Unexplained Anemia in the

Elderly
William B. Ershler, MD

KEYWORDS
 Unexplained anemia  Elderly  Comorbidity

KEY POINTS
 Despite research conducted to demystify unexplained anemia in the elderly (UAE), there
remains a healthy subset of anemia (30%–50%) that cannot be more confidently classified
than “unexplained.”
 UAE has emerged as a stand-alone clinical entity, likely representing an amalgam of age
and/or disease-altered physiologies.
 Coincident with our recognition of UAE, there has developed a robust literature of primarily
observational studies in which unfavorable geriatric outcomes have been linked to even
mild decrements in hemoglobin level.

On examining a large data set for the prevalence and mechanisms explaining the
occurrence of anemia in community-dwelling older people, Guralnik and colleagues1
described a category that they termed “unexplained anemia of the elderly” (UAE).2
Hematologists, generally not modest when considering matters relating to blood,
may take umbrage at the term “unexplained” and construct explanatory mechanisms
for such anemia from data at hand (eg, a little bit of iron deficiency, low-level inflam-
mation, androgen deficiency with added renal insufficiency, and possibly nascent
myelodysplasia) but still, despite research conducted to demystify UAE, there remains
a healthy subset of anemia (30%–50%) that cannot be more confidently classified than
“unexplained.” Thus, UAE has emerged as a stand-alone clinical entity, likely repre-
senting an amalgam of age and/or disease-altered physiologies.
Coincident with our recognition of UAE, there has developed a robust literature, pri-
marily observational, in which unfavorable geriatric outcomes have been linked to
even mild decrements in hemoglobin level.

CONSEQUENCES OF ANEMIA IN GERIATRIC POPULATIONS

Approximately 10% of community-dwelling older adults have anemia based on the

application of the commonly used World Health Organization (WHO) thresholds of

Disclosure: The author has nothing to disclose.

Division of Benign Hematology, Inova Schar Cancer Institute, Inova Fairfax Hospital, 3300
Gallows Road, Suite O-581, Falls Church, VA 22042, USA
E-mail address: william.ershler@inova.org

Clin Geriatr Med 35 (2019) 295–305

https://doi.org/10.1016/j.cger.2019.03.002 geriatric.theclinics.com
0749-0690/19/ª 2019 Elsevier Inc. All rights reserved.
296 Ershler

hemoglobin <13 g/dL for men and less than 12 g/dL for women.1,3–6 Anemia in older peo-
ple, particularly unexplained anemia (UA) (as described in the section entitled DEFINING
UNEXPLAINED ANEMIA below) tends to be mild, with hemoglobin levels typically 1 g/dL
below the WHO standard. Yet, a large and expanding literature describes the association
of anemia with distinct morbidities and mortality. For example, having anemia is associ-
ated with increased hospitalization7–9 and longer hospital stays.10 Low hemoglobin
levels also associate with cognitive decline,11 depression,12 impaired quality of life,13
diminished overall physical function,14 falls,15 and, as mentioned, higher mortality.10,16,17
Considering demographic trends indicating that within 3 decades approximately 25% of
the world’s population will be 60 years or older,18 the overall societal burden of anemia is,
and will increasingly become, even more substantial.
Yet, there remains no definitive consensus that anemia treatment favorably affects
any of these associated adverse outcomes. In this review, we expand on what is and is
not known about UAE and provide a framework for when to intervene.

PHYSIOLOGIC PATHWAYS TO ANEMIA IN THE ELDERLY

Beyond 50 years of age, anemia occurs more frequently with each advancing decade,
and is particularly prevalent among the most frail (Tables 1–3).1,4,5,17,19–22 Approxi-
mately 10% of community-dwelling adults older than 65 have anemia based on the
previously mentioned WHO thresholds for diagnosis.1,4–6 Anemia prevalence varies
significantly by race: the lower median hemoglobin in elderly African American individ-
uals translates to a threefold higher prevalence compared with white individuals.1,23,24
Yet, the adverse consequences of even mild anemia experienced in the general pop-
ulation is not observed in mildly anemic African American individuals.25
Strategies to uncover an etiology of anemia is essentially no different for older than
younger adults. From a rather limited data set including hemoglobin level, red blood
cell indices, and serum chemistries, a single cause of anemia can be defined for
most cases, particularly in younger patients. For example, iron deficiency in menstru-
ating women or renal insufficiency in a diabetic or hypertensive middle-aged adult.
When investigating older patients arriving at a satisfactory explanation for anemia,
particularly mild anemia (hemoglobin 10.5–12 g/dL) is often not successful.
Approximately one-third of anemic older persons lack a clear mechanism account-
ing for the anemia,1,5,19,21,26–30 and such individuals are now considered to have UAE.
In light of the robust, albeit associative data on the negative implications of even minor
anemia (as discussed previously), further examination and eventual interventional tri-
als have become a topic of focused interest in clinical geriatric hematology.

Table 1
Common pathways to anemia in the elderly

Abbreviation Pathway
Iron Deficiency IDA
Anemia of chronic disease (anemia of chronic inflammation) ACD/ACI
Chronic kidney disease CKD
Vitamin B12/folate deficiency
Endocrine senescence Thyroid, androgen
Malnutrition
Myelodysplasia MDS
Unexplained anemia of the elderly UAE
 Unexplained Anemia in the Elderly 297

Table 2
Anemia in geriatric populations

% %
Study Population Anemic UAE
Guralnik et al,1 2004 Community (NHANES III) 11 33
Ble et al,57 2005 Community (InCHIANTI) 10 37
Artz and Thirman44 2011 Hematology referral, University of Chicago N/A 44
Price et al,31 2011 Hematology referral, Stanford University N/A 35
Artz et al,21 2004 Nursing home, NGRC 49 44

Abbreviations: InCHIANTI, Invecchiare in Chianti, aging in the Chianti area; NGRC, National Geri-
atrics Research Consortium; NHANES, National Health and Nutrition Examination Survey.

At 2 academic centers within the United States, multidisciplinary clinics are actively
addressing key questions regarding UAE (Table 4). Investigators at Stanford Univer-
sity developed an aggressive algorithm of laboratory studies to more tightly estab-
lished the incidence of “unexplained” anemia in the community.31 Enrolled subjects
had been referred for anemia evaluation at either the University or the affiliated Depart-
ment of Veterans Affairs Hospital hematology clinics. Laboratory testing included a
complete blood count with red cell indices, iron indices (serum iron, transferrin satu-
ration, and ferritin), vitamin B12 and folic acid, thyroid-stimulating hormone, erythro-
poietin level, and serum protein electrophoresis. Additional evaluations were added
as clinically indicated and these included bone marrow aspirate and biopsy, inter-
leukin (IL)-6, and hepcidin assays. A similar systematic evaluation of geriatric anemia
was undertaken at the University of Chicago. The results summarized in Table 4 indi-
cate that despite significant demographic differences in subjects evaluated at the 2
different sites, thorough investigation was remarkably similar with regard to identifying
a significant subpopulation of anemic patients who did not meet established criteria
for a more precise diagnosis than “unexplained anemia.”
The Stanford study included a review of the peripheral smear of all patients by each
of the investigators. In so doing, they discovered 31 patients (16%) with macrocytic
red cells, other cytopenias, and/or dysplastic features considered worrisome for
evolving myelodysplasia. In the Chicago study, in which close to 70% of the study par-
ticipants were African American, the investigators found approximately 5% to meet
criteria for thalassemia.
Additional reports from other institutions regarding anemia pathogenesis in the
elderly have described iron deficiency in 20%, anemia of chronic disease or inflamma-
tion in 15% to 35%, chronic kidney disease in fewer than 10%, and folate/vitamin B12
deficiencies in 10% with a residual subset of approximately one-third UAE.1,6,21,26,32
In light of the multitude of adverse outcomes associated with anemia in older pa-
tients (mentioned previously) it remains important to pursue serious and/or treatable
underlying medical conditions, including iron, folate, or B12 deficiency; blood loss;
kidney disease; infection; and hematologic or nonhematologic malignancy
(see Table 3).
Red blood cell indices may be particularly useful in guiding the anemia workup.
Smaller red cells (mean corpuscular volume [MCV] <80 fL) points to iron deficiency,
inflammation, chronic disease, or thalassemia, all of which can be confirmed by readily
available chemistries or genetic testing if thalassemia is suspected. However, clini-
cians need to be aware that MCV increases with advancing age33 and elderly patients
may be severely iron deficient despite normal MCV. In elderly patients with large red
 298
Ershler
Table 3
Laboratory findings in the common anemias of the elderly

Anemia ESR/
Type MCV Iron/TIBC Ferritin CRP Epo CrCl Test Albumin Misc
IDA Small Low/High Low nl High nl nl nl
AI/ACD Small Low/Low Low to High High Bl nl nl Low to nl
CKD nl nl nl nl Low <30 mL/min nl Low to nl
Hypothyroid Large nl nl nl High nl nl nl TSH high
B12/folate Large nl nl nl High nl nl nl Vitamin levels low, MMA high
MDS Large nl nl nl High nl nl nl Marrow can be diagnostic
Malnutrition nl nl nl nl Bl nl Low to nl Low
UAE nl nl nl nl Bl nl Low to nl nl

Abbreviations: ACD, anemia of chronic disease; AI, anemia of inflammation; Bl, blunted response (see text); CKD, chronic kidney disease; CrCl, creatinine clearance;
CRP, C-reactive protein; Epo, erythropoietin; ESR, erythrocyte sedimentation rate; IDA, iron deficiency anemia; MDS, myelodysplastic syndrome; MMA, methylma-
lonic acid; nl, normal; TIBC, total iron binding capacity; TSH, thyroid-stimulating hormone; UAE, unexplained anemia of the elderly.
 Unexplained Anemia in the Elderly 299

Table 4
Evaluation of geriatric anemia at 2 academic hematology units

Stanford31 n 5 190 Chicago44 n 5 174

Study similarities Age (w77 y), prevalent DM, hypertension
Differences Mostly male, white, veterans Mostly female, African American
Anemia Type % Stanford % Chicago
UAE 35 44
IDA 12 25
AI (ACD) 6 10
Heme malignancy 6 7
CKD 4 3
MDS 16
Thalassemia 5
Other/Incomplete 12

Abbreviations: ACD, anemia of chronic disease; AI, anemia of inflammation; CKD, chronic kidney
disease; DM, diabetes mellitus; IDA, iron deficiency anemia; MDS, myelodysplasia; UAE, unex-
plained anemia of the elderly.

cells, common causes such as myelodysplasia, B12 deficiency, liver disease, chemo-
therapy, or alcoholism are to be considered. Peripheral blood smear should be exam-
ined for dysplastic features that could indicate underlying myelodysplasia (MDS).
Bone marrow sampling using immunohistochemical and molecular/genetic studies
might provide diagnostic and therapeutic value for the spectrum of hematologic dis-
orders classified as MDS.34,35 These studies have become particularly more relevant,
as novel and well-tolerated pharmacologic approaches are currently available for
older patients with MDS.36
Because the hemoglobin threshold below which physical function and overall sur-
vival is impaired may be lower for African American compared with white individ-
uals,24,37 controversy exists about whether the causes of anemia differ sufficiently
to justify using a lower hemoglobin threshold to prompt an evaluation in older African
American individuals.24,38

DEFINING UNEXPLAINED ANEMIA

For the 33% to 50% of geriatric patients with anemia who do not meet standard
criteria for anemia subclassification, the diagnosis of UA is becoming increasingly
recognized.39–43 Most commonly, this is a mild, hypoproliferative anemia with hemo-
globin levels in the 10 to 12 g/dL range with normocytic indices. Ironically, more severe
anemias are rarely difficult to classify. UAE is likely multifactorial, with variable contri-
butions from renal, endocrine deficiency (blunted erythropoietin response), chronic
inflammation, androgen deficiency, and possibly nascent myelodysplasia.

Renal Endocrine Deficiency

Despite anemic hemoglobin levels and seemingly normal exocrine function, several
series of patients with UAE have demonstrated serum erythropoietin levels signifi-
cantly lower than expected for degree of anemia.21,31,44 Of note, although serum
erythropoietin levels were shown to rise gradually over time in healthy volunteers
enrolled and studied for more than 40 years in the Baltimore Longitudinal Study of Ag-
ing (BLSA), those who developed hypertension and/or diabetes while continuing as
volunteer BLSA participants were shown to have erythropoietin levels that did not
300 Ershler

rise but remained stable or even fell. It was these same individuals with stable or drop-
ping erythropoietin levels who developed anemia during their course on the longitudi-
nal study.45
Smoldering Inflammation
Despite the absence of clinically apparent acute or chronic inflammatory disease, sub-
jects with UA exhibit markers for low-level smoldering inflammation.46,47 Furthermore,
the degree to which this is present seems to presage several features of frailty,
including functional decline and development of age-related disease. Inflammatory
markers, such as IL-6 and hepcidin, have been shown to be elevated in most, but
not all patients with UAE.31,44,48
Androgen Deficiency
Before more modern immunosuppressive therapies and stem cell transplantation, an-
drogens were commonly used to treat aplastic anemia and other hypoplastic marrow
conditions.49 Such treatment was given with the expectation that hemoglobin would
rise by 0.8 to 1.0 g/dL. Furthermore, hypogonadal men or those who had been treated
with hormonal ablation are typically anemic, with hemoglobin levels frequently 1 g/dL
below the lower limit of normal. Because testosterone levels decline with age,2 Fer-
rucci and colleagues50 studied the interaction of testosterone and anemia in a
population-based sample of community-dwelling elderly (InCHIANTI study). They
found in both older men and women a direct and significant correlation between
low testosterone and anemia, either at initial evaluation or at the time of follow-up
3 years later.50
Malnutrition
Weight loss and nutritional inadequacy are commonly observed in frail nursing home
patients,51 as is the occurrence of anemia.52 In a recent research report from
Switzerland examining frequency and pathogenesis of anemia in 392 institutionalized
elderly, the prevalence of anemia was 39%.42 After thorough anemia investigation and
using multivariate analysis, those who met criteria for anemia were more likely to have
low serum albumin and prealbumin levels. Approximately one-third of the anemic pa-
tients were classified as UAE and 91% of these had low serum albumin and prealbu-
min. Thus, markers of malnutrition were strongly associated with anemia in the frail
elderly. The investigators concluded that screening for undernutrition should be
included in anemia assessment, particularly in frail nursing home patients.
Comorbidity Burden
Michalak and colleagues53 from Poland highlight another perspective. Comorbidity, a
known feature of advancing age,54,55 was examined in the context of anemia occur-
rence in a retrospective analysis of 981 patients aged 60 years seen in a primary
care practice over a 2-year span. Of the 981 analyzed patients, 17.2% were anemic
and, of these, 28.4% were classified as “unexplained.” The study highlighted the
importance of repeated hospitalizations and the occurrence of anemia. They found
that hospital-acquired anemia was more likely to be apparent in those undergoing
invasive medical procedures, excessive testing, and/or who were on anticoagulants.
For the study population as a whole, by univariate analysis, patients with 2 to 5 comor-
bidities had a 2-fold to 14-fold risk of anemia. By multivariate logistic regression, fac-
tors increasing the risk of anemia were age 80 years, the number of comorbidities
(2 to 4), and recent hospitalization(s). Accordingly, comorbidity burden and hospitali-
zations are factors to be considered in both overall anemia and UA in the elderly. For
 Unexplained Anemia in the Elderly 301

UAE, one might expect that comorbidities and hospitalizations influence erythropoi-
esis by associated acquired iron deficiency, acute/chronic inflammation, and malnu-
trition. Nonetheless, by multivariate analysis with these factors included,
comorbidity and hospitalization stood alone as risk factors for anemia.

APPROACH TO ELDERLY PATIENTS WITH ANEMIA

Elderly patients who present with severe anemia (hemoglobin <7 g/dL) most
frequently have evidence for acute or chronic bleeding, hemolysis, or bone marrow
compromised by hematologic or nonhematologic neoplasia. Workup is prompt,
often involving endoscopies or hematologist consultation. However, many elderly
patients will more commonly present with moderate or even minor anemia, and
workup will reveal characteristics of UA. It is our practice to conduct a standard lab-
oratory evaluation for anemia, including complete blood count with red cell indices
and reticulocyte count; and in addition, an assessment of iron, percent transferrin
saturation and total iron binding capacity, B12, albumin, total serum protein, serum
creatinine, and erythrocyte sedimentation rate. From these studies, approximately
70% of ambulatory anemic patients will be readily classified. The great majority of
the remaining 30% will fit current criteria of UA. Some patients with UA will have
dysplastic features on their peripheral blood smear, macrocytic red blood cells or
other cytopenias, and such patients should be referred to a hematologist for addi-
tional studies to confirm suspicion of myelodysplasia or other primary bone marrow
disorder.

APPROACH TO MANAGEMENT OF UNEXPLAINED ANEMIA IN THE ELDERLY

There have been no published reports that describe the natural history of UA or
whether treatment can ameliorate any of the adverse associations described previ-
ously. Nonetheless, the blunted erythropoietin level observed in most patients pre-
sents a tempting target for intervention. A well-constructed clinical trial examining
the effects of recombinant erythropoietin (eg, Procrit, Aranesp) on hemoglobin level,
relevant physical and psychological functions, and safety remains to be conducted.
Features of this study should include careful selection of volunteers who meet
criteria for UAE and study outcomes other than hemoglobin level alone that include
relevant physical function (eg, 6-minute walk), cognition, and quality of life. Further,
an optimal study would be of sufficient duration to allow a reasonable chance that
sustained improvement in hemoglobin level would favorably influence those
outcomes.
Another target for treatment of UA in the elderly includes testosterone replacement.
In this regard, a recent multi-institutional randomized trial examining whether testos-
terone treatment of older men with previously determined low testosterone levels
was recently published.56 Testosterone gel with doses adjusted to maintain testos-
terone levels in normal range was administered for 12 months. The investigators
looked specifically for treatment effect for those subjects with UA. Of 788 enrolled
subjects, 126 were anemic, and 62 of these were classified as UA. More than 50%
of anemic subjects (total group and specifically UA) had a >1 g/dL rise in hemoglobin
by the 12th month of treatment. Despite this encouraging finding, the investigators
appropriately pointed out that the overall health benefits of improved hemoglobin level
remain to be established.
Other potential targets for UA treatment under consideration include anti-
inflammatory strategies (such as hepcidin inhibitors) or nutritional supplements,
particularly for frail elderly with established malnutrition.
302 Ershler

Although UA is being increasingly recognized and its importance more generally un-
derstood, because of its heterogenous pathophysiology, only by well-constructed
clinical trials will effective treatment interventions be established.

SUMMARY

The prevalence of anemia increases with advancing age, and despite thorough inves-
tigation, approximately one-third will be classified as “unexplained.” UA is typically
hypoproliferative, normocytic, and with a low reticulocyte count. Serum erythropoietin
levels are lower than would be expected for degree of anemia. Chronic inflammation,
low testosterone levels, malnutrition, and possibly nascent myelodysplasia are varia-
bly contributing factors. No clearly established beneficial treatment strategy has been
established, but the association of UA with a wide range of adverse outcomes,
including impaired quality of life, physical function, and mortality, is sufficiently
compelling to justify expanding clinical research focused on both basic and clinical
aspects.

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