Anemia in Older Adults: Causes, Clinical Impact, and Evidence-Based Management

Abstract

Anemia is a common yet often underdiagnosed condition in older adults, affecting approximately 10-24% of individuals aged 65 and above. Its prevalence increases with advancing age and is associated with significant morbidity, including fatigue, cognitive decline, cardiovascular complications, and increased mortality. Unlike anemia in younger populations, anemia in older adults is frequently multifactorial, with causes ranging from nutritional deficiencies and chronic diseases to myelodysplastic syndromes and medication-induced bone marrow suppression. This review provides an in-depth analysis of the etiologies, clinical implications, diagnostic approaches, and management strategies for anemia in the elderly, with a particular focus on evidence-based pharmacological interventions. We also discuss emerging therapies and the role of deprescribing potentially causative medications. Given the aging global population, understanding anemia in older adults is crucial for clinicians across specialties, including geriatrics, hematology, and primary care.

Introduction

Anemia in older adults is a significant public health concern due to its high prevalence and association with adverse outcomes, including functional decline, increased hospitalization rates, and reduced quality of life. The World Health Organization (WHO) defines anemia as a hemoglobin level below 13 g/dL in men and 12 g/dL in women, but emerging evidence suggests that even mild anemia in the elderly warrants clinical attention. Unlike younger patients, where iron deficiency or acute blood loss may be the primary cause, anemia in older individuals often stems from a complex interplay of chronic inflammation, renal insufficiency, hematologic malignancies, and medication side effects.

The clinical implications of anemia in this population are profound. Studies have linked it with increased frailty, higher fall risk, cognitive impairment, and worsened outcomes in heart failure and chronic kidney disease (CKD). Despite these risks, anemia in older adults is frequently overlooked or attributed to "normal aging," leading to delayed diagnosis and suboptimal management. This review aims to synthesize current evidence on the pathophysiology, diagnostic workup, and therapeutic approaches, with an emphasis on optimizing anemia medication while minimizing polypharmacy risks.

Etiologies of Anemia in Older Adults

Nutritional Deficiencies

Iron deficiency remains a leading cause of anemia in the elderly, though its presentation may differ from younger populations. While gastrointestinal blood loss (e.g., from peptic ulcers, angiodysplasia, or malignancy) is common, poor dietary intake and malabsorption (e.g., atrophic gastritis, celiac disease) also contribute significantly. Vitamin B12 and folate deficiencies are equally important, particularly in individuals with chronic proton pump inhibitor (PPI) use or pernicious anemia. Unlike classic megaloblastic anemia, older adults may present with subtle neurological symptoms before hematologic manifestations become apparent.

Anemia of Chronic Disease (ACD) and Inflammation

Anemia of chronic disease, also termed anemia of inflammation, is prevalent in older adults with conditions such as rheumatoid arthritis, chronic infections, or malignancies. This form of anemia is driven by elevated hepcidin levels, which impair iron utilization and erythropoiesis. Interleukin-6 (IL-6) and other inflammatory cytokines suppress erythropoietin production and reduce red blood cell lifespan, resulting in a normocytic or microcytic anemia that is often refractory to iron supplementation alone.

Chronic Kidney Disease (CKD)-Related Anemia

Declining renal function leads to reduced erythropoietin production, a key factor in anemia development among older adults. The prevalence of anemia increases with CKD stage, affecting nearly 50% of patients with stage 4 or 5 CKD. Additionally, uremia-induced platelet dysfunction and increased bleeding risk exacerbate anemia in this population. While erythropoiesis-stimulating agents (ESAs) have been a cornerstone of treatment, recent guidelines emphasize cautious use due to cardiovascular risks.

Hematologic Disorders

Myelodysplastic syndromes (MDS) and other clonal hematopoiesis disorders become increasingly common with age. MDS should be suspected in older adults with unexplained macrocytic anemia, especially if accompanied by cytopenias or dysplastic changes on peripheral smear. Similarly, occult myeloproliferative neoplasms or early-stage leukemias may present with isolated anemia.

Medication-Induced Anemia

Several commonly prescribed medications contribute to anemia in older adults. Nonsteroidal anti-inflammatory drugs (NSAIDs) and anticoagulants increase bleeding risk, while PPIs and metformin can impair iron and B12 absorption, respectively. Chemotherapeutic agents, sulfonamides, and anticonvulsants may cause bone marrow suppression. A thorough medication review is essential in the diagnostic workup of unexplained anemia.

Clinical Implications of Anemia in Aging

Functional Decline and Frailty

Anemia is strongly associated with reduced physical performance, muscle weakness, and frailty in older adults. Even mild anemia (hemoglobin 10-12 g/dL) correlates with slower gait speed, decreased grip strength, and higher dependency in activities of daily living (ADLs). The mechanisms likely involve tissue hypoxia, increased oxidative stress, and chronic inflammation.

Cognitive Impairment and Dementia Risk

Chronic anemia has been linked to accelerated cognitive decline and a higher incidence of dementia, including Alzheimer’s disease. Proposed mechanisms include cerebral hypoperfusion, microvascular damage, and iron dysregulation in the brain. Correction of anemia, particularly when due to reversible causes, may mitigate cognitive deterioration.

Cardiovascular Complications

Anemia exacerbates cardiovascular disease by increasing cardiac output and inducing left ventricular hypertrophy. In heart failure patients, anemia is an independent predictor of hospitalization and mortality. The interplay between anemia, CKD, and cardiovascular disease creates a vicious cycle that requires integrated management.

Diagnostic Approach to Anemia in Older Adults

Initial Laboratory Evaluation

A stepwise diagnostic approach begins with a complete blood count (CBC), reticulocyte count, and peripheral smear to assess red cell morphology. Iron studies (ferritin, transferrin saturation), serum B12, folate, and renal function tests help identify common causes. Elevated inflammatory markers (C-reactive protein, ESR) may suggest ACD, while abnormal serum protein electrophoresis should raise suspicion for monoclonal gammopathies.

Advanced and Specialized Testing

When initial tests are inconclusive, additional investigations may include:

• Bone marrow biopsy (for suspected MDS or malignancy)

• Genetic testing (e.g., for hereditary hemochromatosis or MDS-related mutations)

• Endoscopic evaluation (for occult gastrointestinal bleeding)

• Erythropoietin levels (in CKD or unexplained anemia)

Management Strategies for Anemia in Older Adults

Nutritional Deficiency Correction

Oral iron supplementation (ferrous sulfate 325 mg daily) remains first-line for iron deficiency, though intravenous iron may be needed in malabsorption or intolerance. Vitamin B12 deficiency typically requires intramuscular injections or high-dose oral replacement, especially in pernicious anemia. Folate supplementation (1 mg daily) is indicated in deficiency states.

Pharmacological Therapies

Erythropoiesis-stimulating agents (ESAs) such as epoetin alfa and darbepoetin are used in CKD and cancer-related anemia, but their use requires careful monitoring due to thromboembolic risks. Emerging therapies like hypoxia-inducible factor (HIF) stabilizers (e.g., roxadustat) offer new options for CKD anemia by mimicking physiological erythropoietin regulation.

Deprescribing and Medication Optimization

A critical yet often overlooked aspect of management involves reviewing and discontinuing medications that may exacerbate anemia. PPIs should be used at the lowest effective dose, while NSAIDs and anticoagulants require regular bleeding risk assessments.

Transfusion Considerations

Red blood cell transfusions are reserved for symptomatic anemia (hemoglobin <7-8 g/dL) or acute coronary syndromes with hemoglobin <10 g/dL). In frail older adults, a restrictive transfusion strategy is generally preferred to minimize volume overload and transfusion reactions.

Future Directions and Emerging Therapies

Novel agents targeting hepcidin (e.g., monoclonal antibodies) and oral HIF stabilizers are under investigation for anemia of chronic disease. Personalized medicine approaches, including genetic profiling in MDS, may refine treatment selection.

Conclusion

Anemia in older adults is a multifactorial condition with significant clinical consequences. A systematic diagnostic approach and tailored treatment, incorporating nutritional support, anemia medications, and deprescribing, are essential for optimal outcomes. Given its impact on morbidity and mortality, anemia should never be dismissed as an inevitable consequence of aging.

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