Unexplained Anemia of Aging

Etiology, Health Consequences, and Diagnostic Criteria

Jack Guralnik MD, PhD; William Ershler MD; Andrew Artz MD; Alejandro Lazo-Langner MD; Jeremy Walston MD; Marco Pahor MD; Luigi Ferrucci MD, PhD; William J. Evans PhD


J Am Geriatr Soc. 2022;70(3):891-899. 

In This Article

Diagnostic Criteria and Etiology for UAA

The etiology of anemia in older patients is complex and falls into four often overlapping categories: (1) deficiencies of nutrients, including iron, vitamin B12, and folic acid; (2) anemia of inflammation or chronic disease, congestive heart failure (CHF), malignancy, auto-immune disease or infections; (3) chronic kidney disease (CKD); (4) hematologic malignancies;[6] and (5) UAA, which is diagnosed mainly by exclusion. Although there is not yet a consensus regarding its etiology, UAA is a recognized disease among older patients with anemia who do not meet the standard criteria for anemia subclassification.[8–10]

The causes of UAA are likely multifactorial, with variable contributions from renal disease, endocrine deficiency (blunted erythropoietin response), chronic inflammation, androgen deficiency, nascent myelodysplasia, and other underlying conditions. Ferrucci et al.[11] reported a significant correlation between low circulating testosterone and anemia in community-dwelling men and women over the age of 65 from the InChianti study, a relationship that was independent of circulating erythropoietin levels.[12] Tettamanti et al.[5] suggested a number of potential causes for low Hb in people over 65 years, including undiagnosed myelodysplastic syndrome, hypogonadism (testosterone <275 ng/ml), impaired bone marrow response to EPO (decreased responsiveness), low-grade chronic inflammation (elevated IL-6, TNF-α, or hepcidin), vitamin D deficiency [25(OH) < 20 ng/ml], and unrecognized iron deficiency. Aging is also associated with dysfunction of hematopoiesis, evidenced by an age-related decrease in the number of hematopoietic stem cells in the bone marrow and the circulation13.14 Many men and women with anemia have elevated inflammatory markers in the absence of a diagnosed acute or chronic disease,[11] and should be considered and treated similarly to patients with UAA.

Although not unexplained, perioperative bleeding represents a significant cause of anemia for many older patients undergoing hip fracture repair.[15] Preoperative anemia in older patients is also common (up to 20% of patients) with limited treatment options. For example, intravenous iron is relatively save but not effective in raising hemoglobin levels in this patient group.[16] The drop in hemoglobin resulting from a hip fracture prior to surgery is substantial,[17] and the drop is exacerbated during the surgery. In the early postoperative period after hip fracture repair surgery, uncorrected anemia (Hb <100 g/L) was an independent risk factor for inability to walk on the third postoperative day, independent of the type of surgery or prefracture function.

Guralnik et al.[4,18] used the criteria established for the NHANES study to identify potential causes of anemia (left column, Table 2). In cases of anemia (Hb < 13 g/dl), UAA could be ruled out if a patient meets any these criteria. The right column of Table 2 contains our proposed expansion of the exclusion criteria used by Guralnik et al.