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

Disclosures

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

Abstract and Introduction

Abstract

Background: Up to 15% of people aged 60 and over are anemic, and the prevalence of anemia increases with age. In older men and women, anemia is associated with increases in the risk of death and all-cause hospitalization, poor functional capacity, quality of life, and depression.

Methods and Results: We reviewed the literature describing anemia in aging populations, focusing on the specific diagnostic criteria of anemia and potential causes in older men and women. Even after extensive etiologic workup that involves careful medical history, physical examination, laboratory measurements, and additional studies such as bone marrow biopsy, anemia of aging is unexplained in up to 40% of older patients with anemia. As a result, treatment options remain limited.

Conclusions: The prevalence of unexplained anemia of aging (UAA; also called unexplained anemia of the elderly, UAE), its deleterious impacts on health, physical function, and quality of life, and the lack of effective treatment or therapy guidelines represent a compelling unmet clinical need. In this review and consensus document, we discuss the scope of the problem, possible causes of UAA, diagnostic criteria, and potential treatment options. Because even mild anemia is strongly linked to poor clinical outcomes, it should receive clinical attention rather than simply being considered a normal part of aging.

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Table 1. Prevalence of diagnostic causes of anemia in older patients, including UAA
Source	N	Age	%CKD	%IDA	%ACI/ACD	%B₁₂/folate deficiency	%UAA
NHANES III⁴	2096	≥65	8.2	16.6	19.7	B₁₂: 5.9 B₆: 6.4 Both: 2.0	33.6
Health and Anemia⁵	8744	≥65	15.0	16.0	17.4	10.1	26.4
Community dwelling outpatients⁶⁴	190	≥65	4.0	12.0	6.0	NA	35
InChianti⁶⁵	582	≥65	10.4	17.6	24.5	10.5	37.2
Leiden (≥ 85y)⁶⁶	490	≥85 years	7.0	32.4	20.1	8.7	25.4
Polish Clinic patients⁷	981	≥60	NA	NA	NA	NA	28.4
Innsbruck Medical University cohort⁸	4117	≥64	11.3	14.4	62.1	B₁₂: 2.0 B₆: 6.7	-
Community dwelling⁶	174	≥65	9.8	25	9.8	1	44

Abbreviations: ACD, anemia of chronic disease; ACI, anemia of chronic inflammation; CKD, chronic kidney disease; IDA, iron deficiency anemia; UAA, unexplained anemia of aging.

Table 2. Diagnostic exclusion criteria for unexplained anemia of aging
Potential cause	Guralnik et al. criteria	Expanded criteria
Diagnosis of anemia	World Health Organization criteria: Men <13 g/dl Women <12 g/dl	men and postmenopausal women <13 g/dl
Iron Status	Ferritin <12 ng/ml Transferrin saturation < 15%	Ferritin <40 ng/ml⁶⁷ Transferrin saturation < 15%
B12	< 200 pg/ml	< 200 pg/ml
Folate	red blood cell folate <102.6 ng/ml Home exam: serum folate <2.6 ng/ml	Red blood cell folate <102.6 ng/ml Alternative: serum folate <2.6 ng/ml
Chronic kidney disease	Creatinine clearance <30 ml/m	Creatinine clearance <30 ml/m
Chronic inflammation	Serum iron <60 μg/dl	Diagnosed inflammatory disease and serum iron <60 μg/dl¹⁰
Thyrotropin/TSH		<0.1 mU/ml or >10 mU/ml (except in cases of corrective thyroid therapy without erythroid response)
Other		No history of evidence of hematologic malignancy or myelodysplastic syndrome

Table 3. Mild anemia increases hospitalization and mortality
Years of follow-up		Percent hospitalized				Percent deceased
Years of follow-up		0.5	1.0	1.5	2.0	0.5	1.0	1.5	2.0
Women	Nonanemic	5	11	16	21	0.5	2	2.5	5
Women	Mildly anemic	13	20	26	29	3	7.5	10	13
Men	Nonanemic	10	18	24	30	1	2	4	10
Men	Mildly anemic	17	28	35	42	5	9	14	17

Note: Percent of patients experiencing one or more hospitalizations or deceased, stratified by sex and mild anemia status, over a 2-year follow-up in the Health and Anemia population-based study (2003–2007). Mild anemia was defined as Hb concentration between 10.0 and 11.9 g/dl in women and between 10.0 and 12.9 g/dl in men. Source: From Reference 38.

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Unexplained Anemia of Aging

Etiology, Health Consequences, and Diagnostic Criteria

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