First Last
©2006 UpToDate®
printer-friendly format
New Search Contents My UpToDate CME 85.0 Help
A newer version of UpToDate is now available, and the information in this version
may no longer be current.
Anemia of chronic disease (anemia of chronic inflammation)
Stanley L Schrier, MD
UpToDate performs a continuous review of over 350 journals and other resources.
Updates are added as important new information is published. The literature review
for version 14.3 is current through August 2006; this topic was last changed on
July 24, 2006. The next version of UpToDate (15.1) will be released in February
2007.
INTRODUCTION — The anemia of chronic disease (ACD), also termed the anemia
of chronic inflammation, was initially thought to be associated primarily with
infectious, inflammatory, or neoplastic disease. However, other observations have
shown that ACD can be seen in a variety of conditions, including severe trauma, heart
disease, diabetes mellitus, and in those with acute or chronic immune activation [1-6].
The anemia is typically normochromic, normocytic, and hypoproliferative. (See
"Hematologic manifestations of HIV infection: Anemia", see "Hematologic
manifestations of systemic lupus erythematosus in adults", see "Hematologic
manifestations of rheumatoid arthritis", and see "Hematologic consequences of
malignancy: Anemia").
The pathogenesis, laboratory findings, and treatment of this form of anemia will be
discussed here. Because of its similarities to ACD, this review will also deal with the
anemia resulting from cancer and its treatment [7].
PATHOGENESIS — ACD is thought to primarily reflect a reduction in red blood cell
(RBC) production by the bone marrow. However, there may also be a component due
to mild shortening of RBC survival. Three factors are thought to contribute to the
hypoproliferative state [8]: Trapping of iron in macrophages, resulting in reduced
plasma iron levels (hypoferremia), making iron relatively unavailable for new
hemoglobin synthesis [9-11]. Inability of the morphologically normal marrow to
increase erythropoiesis in response to the anemia. EPO levels are somewhat elevated
in ACD, but there is virtually no increase in erythropoiesis, perhaps due to increased
apoptotic death of red cell precursors [2,8,12,13]. A relative decrease in EPO
production. Patients with ACD have lower levels of EPO than do patients with iron
deficiency and a similar degree of anemia [11]. This relative impairment in EPO
release is not thought to be of major clinical importance, given the impairment in
responsiveness to EPO [8].
Why these changes occur is becoming increasingly understood. It has been suggested
that the underlying medical condition causes the release of cytokines such as the
interleukins and tumor necrosis factor (TNF); these cytokines may then unleash a
cascade including the secretion of interferon (IFN)-beta and IFN-gamma which, when
given to experimental animals, can produce the picture of ACD with the three
abnormalities noted above [8,14-16]. In support of this suggestion is the observation
that treatment of patients with rheumatoid arthritis using an anti-TNF-alpha antibody
led to a reduction in IL-6 levels, a decrease in the proportion of apoptotic red cell
precursors, and an improvement in their anemia [13,17]. (See "Acute phase proteins",
section on Cytokine induction).
Hepcidin — One acute phase protein which appears to be directly involved in iron
metabolism is hepcidin [18]. Evidence from transgenic mouse models indicates that
hepcidin is the predominant negative regulator of iron absorption in the small
intestine, iron transport across the placenta, as well as iron release from macrophages
(show figure 1) [19]. (See "Regulation of iron balance", section on Hepcidin).
In an animal model of inflammation, a single injection of turpentine induced an acute
sixfold increase in liver hepcidin mRNA and a twofold decrease in serum iron [20].
The latter effect was completely blunted in hepcidin-deficient mice [21]. In other
murine studies, direct injection of human hepcidin induced hypoferremia within 4
hours, while implantation of tumor xenografts overexpressing human hepcidin
resulted in more severe anemia, lower serum iron levels, and increased hepatic iron
compared with mice harboring control tumors [22].
In the few human studies reported to date, increased hepcidin production [23],
increased urinary excretion of hepcidin [18], and increased serum levels of
prohepcidin [11] have been noted in patients with infections, malignancy, or
inflammatory states.
The importance of Interleukin (IL)-6 in this pathway was shown by the following
observations [11,24,25]: The effect of an injection of turpentine on liver hepcidin
mRNA and serum iron, as noted above, was completely blunted in Interleukin (IL)-6
knockout mice. The acute increase in hepcidin mRNA in cultured hepatocytes
following stimulation with bacterial lipopolysaccharide (LPS) was completely blunted
when LPS was combined with an antibody to IL-6. Infusion of IL-6 into normal
human volunteers acutely raised urinary excretion of hepcidin along with a significant
drop in serum iron. Following injection of bacterial LPS into 10 healthy human
volunteers, IL-6 was dramatically induced within 3 hours; urinary hepcidin peaked
within 6 hours, followed by a significant decrease in serum iron. In one study, serum
levels of IL-6 and C-reactive protein in patients with ACD were raised more than 10fold over those in controls or in patients with IDA and similar levels of hemoglobin
[11].
Together, these studies suggest that IL-6 is required for the induction of hepcidin and
hypoferremia during inflammation in both animals and humans (show figure 2).
Acute variant — Acute event-related anemia, such as that occurring after surgery,
major trauma, myocardial infarction, or sepsis, a condition also called the "anemia of
critical illness", shows many of the above-noted changes, presumably secondary to
tissue damage and acute inflammatory changes [26,27]. It has many of the features of
ACD (eg, low serum iron, high ferritin, blunted response to EPO), and may be an
acute variant of ACD [28,29].
LABORATORY FINDINGS — Anemia in ACD is of variable severity. Many
patients have a mild anemia, with a hemoglobin concentration of 10 to 11 g/dL.
However, more severe anemia, with a hemoglobin concentration <8 g/dL occurs in
approximately 20 percent of cases. The absolute reticulocyte count is frequently low
(<25,000/microL), a reflection of the overall decrease in RBC production. (See
"Approach to the adult patient with anemia", section on Understanding the
reticulocyte count).
The anemia may be accompanied by an elevation in cytokines (eg, IL-6) as well as
acute phase reactants (eg, fibrinogen, erythrocyte sedimentation rate, C-reactive
protein) [30,31]. The serum iron concentration and transferrin level (also measured as
total iron binding capacity, TIBC) are both low and the percent saturation of
transferrin is usually normal, which should distinguish ACD from iron deficiency
anemia, in which transferrin saturation is low. However, approximately 20 percent of
patients with ACD have low transferrin saturations in the iron deficiency range (as
low as 10 percent), even though only about one-quarter of such patients are truly iron
deficient [2]. In the remaining patients, the inability to release iron from macrophages
is presumably responsible for the low serum iron levels and low transferrin saturation
(show figure 2 and show figure 1). (See "Causes and diagnosis of anemia due to iron
deficiency", section on Serum iron and transferrin (TIBC)).
The serum ferritin concentration, which is usually normal or elevated in ACD, may
become a poor index of iron stores in chronic inflammatory diseases because ferritin
is also an acute phase reactant. (See "Acute phase proteins" and see "Causes and
diagnosis of anemia due to iron deficiency", section on Inflammatory states). In
addition, the destruction of hepatic or splenic tissue due to the primary disease may
release relatively large amounts of ferritin into the circulation.
Examination of the bone marrow for its content and distribution of iron may be
helpful. In the most classical presentation of ACD, bone marrow macrophages will
contain normal or increased amounts of storage iron, while erythroid precursors will
show decreased or absent staining for iron (ie, decreased numbers of sideroblasts)
(show bone marrow 1) [32,33].
Differential diagnosis — ACD is usually a normochromic hypoproliferative anemia
that does not affect other blood cell lines. Other disorders that can present with similar
findings include chronic renal failure and several endocrine disorders, including
hyperthyroidism, hypothyroidism, panhypopituitarism, and primary and secondary
hyperparathyroidism.
Some patients with ACD have more prominent anemia (hemoglobin concentration <8
g/dL) with hypochromic and microcytic red cells. In this setting, the differential must
include chronic iron deficiency, thalassemia variants, and the sideroblastic variants of
the myelodysplastic syndrome. (See "Causes and diagnosis of anemia due to iron
deficiency", section on Differential diagnosis, see "Clinical manifestations and
diagnosis of the myelodysplastic syndromes", and see "Clinical aspects, diagnosis,
and treatment of the sideroblastic anemias", section on Diagnosis). As noted above,
measurement of serum iron, transferrin (total iron binding capacity), and ferritin may
not clearly distinguish between these disorders. In this setting, a history of an acute or
chronic inflammatory disease with no evidence of occult blood loss is suggestive of
ACD.
Because the differentiation between iron deficiency anemia (IDA) and ACD is
clinically important and sometimes difficult, some authors have proposed using
measurement of serum levels of soluble transferrin receptor (sTfR) to help distinguish
between the two. The biologic principle is that in iron deficiency states, cellular
membrane transferrin receptor density increases, with the result that truncated forms
of transferrin receptors (sTfR) appear in the serum in increased amounts. Some
authors claim that measurement of sTfR can distinguish between IDA and ACD
[34,35]. However, another study noted that sTfR levels were no more useful than
measurement of total iron binding capacity [36]. (See "Hematologic manifestations of
rheumatoid arthritis", section on Iron deficiency anemia). Measurement of the ratio of
sTfR to the logarithm of ferritin (TfR-ferritin index) may overcome these limitations
(show figure 3). (See "Causes and diagnosis of anemia due to iron deficiency",
section on TfR-ferritin index).
In difficult cases, the diagnosis can often be established by bone marrow examination.
Findings in the most common disorders include: ACD — Iron staining is usually
normal or increased (show bone marrow 1); specifically, bone marrow macrophages
usually show normal to increased iron, while erythroid precursors show decreased to
absent amounts of iron (ie, decreased to absent sideroblasts). Iron deficiency —
absence of stainable iron. (See "Causes and diagnosis of anemia due to iron
deficiency", section on Differential diagnosis). Myelodysplastic syndrome — Single
or multi-lineage dysplastic changes with or without increased number of sideroblasts,
including ring forms (show bone marrow 2). (See "Clinical aspects, diagnosis, and
treatment of the sideroblastic anemias", section on Diagnosis, and see "Clinical
manifestations and diagnosis of the myelodysplastic syndromes", section on
Laboratory findings).
Alternatively, when an inflammatory state may be accompanied by iron deficiency,
one may monitor the response to a trial of iron supplementation. (See "Causes and
diagnosis of anemia due to iron deficiency", section on Inflammatory states).
Hemoglobin electrophoresis and examination of the peripheral blood smear should be
performed if one of the thalassemic disorders is being considered. (See "Clinical
manifestations of the thalassemias", section on Laboratory features).
TREATMENT — The preferred therapy for ACD is correction of the underlying
disorder, rather than replacement therapy with red cell transfusions (show table 1) or
erythropoietin. (See "Use of red blood cells for transfusion" and see "Indications for
red cell transfusion in the adult"). Most patients have mild anemia that produces no
symptoms, being compatible with the patient's often limited life-style. Some patients,
however, have more severe anemia, leading to impaired function and an impaired
quality of life [1,2,37]. (See "Evaluation of health-related quality of life").
Other complicating factors, such as blood loss, deficiencies of iron, folate, and/or
vitamin B12 should be appropriately treated, if present. (See "Approach to the adult
patient with anemia"). If the anemia is due to underlying malignancy, successful
treatment with combinations of surgery, chemotherapy, and/or radiation therapy may,
in the long term, improve the anemia. However, the anemia may be transiently or
permanently exacerbated secondary to the myelosuppressive effects of chemotherapy
and radiation, and may be improved by use of recombinant human erythropoietin (see
below) [38].
Erythropoietin — Measurement of the plasma erythropoietin (EPO) concentration
may be helpful in ACD. Patients with cancer, rheumatoid arthritis, or AIDS who have
EPO levels <500 IU/mL (although some authors suggest a cut-off of 100 mU/mL)
frequently respond to the administration of recombinant human EPO [39-43]. One
report in HIV-infected patients, for example, found a mean 4.6 percentage point
increase in hematocrit and reduction in transfusion requirements that was only seen in
those with a baseline plasma EPO 500 IU/mL [41]. (See "Hematologic manifestations
of HIV infection: Anemia", section on Recombinant human erythropoietin).
A meta-analysis of 22 trials involving the use of EPO for the anemia associated with
cancer therapy found that EPO significantly decreased the percent of patients
transfused (relative risk 0.38) [44]. A significant improvement in quality of life was
seen in studies with mean pretreatment hemoglobin concentrations 10 g/dL; quality of
life appeared to be maximal at hemoglobin levels between 11 and 13 g/dL. These
results are supported by the ASH/ASCO published guidelines for the use of EPO in
malignant diseases (see "Dosage" below), and are similar to those recommended for
the treatment of chronic renal disease [45-47]. (See "Erythropoietin for the anemia of
chronic kidney disease"). However, several methodologic issues hamper full
interpretation of the available data [48].
Effect on survival — In addition to enhanced quality of life, nonrandomized studies
in patients treated for lung or head and neck cancer have suggested that patients with
hemoglobin values >12 [49] or >14.5 g/dL [50] have both improved response to
treatment and better survival [49-54]. (See "Rationale and general aspects of
concomitant chemoradiotherapy in locoregionally advanced head and neck cancer",
section on Methods to overcome hypoxia and section on The tumor cell
microenvironment).
This hypothesis was directly tested in a prospective, randomized, placebo-controlled
setting, using EPO in a manner not approved by the FDA, nor supported by the
ASH/ASCO guidelines (see "Dosage" below). The stated aim was to keep
hemoglobin concentrations above 14 g/dL in women and 15 g/dL in men before and
during curative radiotherapy for head and neck cancer. Unexpectedly, locoregional
control and survival were significantly worse in the EPO-treated group [55].
A similar randomized study of EPO versus placebo in 939 women with metastatic
breast cancer (BEST trial), designed to keep hemoglobin concentrations within the
range of 12 to 14 m/dL, was terminated early due to an increase in mortality in the
EPO-treated group during the first four months of the study [56,57]. The increased
mortality was due to an increase in disease progression as well as an increased
incidence of thrombotic and vascular events [56-58]. Imbalances in pretreatment
prognostic factors between the two study arms could not be ruled out as an
explanation for these survival differences.
These results were surprising given the large number of published studies using EPO
in cancer patients, and the consistent association of anemia with inferior outcomes
[47,59]. Why this might have occurred is not known, and confirmation of these results
is required. Other than protocol-specific issues, as noted above, there are at least two
possible explanations: A number of tumors have been reported to possess EPO
receptors (EPO-R) responsible for promotion of angiogenesis, tumor growth, and
tumor cell survival [57,60,61]. This argument is weakened by the fact that acute
myeloid leukemia (AML) cells have receptors for granulocyte colony-stimulating
factor (G-CSF), and that the administration of G-CSF during AML induction has had
no deleterious effect on survival. (See "Treatment of acute myeloid leukemia in
adults", section on Use of hematopoietic growth factors). In addition, a study in a
rodent model, using four different EPO-R-expressing tumors, showed no effect of
exogenously-administered recombinant human EPO on in vivo tumor growth or
angiogenesis [62]. Higher levels of hemoglobin in the EPO-treated patients may have
led to an increased incidence of thrombotic and vascular events [59,63,64], similar to
results seen in patients with end-stage renal disease treated to high levels of
hemoglobin with EPO [65], or the use of EPO by athletes to improve performance
("blood doping") [66]. (See "Erythropoietin for the anemia of chronic kidney disease",
section on Side effects).
Accordingly, an FDA advisory has been issued, warning that target hemoglobin levels
in EPO-treated patients should not exceed 12 g/dL [67].
Dosage — EPO is given in a starting dose of 100 to 150 U/kg subcutaneously three
times weekly along with supplemental oral iron. Responders may show a rise in the
hemoglobin concentration of at least 0.5 g/dL by two to four weeks [42,68]. However,
a meta-analysis of data from four randomized trials in 604 patients with non-myeloid
malignancies concluded that up to 46 percent of those not showing a rise in
hemoglobin by two to four weeks may ultimately respond [69].
If there is no elevation in the hemoglobin concentration by six to eight weeks, the
regimen can be intensified to daily therapy or 300 U/kg three times weekly. It is not
worthwhile to continue EPO in patients who do not have a clinically meaningful
response by 12 weeks (show table 2) [42].
However, most clinicians use 30,000 to 40,000 U of EPO given SQ once per week, a
single dose which is numerically equivalent to a dose of 140 to 190 U/kg three times
per week for a 70 kg person [70,71]. This dose can be increased to 60,000 U if there is
no response (ie, hemoglobin rise <1 g/dL) at four weeks. When this single dose
schedule was employed in anemic patients, results were similar to thrice-weekly EPO
dosing, with an increase in mean hemoglobin concentration, a reduction in transfusion
requirement, and an improvement in quality of life measures for patients receiving
chemotherapy [72], as well as those receiving radiation therapy plus chemotherapy
[73]. This simplified, well tolerated dosing regimen has also been recommended for
treatment of the anemia associated with HIV infection [74]. (See "Hematologic
manifestations of HIV infection: Anemia", section on Recombinant human
erythropoietin).
The Food and Drug Administration has approved the use of recombinant human
erythropoietin (EPO, Epogen, Procrit) for the treatment of anemia in patients with
non-myeloid malignancies, where anemia is due to the effect of concomitant
administration of chemotherapy. Specifically, it is indicated to decrease the need for
transfusions in patients who will be receiving concomitant chemotherapy for a
minimum of two months.
Darbepoetin — Darbepoetin (Aranesp™, Amgen) is a newer formulation of
erythropoietin that was initially called novel erythropoiesis stimulating protein
(NESP). It is produced in Chinese hamster ovary cells by recombinant DNA
technology and has a longer in vivo half-life than erythropoietin (show figure 4), with
the demonstration of efficacy when given as infrequently as once every three to four
weeks in patients with a variety of hematologic and non-hematologic malignancies
[75-78]. (See "Darbepoetin alfa for the management of anemia in chronic kidney
disease").
A double-blind trial of weekly darbepoetin (initial dose: 2.25 µg/kg SQ) versus
placebo in 314 anemic patients (hemoglobin 11.0 g/dL) with lung cancer receiving
chemotherapy showed the following results favoring treatment with darbepoetin over
placebo [79]: Fewer patients requiring transfusion during the first 28 days of
treatment (27 versus 52 percent; mean difference 25 percent; 95 percent confidence
interval: 14 to 36) Higher rates of hematopoietic response (increase in hemoglobin
level 2.0 g/dL or a hemoglobin 12.0 g/dL) of 66 versus 24 percent (mean difference
42 percent, 95% CI: 31-53) More patients showing a 25 percent improvement in the
FACT-fatigue score (32 versus 19 percent, mean difference 13 percent, 95 percent
confidence interval: 2 to 23 percent)
Recommended dose schedules — Darbepoetin was approved by the FDA on July 19,
2002 for the treatment of chemotherapy-induced anemia in nonmyeloid malignancies.
The suggested initial dose for this indication is 2.25 microg/kg SQ once per week,
which is different from the initial dose suggested for correction of anemia in chronic
renal failure (0.45 microg/kg SQ or IV once per week).
Guidelines for the use of darbepoetin in patients with chemotherapy- induced anemia
have been published (show table 3), and suggest an initial dose of 200 microg SQ
every two weeks [80], a dose also included in the 2004 NCCN Guidelines [81]. In
three separate randomized trials for the treatment of chemotherapy-induced anemia in
patients with breast, lung, or gynecologic malignancy, this dose schedule for
darbepoetin (200 microg SQ every two weeks) was found to achieve comparable
clinical and hematologic outcomes to erythropoietin given at a dose of 40,000 U SQ
once per week [82-84].
Other treatment schedules for darbepoetin have been employed. As an example, a
European trial compared the use of two different schedules of darbepoetin in anemic
patients with nonmyeloid malignancies scheduled to receive at least 12 weeks of
chemotherapy [77]. Subjects were randomly assigned to receive either 500 microg
every three weeks or 2.25 microg/kg every week; both were given for a total of 15
weeks. The percent of patients requiring transfusion (23 versus 30 percent), achieving
a target hemoglobin >11 g/dL (84 versus 77 percent), and developing
cardiovascular/thrombotic events (8 percent in both groups) was similar in the two
treatment arms.
As a result of this latter study [77], the United States FDA approved the use of
darbepoetin in a starting dose of 500 micrograms once every three weeks as an
alternative to the recommended starting dose of 2.25 microg/kg once per week for the
treatment of chemotherapy- induced anemia in patients with non-myeloid
malignancies.
Supplemental iron — To achieve and maintain the target hemoglobin levels noted
above with either erythropoietin or darbepoetin, sufficient body iron stores are
required. Supplemental iron should be administered, as needed, to maintain a
transferrin saturation of 20 percent, and a serum ferritin level of 100 ng/mL [85]. (See
"Iron balance in dialysis patients", section on Diagnosis of iron deficiency).
SUMMARY AND RECOMMENDATIONS
Anemia of chronic disease — The anemia of chronic disease (ACD) is commonly
seen in patients with chronic infection, inflammation, or malignancy. It is a mild
normocytic normochromic anemia, with low levels of serum iron and transferrin,
normal to increased serum levels of ferritin, normal to increased levels of serum
erythropoietin, and a low reticulocyte response for the degree of anemia. Coexisting
iron deficiency is common; its presence is suggested by the finding of low serum
ferritin levels, absence of stainable iron on bone marrow aspiration/biopsy, or
response to a therapeutic trial of oral iron.
Treatment — ACD is most effectively treated via approaches directed against the
underlying infection, inflammatory condition, or malignancy. If this is not possible,
supportive care is given through periodic red cell transfusions or use of EPO or
darbepoetin. Treatment of the anemia associated with chemotherapy in nonmyeloid
malignancies is similar to that of ACD. In both disorders, the therapeutic endpoint
should be a hemoglobin of approximately 12 g/dL.
EPO can be given once per week (show table 2), while darbepoetin appears to have an
effectiveness equal to that of EPO when given once every two or three weeks (show
table 3) [82,86,87]. Supplemental iron should be given to maintain a transferrin
saturation 20 percent and a serum ferritin 100 ng/mL.
Anemia in cancer patients — Anemia is commonly seen in patients with malignant
disease, both as a complication of the illness as well as its treatment with
chemotherapy. The latest meta-analysis involving 57 randomized controlled trials in
cancer patients has concluded the following concerning the results of treatment with
erythropoietin or darbepoietin [88]: It significantly reduced the risk for blood
transfusion (relative risk (RR) 0.64; 95% CI 0.60-0.68) It significantly improved
hematologic response, as defined by an increase in hemoglobin of at least 2 g/dL (RR
3.43; 95% CI 3.07-3.84) It significantly increased the risk of thromboembolic events
(RR 1.67; 95% CI 1.35-2.06) It reduced overall survival, although this reduction was
not statistically significant (hazard ratio of death 1.08; 95% CI 0.99-1.18)
Treatment — Formal guidelines for the use of EPO and darbepoetin in anemic
patients with cancer have been published and endorsed by the American Society of
Hematology (ASH) and the American Society of Clinical Oncology (ASCO, show
table 2) [47,89], the European Organisation for Research and Treatment of Cancer
(EORTC) [90], and the National Comprehensive Cancer Network (NCCN) [81].
While multiple randomized trials have shown erythropoietin and darbepoetin to be
equally effective, the latter appears to be more convenient, as it can be given as
infrequently as once every two to three weeks.
Because of the potential risk of thromboembolic phenomena at higher hemoglobin
levels, target hemoglobin levels in EPO-treated patients should not exceed 12 g/dL
[67].
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES 1. Cash, JM, Sears, DA. The anemia of chronic disease: Spectrum of
associated diseases in a series of unselected hospitalized patients. Am J Med 1989;
87:638.
2. Schilling, RF. Anemia of chronic disease: a misnomer. Ann Intern Med 1991;
115:572.
3. Weiss, G. Pathogenesis and treatment of anaemia of chronic disease. Blood Rev
2002; 16:87.
4. Means, RT Jr. Recent developments in the anemia of chronic disease. Curr
Hematol Rep 2003; 2:116.
5. Weiss, G, Goodnough, LT. Anemia of chronic disease. N Engl J Med 2005;
352:1011.
6. Opasich, C, Cazzola, M, Scelsi, L, et al. Blunted erythropoietin production and
defective iron supply for erythropoiesis as major causes of anaemia in patients with
chronic heart failure. Eur Heart J 2005; 26:2232.
7. Ludwig, H, Van Belle, S, Barrett-Lee, P, et al. The European Cancer Anaemia
Survey (ECAS): a large, multinational, prospective survey defining the prevalence,
incidence, and treatment of anaemia in cancer patients. Eur J Cancer 2004; 40:2293.
8. Means, RT Jr, Krantz, SB. Progress in understanding the pathogenesis of the
anemia of chronic disease. Blood 1992; 80:1639.
9. Means, RT Jr. Advances in the anemia of chronic disease. Int J Hematol 1999;
70:7.
10. Ludwiczek, S, Aigner, E, Theurl, I, Weiss, G. Cytokine-mediated regulation of
iron transport in human monocytic cells. Blood 2003; 101:4148.
11. Theurl, I, Mattle, V, Seifert, M, et al. Dysregulated monocyte iron homeostasis
and erythropoietin formation in patients with anemia of chronic disease. Blood 2006;
107:4142.
12. Papadaki, HA, Kritikos, HD, Gemetzi, C, et al. Bone marrow progenitor cell
reserve and function and stromal cell function are defective in rheumatoid arthritis:
evidence for a tumor necrosis factor alpha-mediated effect. Blood 2002; 99:1610.
13. Papadaki, HA, Kritikos, HD, Valatas, V, et al. Anemia of chronic disease in
rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid
cells: improvement following anti-tumor necrosis factor-alpha antibody therapy.
Blood 2002; 100:474.
14. Means, RT Jr, Krantz, SB. Inhibition of human erythroid colony-forming units by
tumor necrosis factor requires beta interferon. J Clin Invest 1993; 91:416.
15. Means, RT Jr, Krantz, SB, Luna, J, et al. Inhibition of murine erythroid colony
function in vitro by interferon gamma and correction by interferon receptor
immunoadhesin. Blood 1994; 83:911.
16. Voulgari, PV, Kolios, G, Papadopoulos, GK, et al. Role of cytokines in the
pathogenesis of anemia of chronic disease in rheumatoid arthritis. Clin Immunol
1999; 92:153.
17. Davis, D, Charles, PJ, Potter, A, et al. Anaemia of chronic disease in rheumatoid
arthritis: In vivo effects of tumour necrosis factor alpha blockade. Br J Rheumatol
1997; 36:950.
18. Nemeth, E, Valore, EV, Territo, M, et al. Hepcidin, a putative mediator of anemia
of inflammation, is a type II acute-phase protein. Blood 2003; 101:2461..
19. Ganz, T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of
inflammation. Blood 2003; 102:783.
20. Nicolas, G, Chauvet, C, Viatte, L, et al. The gene encoding the iron regulatory
peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest
2002; 110:1037.
21. Roy, CN, Custodio, A, De Graaf, J, et al. An Hfe-dependent pathway mediates
hyposideremia in response to lipopolysaccharide-induced inflammation in mice. Nat
Genet 2004; 36:481.
22. Rivera, S, Liu, L, Nemeth, E, et al. Hepcidin excess induces the sequestration of
iron and exacerbates tumor-associated anemia. Blood 2005; 105:1797.
23. Weinstein, DA, Roy, CN, Fleming, MD, et al. Inappropriate expression of
hepcidin is associated with iron refractory anemia: implications for the anemia of
chronic disease. Blood 2002; 100:3776.
24. Nemeth, E, Rivera, S, Gabayan, V, et al. IL-6 mediates hypoferremia of
inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J
Clin Invest 2004; 113:1271.
25. Kemna, E, Pickkers, P, Nemeth, E, et al. Time-course analysis of hepcidin, serum
iron, and plasma cytokine levels in humans injected with LPS. Blood 2005; 106:1864.
26. van Iperen, CE, van de, Wiel A, Marx, JJ. Acute event-related anaemia. Br J
Haematol 2001; 115:739.
27. Jelkmann, W. Proinflammatory cytokines lowering erythropoietin production. J
Interferon Cytokine Res 1998; 18:555.
28. Rodriguez, RM, Corwin, HL, Gettinger, A, et al. Nutritional deficiencies and
blunted erythropoietin response as causes of the anemia of critical illness. J Crit Care
2001; 16:36.
29. Corwin, HL, Gettinger, A, Pearl, RG, et al. Efficacy of recombinant human
erythropoietin in critically ill patients: a randomized controlled trial. JAMA 2002;
288:2827.
30. Vreugdenhil, G, Lowenberg, B, van Eijk, HG, Swaak, AJ. Anaemia of chronic
disease in rheumatoid arthritis. Raised serum interleukin-6 (IL-6) levels and effects of
IL-6 and anti-IL-6 on in vitro erythropoiesis. Rheumatol Int 1990; 10:127.
31. Maccio, A, Madeddu, C, Massa, D, et al. Hemoglobin levels correlate with
interleukin-6 levels in patients with advanced untreated epithelial ovarian cancer: role
of inflammation in cancer-related anemia. Blood 2005; 106:362.
32. Ellis, LD, Jensen, WN, Westerman, MP. Marrow Iron. An Evaluation of depleted
stores in a series of 1,332 needle biopsies. Ann Intern Med 1964; 61:44.
33. Gardner, DL, Roy, LM. Tissue iron and the reticulo-endothelial system in
rheumatoid arthritis. Ann Rheum Dis 1961; 20:258.
34. Suominen, P, Mottonen, T, Rajamaki, A, Irjala, K. Single values of serum
transferrin receptor and transferrin receptor ferritin index can be used to detect true
and functional iron deficiency in rheumatoid arthritis patients with anemia. Arthritis
Rheum 2000; 43:1016.
35. Fitzsimons, EJ, Houston, T, Munro, R, et al. Erythroblast iron metabolism and
serum soluble transferrin receptor values in the anemia of rheumatoid arthritis.
Arthritis Rheum 2002; 47:166.
36. Wians, FH Jr, Urban, JE, Keffer, JH, Kroft, SH. Discriminating between iron
deficiency anemia and anemia of chronic disease using traditional indices of iron
status vs transferrin receptor concentration. Am J Clin Pathol 2001; 115:112.
37. Lind, M, Vernon, C, Cruickshank, D, et al. The level of haemoglobin in anaemic
cancer patients correlates positively with quality of life. Br J Cancer 2002; 86:1243.
38. Samol, J, Littlewood, TJ. The Efficacy of rHuEPO in Cancer-Related Anaemia.
Br J Haematol 2003; 121:3.
39. Spivak, JL. Recombinant human erythropoietin and the anemia of cancer. Blood
1994; 84:997.
40. Pincus, T, Olsen, NJ, Russell, IJ, et al. Multicenter study of recombinant human
erythropoietin in correction of anemia in rheumatoid arthritis. Am J Med 1990; 89:16.
41. Henry, DH, Beall, GN, Benson, CA. et al. Recombinant human erythropoietin in
the treatment of anemia associated with human immunodeficiency virus (HIV)
infection and zidovudine therapy. Ann Intern Med 1992; 117:739.
42. Ludwig, H, Fritz, E, Leitgeb, C, et al. Prediction of response to erythropoietin
treatment in chronic anemia of cancer. Blood 1994; 84:1056.
43. Osterborg, A, Brandberg, Y, Molostova, V, et al. Randomized, double-blind,
placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in
hematologic malignancies. J Clin Oncol 2002; 20:2486.
44. Seidenfeld, J, Piper, M, Flamm, C, et al. Epoetin treatment of anemia associated
with cancer therapy: a systematic review and meta-analysis of controlled clinical
trials. J Natl Cancer Inst 2001; 93:1204.
45. Cella, D, Zagari, MJ, Vandoros, C, et al. Epoetin alfa treatment results in
clinically significant improvements in quality of life in anemic cancer patients when
referenced to the general population. J Clin Oncol 2003; 21:366.
46. Crawford, J, Cella, D, Cleeland, CS, et al. Relationship between changes in
hemoglobin level and quality of life during chemotherapy in anemic cancer patients
receiving epoetin alfa therapy. Cancer 2002; 95:888.
47. Rizzo, JD, Lichtin, AE, Woolf, SH, et al. Use of epoetin in patients with cancer:
evidence-based clinical practice guidelines of the American Society of Clinical
Oncology and the American Society of Hematology. Blood 2002; 100:2303.
48. Bottomley, A, Thomas, R, van, SK, et al. Human recombinant erythropoietin and
quality of life: a wonder drug or something to wonder about? Lancet Oncol 2002;
3:145.
49. Waters, JS, O'Brien, ME, Ashley, S. Management of anemia in patients receiving
chemotherapy. J Clin Oncol 2002; 20:601.
50. Glaser, CM, Millesi, W, Kornek, GV, et al. Impact of hemoglobin level and use of
recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for
squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol
Phys 2001; 50:705.
51. Robnett, TJ, Machtay, M, Hahn, SM, et al. Pathological response to preoperative
chemoradiation worsens with anemia in non-small cell lung cancer patients. Cancer J
2002; 8:263.
52. Caro, JJ, Salas, M, Ward, A, Goss, G. Anemia as an independent prognostic factor
for survival in patients with cancer: a systemic, quantitative review. Cancer 2001;
91:2214.
53. Casas, F, Vinolas, N, Ferrer, F, et al. Improvement in performance status after
erythropoietin treatment in lung cancer patients undergoing concurrent
chemoradiotherapy. Int J Radiat Oncol Biol Phys 2003; 55:116.
54. Langer, CJ, Choy, H, Glaspy, JA, Colowick, A. Standards of care for anemia
management in oncology: focus on lung carcinoma. Cancer 2002; 95:613.
55. Henke, M, Laszig, R, Rube, C, et al. Erythropoietin to treat head and neck cancer
patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebocontrolled trial. Lancet 2003; 362:1255.
56. Leyland-Jones, B, Semiglazov, V, Pawlicki, M, et al.Maintaining normal
hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic
breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005;
23:5960.
57. Brower, V. Erythropoietin may impair, not improve, cancer survival. Nat Med
2003; 9:1439.
58. Rosenzweig, MQ, Bender, CM, Lucke, JP, et al. The decision to prematurely
terminate a trial of R-HuEPO due to thrombotic events. J Pain Symptom Manage
2004; 27:185.
59. Bohlius, J, Langensiepen, S, Schwarzer, G, et al. Recombinant human
erythropoietin and overall survival in cancer patients: results of a comprehensive
meta-analysis. J Natl Cancer Inst 2005; 97:489.
60. Acs, G, Acs, P, Beckwith, SM, et al. Erythropoietin and erythropoietin receptor
expression in human cancer. Cancer Res 2001; 61:3561.
61. Yasuda, Y, Fujita, Y, Matsuo, T, et al. Erythropoietin regulates tumour growth of
human malignancies. Carcinogenesis 2003; 24:1021.
62. Hardee, ME, Kirkpatrick, JP, Shan, S, et al. Human recombinant erythropoietin
(rEpo) has no effect on tumour growth or angiogenesis. Br J Cancer 2005; 93:1350.
63. Luksenburg, H. Safety concerns associated with Aranesp (darbepoetin alfa)
Amgen, Inc. and Procrit (epoetin alfa) Ortho Biotech, L.P., for the treatment of
anemia associated with cancer chemotherapy. FDA Briefing Document May 4, 2004.
Oncologic Drugs Advisory Committee. Available at:
<www.fda.gov/ohrms/dockets/ac/04/briefing/4037B2_04_fda-Aranesp-Procrit.htm>.
64. Hudis, CA, Vogel, CL, Gralow, JR, Williams, D. Weekly epoetin alfa during
adjuvant chemotherapy for breast cancer: effect on hemoglobin levels and quality of
life. Clin Breast Cancer 2005; 6:132.
65. Casserly, LF, Dember, LM. Thrombosis in end-stage renal disease. Semin Dial
2003; 16:245.
66. Shaskey, DJ, Green, GA. Sports haematology. Sports Med 2000; 29:27.
67. FDA advisory on target hemoglobin levels after treatment with EPO:
www.fda.gov/medwatch/SAFETY/2005/safety05.htm#aranesp (Accessed 3/8/05).
68. Gonzalez-Baron, M, Ordonez, A, Franquesa, R, et al. Response predicting factors
to recombinant human erythropoietin in cancer patients undergoing platinum-based
chemotherapy. Cancer 2002; 95:2408.
69. Littlewood, TJ, Zagari, M, Pallister, C, Perkins, A. Baseline and early treatment
factors are not clinically useful for predicting individual response to erythropoietin in
anemic cancer patients. Oncologist 2003; 8:99.
70. Soignet, S. Management of cancer-related anemia: epoetin alfa and quality of life.
Semin Hematol 2000; 37:9.
71. Cazzola, M, Beguin, Y, Kloczko, J, Spicka, I. Once-weekly epoetin beta is highly
effective in treating anaemic patients with lymphoproliferative malignancy and
defective endogenous erythropoietin production. Br J Haematol 2003; 122:386.
72. Gabrilove, JL, Cleeland, CS, Livingston, RB, et al. Clinical evaluation of onceweekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin
and quality of life are similar to three-times-weekly dosing. J Clin Oncol 2001;
19:2875.
73. Shasha, D, George, MJ, Harrison, LB. Once-weekly dosing of epoetin-alpha
increases hemoglobin and improves quality of life in anemic cancer patients receiving
radiation therapy either concomitantly or sequentially with chemotherapy. Cancer
2003; 98:1072.
74. Volberding, P. Consensus statement: anemia in HIV infection--current trends,
treatment options, and practice strategies. Anemia in HIV Working Group. Clin Ther
2000; 22:1004.
75. Kotasek, D, Steger, G, Faught, W, et al. Darbepoetin alfa administered every 3
weeks alleviates anaemia in patients with solid tumours receiving chemotherapy;
results of a double-blind, placebo-controlled, randomised study. Eur J Cancer 2003;
39:2026.
76. Hedenus, M, Adriansson, M, Miguel, JS, Kramer, MH. Efficacy and safety of
darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a
randomized, double-blind, placebo-controlled study. Br J Haematol 2003; 122:394.
77. Canon, JL, Vansteenkiste, J, Bodoky, G, et al. Randomized, double-blind, activecontrolled trial of every-3-week darbepoetin alfa for the treatment of chemotherapyinduced anemia. J Natl Cancer Inst 2006; 98:273.
78. Boccia, R, Malik, IA, Raja, V, et al. Darbepoetin alfa administered every three
weeks is effective for the treatment of chemotherapy-induced anemia. Oncologist
2006; 11:409.
79. Vansteenkiste, J, Pirker, R, Massuti, B, et al. Double-Blind, Placebo-Controlled,
Randomized Phase III Trial of Darbepoetin Alfa in Lung Cancer Patients Receiving
Chemotherapy. J Natl Cancer Inst 2002; 94:1211.
80. Bloomfield, M, Jaresko, G, Zarek, J, Dozier, N. Guidelines for using darbepoetin
alfa in patients with chemotherapy-induced anemia. Pharmacotherapy 2003; 23:110S.
81. Sabbatini, P, Cella, D, Chanan-Khan, A, et al. Cancer and treatment-related
anemia, version 1.2004. National Comprehensive Cancer Network (NCCN) Clinical
Practice Guidelines in Oncology available at
www.nccn.org/professionals/physician_gls/default.asp (Accessed 3/8/05).
82. Schwartzberg, LS, Yee, LK, Senecal, FM, et al. A randomized comparison of
every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of
chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer.
Oncologist 2004; 9:696.
83. Senecal, FM, Yee, L, Gabrail, N, et al. Treatment of chemotherapy-induced
anemia in breast cancer: results of a randomized controlled trial of darbepoetin alfa
200 microg every 2 weeks versus epoetin alfa 40,000 U weekly. Clin Breast Cancer
2005; 6:446.
84. Glaspy, J, Vadhan-Raj, S, Patel, R, et al. Randomized comparison of every-2week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapyinduced anemia: the 20030125 Study Group Trial. J Clin Oncol 2006; 24:2290.
85. Auerbach, M, Ballard, H, Trout, JR, et al. Intravenous iron optimizes the response
to recombinant human erythropoietin in cancer patients with chemotherapy-related
anemia: a multicenter, open-label, randomized trial. J Clin Oncol 2004; 22:1301.
86. Schwartzberg, LS, Yee, LK, Senecal, FM, et al. Early results of a head-to-head
comparison of darbepoietin alfa 200 mcg given every 2 weeks (q2w) and epoietin alfa
40,000 U given weekly (QW) (abstract). Blood 2003; 102:515a.
87. Patton, J, Reeves, T, Wallace, J. Effectiveness of darbepoetin alfa versus epoetin
alfa in patients with chemotherapy-induced anemia treated in clinical practice.
Oncologist 2004; 9:451.
88. Bohlius, J, Wilson, J, Seidenfeld, J, et al. Recombinant human erythropoietins and
cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl
Cancer Inst 2006; 98:708.
89. Rizzo, JD, Lichtin, AE, Woolf, SH, et al. Use of epoetin in patients with cancer:
evidence-based clinical practice guidelines of the American Society of Clinical
Oncology and the American Society of Hematology. J Clin Oncol 2002; 20:4083.
90. Bokemeyer, C, Aapro, MS, Courdi, A, et al. EORTC guidelines for the use of
erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004; 40:2201.
New Search Contents My UpToDate CME 85.0 Help
©2006 UpToDate® • www.uptodate.com • Contact Us