ANEMIA

OF CHRONIC
DISEASE IN THE
ELDERLY
Maren Mayhew

ABSTRACT
Many experienced clinicians
feel comfortable with the
diagnosis and treatment of
anemia. However, the anemia
of chronic diseases so prevalent in the elderly may represent a diagnostic challenge.
New treatment strategies are
now available for patients
whose quality of life is
adversely affected by this
problem that is commonly
ignored.
Keywords: anemia of chronic

disease, low iron production,

normocytic normochromic
anemia

The anemia of chronic disease (ACD) is a common

problem in elderly patients and may represent a diagnostic challenge even for the experienced nurse practitioner. Although subtle, anemia may have a serious effect on
the quality of life of the elderly patient.This article discusses common anemias in the elderly, with an emphasis
on ACD and its treatment (Box 1).
The most common cause of anemia in the elderly is
ACD, which was recognized as a diagnostic entity in
1962.1 Three causes are generally agreed on: cancer and
cancer treatment, inflammation or infection, and patients
with HIV who are taking zidovudine.The inflammation
or infectious disease category includes malaria, rheumawww.npjournal.org

toid arthritis (RA), and Crohn disease, among others.

Other diseases implicated in ACD are liver disease (alcoholic cirrhosis), heart failure, chronic obstructive pulmonary disease, and diabetes. Multiple trauma can also
cause ACD.The list of diseases or conditions associated
with ACD continues to grow as new research uncovers
the relations.
PREVALENCE AND SIGNIFICANCE
Anemia as a general condition is common in the elderly.2 The prevalence can reach 44% in men older than
85.3 Prevalence has been difficult to quantify in the past,
partly because of limitations of the various research
The Journal for Nurse Practitioners - JNP

261

studies.The following findings have been confirmed by

several studies2:
The prevalence of anemia varies among different
groups.
Hospitalized patients have the highest rate of anemia; high rates are also found in nursing homes.
Anemia is more prevalent in elderly men than
women.
The prevalence increases with age.
An increased prevalence occurs in patients with
Alzheimer disease.
Increased mortality is found in anemic patients.
Anemia has significant adverse effects on the patients
clinical, functional, and economic status. However, studies
have not been done to quantify the effect of anemia on
the elderly patient.2 The main symptom of anemia is
fatigue, and fatigue clearly can have a serious effect on
quality of life.4

Box 1. Medications Discussed in This

Article

TYPES OF ANEMIAS
Anemia is classified either by pathophysiology or cell size
(mean cell volume [MCV], equates to size) (Box 2).5 To
understand anemia in the elderly, it is necessary to address
both pathophysiology to understand cause and cell size as
a method of diagnosis.These classifications have been
combined in this article to facilitate discussion.

Normocytic Normochromic
Increased loss or destruction of blood
Acute blood loss
Hemolytic disorders
Decreased red blood cell (RBC) production
Aplastic anemia, bone marrow infiltration
Early iron deficiency
Chronic renal failure (CRF)
Endocrine deficiency states (hypothyroidism)
ACD

CAUSE
Erythropoiesis as a process normally declines during
aging.This makes it difficult to sort normal aging from
the effect of chronic disease. Also, it is often difficult to
determine the cause of an anemia in the elderly. Studies
estimating the cause of anemia in the elderly find that,
for many patients, no cause can be confirmed.2 In many
cases the cause is multifactorial. Most of the diseases listed under ACD have other mechanisms for causing anemia in addition to the ACD.
The etiology of ACD is not fully understood. It
appears to be caused by inflammatory cytokines such as
interleukin, tumor necrosis factor, and interferon alfa
and beta.6 These cytokines play three roles. The first
role is that red blood cell survival is slightly decreased.
This leads to anemia. The second role is a depressed
response to the anemia. The body produces erythropoiein, but the amount is low compared to what a normal body would make with the same severity of anemia. The bone marrow fails to increase the production
262

The Journal for Nurse Practitioners - JNP

Oral iron (generic)

Intravenous iron sucrose (Venofer)
Epoetin (Procrit, Epogen)
Darbepoetin (Aranesp)
Zidovudine (Retrovir)

Box 2. Classification of Anemia in the

Elderly, Organized by Cell Size and
Pathology
Microcytic Hypochromic
Iron deficiency
Macrocytic
Folate deficiency
Vitamin B12 deficiency

Adapted from Brill JR, Baumgardner DJ. Normocytic anemia. Am

Fam Physician. 2000;62(10):2255-2264.

of red blood cells sufficient to compensate for the anemia. The third role is that inflammation causes iron to
be retained in the reticuloendothelial system rather
than being released to the RBCs developing in the
marrow. Inflammation causes a direct inhibition of this
process. The patient has iron but is unable to use it, so
there is no iron deficiency per se.

Chronic Renal Failure

The main cause of anemia in patients with CRF is
insufficient production of erythropoietin by the diseased
kidneys.7 This is an absolute decrease in production
because of the kidney damage, not a relative decrease as
in ACD.This process leads to decreased RBC production, and the resulting anemia is more severe than that
seen in ACD.
April 2006

Table 1. Laboratory Values Comparing ACD and Iron-Deficiency Anemia

Laboratory Test

ACD

Iron Deficiency

Hematocrit

60% of baseline

Decreased

Hemoglobin

Above 10

Decreased

MCV

Normal or slight reduced

Early: normal; later, decreased

RBC morphology

Undiagnostic

Increased variability

Reticulocyte

Near normal

Decreased

Serum iron

Low

Low

TIBC

Low

High

Ferritin

Normal or increased

Low

Transferrin saturation

Very low

Late: less than 15%

TIBC, total iron-binding capacity

Gastrointestinal Blood Loss and Nutritional Deficit

Iron deficiency in the elderly is often caused by acute or
chronic gastrointestinal (GI) blood loss. Folate and vitamin
B12 deficiencies are also seen in the elderly because of
inadequate intake or absorption. It may be symptoms of
these other deficiency problems that bring the ACD to the
attention of the clinician.
DIAGNOSIS OF ANEMIA

Signs and Symptoms

Most anemias are discovered on routine laboratory tests.
The patient often does not complain of or evidence any
symptoms. Other disease states may be aggravated or
found concurrent with anemia.
The most common symptom of anemia is fatigue.
Although some might assume that the most important
symptom to manage in palliative medicine is pain,
fatigue is one of the top two symptoms (along with
anorexia) for distress in patients who are terminally
ill.8 In fact, fatigue is a problem in 75% to 90% of
patients with terminal illness. It is described as tiredness, a general lack of energy not relieved by rest,
diminished mental capacity, and weakness. It may be
so severe it causes profound difficulty in performing
activities of daily living. Fatigue contributes to
decreased exercise tolerance, frailty, immobility, and
depression. Fatigue is a common complaint in the elderly and it is hard to know when it is significant.
Researchers suggest it is underdiagnosed and undertreated.9 Many diseases in the elderly can cause fatigue
directly and may also produce anemia, which can in
www.npjournal.org

turn increase the fatigue. This makes it extremely difficult to diagnose the true cause of the fatigue. A good
example of this is the deconditioning the patient
experiences as a result of cancer, which is common in
addition to anemia.
It is essential for the clinician to determine what part
anemia might play in contributing to fatigue. Assess the
severity of the fatigue by talking to the patient to determine the effect on the patients quality of life.The
degree of patient distress and disability will help determine how aggressive the clinician should be in the treatment of the anemia.
Research suggests that anemia found in association
with heart failure is correlated with increased mortality.
Approximately 17% of patients with heart failure have
anemia, 60% of which may be found to be ACD. Anemia
contributes to the disease progression of heart failure,
and the anemia can exacerbate ischemic heart disease or
cause high-output failure.10

Differential Diagnosis
The diagnosis of ACD is one made by exclusion, and
it is ultimately a clinical diagnosis. ACD may coexist
with other causes of anemia, especially iron deficiency.
The presence and type of anemia is established by a
complete blood cell (CBC) count, reticulocyte count,
and iron studies (Table 1).
The laboratory tests will determine not only the
structural characteristics but also the severity of the anemia. Most anemias initially present as normocytic. As
they progress, different characteristics become more
apparent. Serum ferritin concentration is directly correThe Journal for Nurse Practitioners - JNP

263

Box 3. Clinical Practice Implication

A. Monitor for fatigue in the patient
B. Monitor for anemia through routine CBC counts
C. If a patient complains of fatigue, do a thorough
assessment to determine the cause of the fatigue
D. If the patient has anemia (confirmed through laboratory work)
1. Evaluate the laboratory findings
2. Perform additional tests as needed to determine
the cause of the anemia
E.To treat
1.Treat any medical condition that is amenable to
treatment
2.Treat any other cause for the anemia
F. If the anemia does not improve
1. Evaluate the effect the anemia is having on the
patients quality of life
2. If it is significant, consider whether treatment
with epoetin might help
lated to the reticuloendothelial iron stores. Reduced
serum ferritin means low iron stores; this is the only
cause of low serum ferritin. Tests will document that
the iron stores in ACD are normal. Another test that
should be obtained is the transferrin saturation. The
transferrin saturation is the ratio of serum iron to
TIBC and will be low in both ACE and iron-deficiency anemia.
Other causes of anemia should be excluded before
ACD can be diagnosed. Thus, the clinician must
search for CRF, iron deficiency and blood loss, vitamin B12 and folate deficiencies, and other problems as
dictated by the laboratory results. The diagnosis of
iron-deficiency anemia is confirmed by bone marrow
examination. This test is expensive and painful and
requires patient cooperation; thus, it is often not feasible in the elderly.1
To summarize, ACD is a mild normocytic normochromic anemia characterized by low reticulocyte
index, low serum iron, and low TIBC, with normal or
increased ferritin, in a patient with a systemic (an
inflammatory component) disease.
TREATMENT

General Principles
It is tempting to base treatment of ACD solely on laboratory values. However, other factors must be considered. Treatment must be based on the cause of the ane264

The Journal for Nurse Practitioners - JNP

mia, and, if the anemia is severe or causing symptoms,

it must be treated and not ignored. Otherwise, it is
usually not necessary to treat ACD. Treatment in that
case would consist of optimal control of the underlying cause (Box 3).
Commonly, patients with ACD have a hemoglobin
level of around 30 and a hematocrit of about 10 and
manage well.The anemia has developed slowly, and the
patient has adjusted to it. Patients with heart failure have
a decreased ability to tolerate anemia.They may become
symptomatic even with hemoglobin or hematocrit at a
higher level. Some patients with ACD complain of
fatigue. Others decrease their activity level to alleviate
the fatigue and do not complain.
However, these changes, even if small, may lead to a
decreased quality of life.The patients are less able to care
for themselves and do what they want to do.They need
a higher level of care, sometimes necessitating placement
in a nursing home or care center.The clinician may consider physical therapy to improve their endurance if they
are able to tolerate it. Other patients need energy conservation techniques, such as doing the most difficult
activities at a time when they are feeling their best and
taking frequent rest periods. Consider other therapy if
these methods are not sufficient.
Transfusions can be useful for immediate treatment
in severe, symptomatic anemia.The drawbacks to the use
of transfusions include allergic reactions, limited blood
supply, and risk of disease transmission.The patient also
must go to a facility to receive the transfusion, thus
increasing the cost, work, and expense.
Iron-deficiency anemias can be treated with oral
iron. The usual recommended dose is between 150
and 200 mg elemental iron daily. Higher doses are
needed when iron is poorly absorbed. The recommended dietary intake of iron for older persons is 10
mg/day. Adverse effects of iron therapy are abdominal
discomfort, nausea, vomiting, and constipation. These
adverse reactions can lead to decreased food intake,
bowel impaction, and other problems, including
unnecessary GI examinations, and can lead to
decreased compliance with iron therapy. One study
showed significantly lower incidence of adverse effects
and effective treatment of iron deficiency with the use
of doses as low as 15 mg instead of 150 mg.11 This
study is particularly impressive in that the subjects
were older than 80. An additional factor to consider is
April 2006

Table 2. Dosage and Administration of Epoetin

Disease

When to Use

Starting Dose

Increase Dose When

Maximum Dose

Decrease or Stop

CRF

50-100

8 wk, CBC

300 U/kg

HCT 36% or

U/kg

not increased

TIW

by 5-6 points

increase of more
than 4 points in
2-wk period

Cancer or

Serum

150

cancer

erythropoietin

U/kg

therapy

level <200

TIW

300 U/kg

NA

600 U/kg

mU/mL
HIV

On zidovudine,

100

In 8 wk, if

serum

U/kg

response not

erythropoietin

TIW

satisfactory

100

level <500 m
mU/kg
Surgery

U/kg
weekly
Information from drug package insert. TIW, three times week.

that with oral iron therapy bowel movements turn

black, masking any GI bleeding that might be present.
Intravenous iron sucrose (Venofer) is indicated for
treatment of iron-deficiency anemia in patients undergoing chronic hemodialysis who are receiving supplemental
erythropoietin therapy.12 It is also used for iron-deficiency anemia in patients who cannot tolerate oral iron. It is
given intravenously by infusion or by slow injection over
a period of at least 15 minutes. Slow infusion rates
decrease the risk of hypotension.The dose is 5 mL iron
sucrose (100 mg elemental iron). Common adverse reactions include allergy, hypotension, cramps or leg cramps,
nausea, headache, vomiting, and diarrhea.

Epoetin Alfa Treatment

Epoetin is an additional therapeutic option that was
shown to be effective in treating many anemias of
decreased RBC production.The use of this drug has
been studied most extensively in the treatment of anemia
of CRF, whereby it is generally effective if the patient is
adequately dialyzed.13
The effectiveness of epoetin therapy is less well documented in ACD. One study found that there was usually a
good patient response to epoetin used in treating ACD
www.npjournal.org

caused by RA,AIDS, malignancies, and inflammatory

bowel disease.14 In cancer, the response rate has been 40%
to 80%, depending on the study.6 In RA, most patients have
shown a positive response to epoetin.15
Epoetin is being tried for patients with heart failure
and anemia. Darbepoetin was shown to increase the
hemoglobin level and to improve symptoms. However, a
decrease in mortality in these patients with heart failure
was not documented.16
An interesting new use of epoetin is for the prevention of blood transfusions during surgery. The
scarcity of blood for transfusions has lead to a search
for alternatives for patients undergoing elective surgery. Although donation of autologous blood is the
preferred alterative, elderly patients are often unable to
make new RBCs quickly enough. Epoetin has been
shown to facilitate the production of autologous blood
that can be donated before elective surgery.17 Patients
who will benefit most are patients with a hematocrit
of 33 to 39 whose blood loss during surgery is expected to be 1000 and 3000 mL.
Epoetin is relatively expensive as a treatment.18 It
costs about $300 per dose of 20,000 units, which
would total about $1,200 per month, given weekly.
The Journal for Nurse Practitioners - JNP

265

Box 4. Epoetin Alfa Treatment

Indications

Adverse Reactions

Anemia as a result of renal failure; anemia as a result of cancer chemotherapy; surgery, reduce need for blood transfusions during surgery; anemia as a result of zidovudine therapy; anemia, symptomatic

The adverse reactions depend on the reason the medication is

being used. It is generally well tolerated. Fever, diarrhea, nausea, edema, and local reaction are the most likely reactions.

Off-label Indications
Anemia (due to hepatitis C management); anemia (due to
malignancy); anemia (due to myelodysplastic syndromes);
anemia (due to donation prophylaxis); anemia (due to postpartum blood loss); anemia (due to rheumatic disease); anemia of prematurity; anemia, sickle cell; Castleman disease;
Gaucher disease; hemoglobinuria, paroxysmal nocturnal

Laboratory Monitoring
Monitor the hemoglobin weekly. CBC counts should be performed regularly according to the package insert. Before
treatment, the patients transferrin saturation should be at least
20%, and the serum ferritin should be elevated. Benefits are
generally apparent after 4 to 8 weeks but may be seen as early
as 2 weeks.

Dosage and Administration

Contraindications
Uncontrolled hypertension; known hypersensitivity to
mammalian cellderived products; known hypersensitivity
to albumin (human)

Warnings
Thrombotic events and increased mortality: In patients
receiving hemodialysis with cardiac disease, epoetin increases
the risk of mortality because of thrombotic events. In
women with metastatic carcinoma of the breast, on
chemotherapy, epoetin showed increased thrombotic events.
Pure red cell aplasia (PRCA) was reported, predominantly in patients with CRF.
Albumin: Epoetin contains albumin; it carries an extremely
remote risk of transmission of viral disease and CreutzfeldtJakob disease. No cases have been identified.
Patients with CRF: Hypertension, blood pressure may rise
during epoetin therapy. Hypertensive encephalopathy and
seizures have been observed.Thrombotic events, patients may
require increased anticoagulation to prevent clotting of the
artificial kidney.
Patients with HIV treated with zidovudine:Treatment has
not been linked to exacerbation of hypertension, seizures,
and thrombotic events.

Epoetin therapy may be reimbursed under Medicare Part

B, providing strict requirements are followed.The companies who deliver the medication and fill out the reimbursement forms for the medication are a good source for
information about reimbursement requirements in your
area. See Table 2 for specific dosage and administration
information in anemias caused by other diseases and Box
4 for additional information about the use of epoetin.
Darbepoetin alfa (Aranesp)20 is another medication
that is closely related to erythropoietin. It is indicated for
anemia, secondary to renal failure, and anemia secondary
to cancer chemotherapy. Off-label indication for this
266

The Journal for Nurse Practitioners - JNP

Epoetin is given subcutaneously. Epoetin dosing was

studied most extensively in CRF and cancer. Epoetin was
injected three times a week in the earlier studies. It is
used weekly in patients before surgery. Weekly use is
becoming more common.19 One dosage used for ACD
caused by cancer is 20,000 units weekly. Epoetin reaches
peak plasma levels in 5 to 24 hours after subcutaneous
injection. The long-lasting form of erythropoietin, darbepoetin, has been used monthly.
Increases in dose should be made no more frequently
than once a month. If the hemoglobin level is increasing
and approaching 12 g/dL, the dose should be reduced by
approximately 25%. Hold the epoetin if the hemoglobin
level continues to increase, until the hemoglobin level
begins to decrease. Restart at a dose 25% below the previous dose. If the hemoglobin level increases by more
than 1 g/dL in 2 weeks, decrease dose by 25%. Once the
target hemoglobin level is achieved, the dose should be
titrated to the lowest dose necessary to maintain the
hemoglobin value.

product is anemia secondary to malignancy. Absorption

of this product is slow with the peak concentration
occurring at 24 to 72 hours in patients with CRF and
71 to 123 in patients with cancer.
Summary
Anemia is a common finding in the elderly. One of the
frequent problems responsible for this condition is ACD,
which is caused by decreased RBC production. It is generally not treated. However, if the anemia is causing significant fatigue, which is interfering with the patients quality
of life, treatment with epoetin may be effective. Epoetin
April 2006

does not have a specific indication by the Food and Drug

Administration listed for use in ACD, but many clinicians
are beginning to use it successfully to improve the quality
of life in elderly patients with ACD.
References
1. Fitzsimons EJ, Brock JH. The anaemia of chronic disease. BMJ.
2001;322(7290):811-812.
2. Beghe C, Wilson A, Ershler WB. Prevalence and outcomes of anemia in
geriatrics: a systematic review of the literature. Am J Med. 2004;116(7A):3S-10S.
3. Ania BJ, Suman VJ, Fairbanks VF, Melton LJ III. Prevalence of anemia in
medical practice: community versus referral patients. Mayo Clin Proc.
1994;69(8):808-809.
4. Gabrilove J. Anemia and the elderly: clinical considerations. Best Pract Res
Clin Haematol. 2005;18(3):417-422.
5. Brill JR, Baumgardner DJ. Normocytic anemia. Am Fam Physician.
2000;62(10):2255-2264.
6. Gardner LB, Benz EJ. Anemia of chronic diseases. In: Hoffman. Hematology:
basic principles and practice. 4th ed. Philadelphia, Pa: Churchill Livingstone;
2005.
7. National Kidney Foundation. NKF-K/DOQI clinical practice guidelines for
anemia of chronic kidney disease: update 2000. Am J Kidney Dis.
2001;37(suppl 1):S182-S238.
8. Ross RD, Alexander CS. Management of common symptoms in terminally ill
patients: part I. Fatigue, anorexia, cachexia, nausea, and vomiting. Am Fam
Physician 2001;64(5):807-814.
9. Cella D, Passik S, Peterman C, Jacobsen PS, Breitbart W. Progress toward
guidelines for the management of fatigue. Oncology. 1998:12(11A):369-377.
10. Givertz MM, Colucci, Braunwald E. Clinical aspects of heart failure;
pulmonary edema, high-output failure. In: Zipes DP, Libby P, Bonow RO,
Braunwald E, eds. Braunwalds heart disease: a textbook of cardiovascular
medicine. 7th ed. Philadelphia, Pa: Saunders; 2005.
11. Rimon E, Kagansky N, Kagansky M, et al. Are we giving too much iron? Lowdose therapy is effective in octogenarians. Am J Med. 2005;118:1142-1147.
12. PI Iron Sucrose (Venofer). Mosbys Drug Consult 2006. 16th ed. St Louis, Mo:
Mosby; 2006.
13. Pendse S, Singh AK. Complications of chronic kidney disease: anemia,
mineral metabolism, and cardiovascular disease. Med Clin N Am.
2005;89(3):549-561.
14. Krantz SB. Erythropoietin and the anaemia of chronic disease. Nephrol Dial
Transplant. 1995;10(suppl l2):10-17.
15. Pincus T, Olsen NJ, Wolfe F, et al. Multicenter study of recombinant human
erythropoietin in corrections of anemia in rheumatoid arthritis. Am J Med.
1990;89(2):161-168.
16. Cleland JG, Sullivan JT, Ball S, et al. Once-monthly administration of
darbepoetin alfa for the treatment of patients with chronic heart failure and
anemia: a pharmacokinetic and pharmacodynamic investigation. J
Cardiovasc Pharmacol. 2005;46(2):155-161.
17. Goodnough LT, Terri TG, Andriole GL. Erythropoietin therapy. N Engl J Med.
1997;336(13):933-938.
18. Epoetin [package insert]. Thousand Oaks, Calif: Amgen.
19. Erythropoietin (Procrit, Epogen) revisited. Med Lett. 2001;43(W1104B):40-41.
20. Darbepoetin [package insert]. Thousand Oaks, Calif: Amgen.

Maren Mayhew, MS, ANP, GNP, CRNP, has worked in

office, nursing home, and home care settings in the Washington,
DC, area for more than 25 years. She has also served as a
faculty member in several NP programs. She has coedited five
books for nurse practitioners, including A Pharmacology
Textbook for Primary Care Providers. In accordance with
national ethical guidelines, she has disclosed that she has no
financial relationships with business or industry. She may be
reached at marenmayhew@comcast.net.
1555-4155/06/$ see front matter
2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.nurpra.2006.03.002

www.npjournal.org

Sign up to receive a
FREE subscription, plus
FREE access to the online
version of the journal.*

Visit
www.npjournal.org
today!
* npjournal.org is open to all visitors
through December 31, 2005. Request
your free subscription today to ensure
continued access.

The Journal for Nurse Practitioners - JNP

267