.
• Previous blood counts are helpful to obtain.
• Most anemia in elderly persons is hypoproliferative (ie, reticulocytosis is inadequately low).
• Generally, the more severe the anemia, the more likely an obvious cause will be detected.
• Approximately one third of older subjects are diagnosed with “unexplained” anemia, this can be further worked up with a bone marrow biopsy and next-generation sequencing.
•  Peripheral smear is very helpful to obtain.

Potential causes for microcytic anemia include the following:

• Anemia of chronic disease
• Iron deficiency
• Lead poisoning
• Sideroblastic anemia
• Thalassemia trait

Potential causes for normocytic anemia include the following:

• Anemia of chronic disease
• Aplastic anemia
• Chronic kidney disease
• Endocrinopathies
• Liver disease
• Mixed nutritional deficiency

Potential causes for macrocytic anemia include the following:

• Vitamin B12 deficiency
• Folate deficiency
• Medications (eg, myelosuppressive chemotherapy, hydroxyurea, trimethoprim, anticonvulsants)
• Alcohol overuse
• Liver disease
• Hypothyroidism
• Chronic obstructive pulmonary disease
• Reticulocytosis
• Spurious (eg, hyperglycemia or cold agglutinin disease)
• Marrow disease, especially myelodysplastic syndromes
• Cold agglutinin disease
• Zinc deficiency
• Copper deficiency

Should the anemia's etiology not be apparent from the initial history and physical examination, a comprehensive evaluation is useful. Recommended studies include the following:

• Complete blood cell count (CBC) with differential
• Examination of peripheral blood smear, to evaluate for such features as dysplasia, basophilic stipiling, hypersegmented neutrophils, bite cells
• Reticulocyte count
• Lactate dehydrogenase (LDH)
• Iron studies
• Vitamin B12
• Folate
• Thyroid-stimulating hormone
• Serum creatinine and estimated glomerular filtration rate
• Serum protein electrophoresis with immunofixation and serum free light chains, especially if total globulins are elevated

In about two thirds of elderly persons with anemia, this evaluation will lead to a presumed etiology for the anemia. A reiterative process is essential: Once a deficiency is identified, blood counts should be reevaluated after identifying the problem, correcting the deficiency, or both.

Additional tests often performed include the following:

• C-reactive protein (CRP)
• Serum erythropoietin (EPO)
• Copper
• Zinc
• Serum and urine protein electrophoresis with immunofixation

Possible hemolysis may be evaluated with the following:

• Liver function tests (Indirect bilirubin and direct bilirubin)
• Serum haptoglobin
• Direct and indirect Coombs tests
•  Urinalysis (urine hemosiderin and urine Hb)
• Splenic ultrasonography, an imaging test, can also be used in the evaluation of hemolysis.

Androgen insufficiency may be evaluated with testosterone and sex hormone–binding globulin (SHBG) levels.

A peripheral blood smear is invaluable, especially when determining if a primary bone marrow process accounts for macrocytic anemia. This generally requires a hematology or pathology review of the peripheral smear, rather than a technician-reported analysis. If no cause is identified, a hematology referral and/or bone marrow examination should be considered. The more severe the anemia and the more severe the macrocytosis, the more likely a specific cause will be identified.

Diagnostic pitfalls

Etiologies of anemia in the elderly that can pose diagnostic challenges include the following:

• Iron deficiency
• Vitamin B12 deficiency
• Chronic inflammation

Iron deficiency

Serum iron is not an adequate test to exclude iron deficiency. Nor does a normocytic anemia exclude iron deficiency, as iron deficiency can coincide with deficiencies of other nutritients, such as vitamin B12, folate, zinc, or copper, which may mask the microcytosis. Because iron deficiency is correctable and often reflects gastrointestinal pathology, including malignancy, every elderly anemic adult requires a thorough evaluation to determine the underlying cause of iron deficiency, including a gastroenterology consult to perform endoscopy, colonoscopy, or a capsule study.

Although in some conditions (eg, thalassemia ^[100] ) serum ferritin may underestimate body iron stores, serum ferritin remains the most useful test for diagnosing iron deficiency anemia. Low serum ferritin (eg, < 30 ng/mL) is highly specific for iron deficiency anemia. ^{[24, 26]} On the other hand, as an acute--phase reactant, ferritin can be elevated in inflammation, complicating the diagnosis of iron deficiency anemia or iron overload in the presence of inflammation. An elevated ferritin therefore requires confirmation of iron overload by liver magnetic resonance imaging (MRI) or liver biopsy.

Intermediate ferritin values of 18 to 44 ng/mL are highly suggestive of iron deficiency in the elderly. Thus, using a higher threshold for serum ferritin in the elderly to account for aging-related inflammation and/or comorbid conditions enables reasonable sensitivity and specificity for iron deficiency anemia. ^{[24, 30]}

The use of CBC indices such as red cell distribution width (RDW), MCV, or mean corpuscular hemoglobin (MCH) and reticulocyte count and peripheral smear may be additional helpful tools. A major pitfall is misinterpreting the MCV. Although microcytosis occurs in iron deficiency anemia, it is a late finding and typically occurs only after chronic iron deficiency leads to an Hb value of less than 10 g/dL. The impact of other factors may abrogate the standard changes in cell size. For example, alcohol use or liver disease leads to increased RBC size. That said, microcytic anemia in an older adult in the absence of an obvious chronic inflammatory disease is highly suspicious for iron deficiency (eg, if an initial MCV of 85 fL and an Hb of 12 g/dL changes to an MCV of 75 fL and an Hb of 9.5 g/dL).

Vitamin B12 deficiency

Currently there is no universally accepted definition of vitamin B12 deficiency. The WHO has suggested using a value of  < 200 pg/mL. However, some consider that too low and instead suggest 400 pg/mL as a cutoff value. 

Homocysteine levels cannot be used to distinguish vitamin B12 deficiency from folate deficiency, as levels are elevated in both conditions. For equivocal levels of vitamin B12 (eg, a level between 200 and 400 pg/mL), checking for methylmalonic acid (MMA) will be helpful, as the combination of increased homocysteine and MMA levels with a slightly decreased vitamin B12 level is consistent with early or mild vitamin B12 deficiency, rather than folate deficiency. However some experts believe elevated MMA may also be observed at the later stage of vitamin B12 deficiency.

MMA is also elevated in the setting of kidney dysfunction. ^[25] In dialysis patients, a level higher than 500-700 mcmol/L might be more indicative of vitamin B12 deficiency, and empiric supplementation with cobalamin that results in improvement in anemia can be confirmatory.

Anemias due to vitamin B12, folate, zinc, or copper deficiency are typically macrocytic but may not be, as these cases may also be associated with iron deficiency. However, the presence of an MCV greater than 115 fL is highly suspicious for the megaloblastoid anemia that is characteristic of those deficiencies. Re-evaluating the anemia after replacing the micronutrients is essential, as persistent anemia indicates that the low nutrient level was only partially causative and other etiologies need to be investigated. However, performing bone marrow biopsy before correcting these micronutrient deficiencies can result in misdiagnosis, as the findings may be mistaken for myelodysplastic syndrome. ^{[101, 102]}

Once vitamin B12 deficiency has been identified, an etiology for it (eg, pernicious anemia, malabsorption) should be investigated and vitamin B12 replenished.

Chronic inflammation

No established diagnostic criteria for anemia of chronic inflammation exist. Hepcidin testing has not been validated as a diagnostic test for anemia of chronic inflammation, and in any case is not clinically available. In NHANES III, anemia of inflammation was defined as a low serum iron level (eg, < 60 μg/dL) without evidence of low iron stores. ^[103] Other features of anemia of inflammation include inappropriately low levels of EPO and elevated inflammatory markers such as CRP or erythrocyte sedimentation rate (ESR). ^[104] An alternative method is to consider anemia of chronic inflammation to exist when the patient has an inflammatory comorbid condition.

Evaluation of “unexplained” anemia

Even after an extensive evaluation, approximately one third of older adults with anemia do not have an obviously discernible cause of anemia. The anemia in these patients is generally mild (Hb from 9-12 g/dL), normocytic, and hypoproliferative (low reticulocyte count). Potential explanations for the anemia have included low testosterone, occult inflammation or infection, reduced hematopoietic reserve with advancing age, inappropriately low serum EPO level, and myelodysplastic syndromes (MDS). The diagnosis of unexplained anemia assumes the clinician has excluded more common known causes.

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.

The threshold to pursue a bone marrow examination to exclude MDS remains unknown. However, the authors advocate considering referral for further evaluation and bone marrow examination in all patients who otherwise have unexplained anemia. A bone marrow aspirate and biopsy are used when a primary marrow disease (eg, MDS, aplastic anemia) is suspected. Occasionally, the marrow is used to investigate possible marrow involvement of non-marrow diseases (eg, infection, lymphoma), or nonmalignant marrow processes (eg, hemophagocytic syndrome, Gaucher disease).

MDS should be diagnosed based on a bone marrow examination and not only on the peripheral smear. Bone marrow examination generally has fewer complications and is less invasive than is generally appreciated.

The glomerular filtration rate, calculated with serum cystatin C, may be a marker to uncover undiagnosed kidney dysfunction. However, this needs to be interpreted in collaboration with a nephrologist. ^[105]

Management of anemia in the elderly usually requires a multidisciplinary approach. The critical element is to identify and treat reversible etiologies for the anemia (eg, nutritional deficiency, infection) and address comorbid conditions. Intervention to correct the anemia itself remains experimental.

While folate deficiency has become vanishingly rare due to folate fortification of flour and other grain products, particular attention needs to be paid in certain settings, such as poor diet combined with alcoholism, or compliance failure with folate and vitamin B12 supplementation in a dialysis patient. Similarly, vitamin B12 deficiency may be infrequently diagnosed, but a diagnostic trial of vitamin B12 therapy may be necessary if the constellation of symptoms and signs are consistent with this etiology. Unless a deficiency has been identified as a cause of anemia in an elderly person, no specific dietary intervention will be fruitful, except in special circumstances such as hemolytic anemias, blood donors, or in dialysis patients receiving EPO. In those cases, ample amounts of vitamin B12, folate, and iron are required to empower effective hematopoiesis.  

For unexplained anemia, no treatment has been well studied. Medications include erythropoiesis-stimulating agents (ESAs), oral mineral supplements (used in mineral deficiencies), and colony-stimulating factors (used to enhance erythropoiesis when endogenous EPO levels are low). In elderly patients who may have active cardiac symptoms, activity restrictions may be considered until an appropriate cardiac evaluation has been performed.

RBC transfusion

For severe symptomatic anemia, RBC transfusion is warranted. Transfusions entail numerous, and often underappreciated, risks of infection, volume overload, transfusion reactions, and costs. Two units of RBCs may represent a considerable volume for elderly patients who have preexisting cardiac dysfunction. As a general rule, geriatric patients should be transfused more slowly than younger adults, and diuretic treatment may be considered to avoid transfusion-associated circulatory overload (TACO).

If one unit adequately improves symptoms and clinical status, no further units should be given, regardless of initial Hb values. Repeated transfusions can result in iron overload and clinical manifestations of hemochromatosis as well as RBCl alloimmunization in some conditions. Recommendations for Hb thresholds vary, depending on severity of anemia, patient comorbidities, and cause. The need for transfusion is also related to the rapidity of the Hb drop, as patients will be more symptomatic from a more acute drop in Hb. Prospective randomized controlled trials are required to definitively clarify the role of transfusions in older individuals with anemia and different types of cardiovascular disease.

Erythropoiesis-stimulating agents

ESAs approved in the United States include epoetin-alfa (Procrit, Epogen), and biosimilar epoietin alfa-epbx (Retacrit), darbepoetin-alfa (Aranesp), and methoxy polyethylene glycol/epoetin beta (Mircera). The primary indication for use of these agents is anemia due to chronic kidney disease (CKD). Although ESA therapy has found widespread use in the treatment of anemia due to CKD (based on a 2006 Kidney Disease Outcomes Quality Initiative [KDOQI] consensus statement), ^[106] the risks and benefits in patients with CKD, particularly older adults not on dialysis and not receiving RBC transfusions, remain underexplored. Iron supplementation is frequently needed to prevent iron-restricted erythropoiesis in elderly patients on ESA treatment.

One study showed that ESAs can treat anemia of unknown etiology, and responses may be similar to those in CKD. No statistically significant increase in cardiovascular events in those receiving ESAs was detected. ^[107]

Considering the possible adverse effects of ESA, which include thrombosis and hypertension and the potential for progression of certain cancers, caution must be exercised in populations at increased danger for such events.  ESAs should be prescribed only be physicians experienced in the use and monitoring of such treatment.