Blood Reviews 26 (2012) 65–71

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Blood Reviews
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REVIEW

The investigation and treatment of secondary anaemia

Sarah L. Davis, T.J. Littlewood ⁎
Department of Haematology, Cancer and Haematology Centre, Oxford Radcliffe Hospitals, Headington, Oxford, OX3 7LJ, United Kingdom

a r t i c l e i n f o a b s t r a c t

Keywords: Secondary anaemia or the anaemia of chronic disease (ACD) is the commonest form of anaemia in hospita-
Anaemia lised patients and the second most prevalent anaemia worldwide after iron deficiency. It is characterised
Chronic disease by defective iron incorporation in erythropoiesis, an impaired response to erythropoietin, a decrease in
Erythropoiesis stimulating agents erythropoietin production and cytokine induced shortening of red cell survival.
Intravenous iron For many patients with ACD the cause is apparent but for many others the underlying disease needs to be de-
Hepcidin
termined and such patients are often referred to haematologists for investigation. The search for the cause
can be a fascinating exercise in good history taking, examination skills and performing and interpreting ap-
propriate investigations. This review covers the pathogenesis and causes of ACD and then discusses the clin-
ical and laboratory investigation of a patient with suspected ACD. Finally, the management of a patient with
ACD is discussed including erythropoiesis stimulating agents (ESAs), intravenous iron and future therapies.
© 2011 Elsevier Ltd. All rights reserved.

1. Introduction anaemia, decreased sensitivity of erythroid precursors to erythropoie-

Secondary anaemia is the commonest form of anaemia in hospita-
lised patients and the second most prevalent worldwide after iron de-
ficiency 1. It occurs in patients with chronic illnesses such as chronic
infections, cancer, autoimmune disorders and chronic kidney disease
and is also known as ‘anaemia of chronic disease’ (ACD) or ‘anaemia
of inflammation’.
For many patients the underlying cause of the ACD is obvious.
Others will present with the ACD and the search for the cause can
be an interesting and rewarding piece of clinical medicine. The anae-
mia is often ignored and assumed not to contribute to the patients'
symptoms. However, there is now strong evidence that it can inde-
pendently worsen morbidity and mortality and negatively impact
on a patient's quality of life 2,3. Therefore, increasingly there is a
drive to improve the management of this anaemia although it will
need to be proven that improving the haemoglobin concentration
will have a positive impact on either patients' quality of life, life ex-
pectancy or both.
This review will briefly cover the pathogenesis of ACD and then
discuss the investigation and management in detail.
2. Pathogenesis
There are four known mechanisms that contribute to the develop-
ment of anaemia in chronic disease; defective iron incorporation in
developing red blood cells, a blunted erythropoietin response to
tin and shortened red cell survival. These are all thought to be immu-
nologically based, and therefore occur in patients with conditions that
cause acute or chronic immune activation such as those listed in
Table 1. In patients with chronic kidney disease the marked reduction
in erythropoietin production is the most important factor in causing
anaemia but these patients also have features of the ACD.
2.1. Defective iron incorporation in developing red blood cells
Approximately 10 years ago, the liver polypeptide, hepcidin 4,5
was discovered. It plays a pivotal role in iron homeostasis 6 and im-
munological driven changes in hepcidin levels are critical for the de-
velopment of ACD.
Table 1
Conditions that can be associated with anaemia of chronic disease.
Autoimmune disease
Rheumatoid arthritis, polymyalgia rheumatica, systemic lupus erythematosus,
inflammatory bowel disease
Malignancy
Solid tumours (especially metastatic), haematological cancers
Infections
AIDS, infective endocarditis, tuberculosis, osteomyelitis

Renal disease
⁎ Corresponding author. Tel.: + 44 1865 235882; fax: + 44 1865 235260.
Chronic kidney disease
E-mail address: tim.littlewood@chch.ox.ac.uk (T.J. Littlewood).

0268-960X/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.blre.2011.10.003
66 S.L. Davis, T.J. Littlewood / Blood Reviews 26 (2012) 65–71

As outlined in Fig. 1, hepcidin is predominantly produced by hepato-
cytes and inhibits iron release from macrophages and iron uptake by in-
testinal epithelial cells. In macrophages it accelerates the degradation of
the trans membrane iron exporter, ferroportin 1 mRNA. In intestinal ep-
ithelial cells it is believed to down-regulate divalent metal transporter 1
(DMT-1) which is involved in the transfer of iron across the intestinal
wall7. Hepcidin expression is controlled by the bone morphogenetic
protein (BMP) receptor, its signalling pathway and the accessory pro-
teins; HFE, hemojuvelin and transferrin receptor 2 (TfR2). High satura-
tion of TfR2 is conveyed to the BMP receptor complex via HFE and
hemojuvelin and this then up-regulates transcription of hepcidin by
Smad48. Hepcidin then acts to down-regulate release of iron from mac-
rophages and iron absorption. In normal conditions; the presence of
hypoxia, iron deficiency and ineffective erythropoiesis reduces the

Fig. 1. The pathophysiology of the anaemia of chronic disease.

Figure reproduced with permission
Anemia of Chronic Disease
The New England Journal of Medicine Authors: Weiss, Goodnough
Year of Publication: 2005
Article DOI: 10.1056/NEJMra041809
 S.L. Davis, T.J. Littlewood / Blood Reviews 26 (2012) 65–71
production of hepcidin resulting in an increased absorption of iron
through gut endothelial cells and increased iron release from tissue
macrophages to the plasma iron pool.
In secondary anaemia, hepcidin levels are increased. This is mainly
mediated by an increase in interleukin-6, the proinflammatory cyto-
kine 9, and occurs via the STAT3 pathway. However, other cytokines
such as BMP and IL-1 have also been shown to have a role in diseases
such as myeloma 10,11. Raised hepcidin levels cause retention of iron
in macrophages and enterocytes and a reduced availability of iron
for erythropoiesis leading to impaired heme synthesis.
2.2. Decreased erythropoietin and a blunted erythroid response
Erythropoetin, produced by peritubular cells within the renal
cortex, regulates marrow erythroid proliferation. Its expression is in-
versely proportional to tissue oxygenation and therefore haemoglo-
bin levels. In ACD there is often an inadequate rise in erythropoietin
level for the degree of anaemia 1. As shown in Fig. 1, autoimmune
dysregulation, appearance of malignant cells or invasion of micro-
organisms leads to activation of T cells and monocytes. These in
turn induce immune mechanisms that lead to the release of cytokines
such as IFNγ, IL-1, IL-6, IL-10 and TNFα. IL-1 and TNFα have been
shown to inhibit erythropoietin expression 12,13.
The responsiveness of erythroid progenitor cells is inversely
proportional to the amount of circulating cytokines and therefore
the severity of the underlying disease 1. Patients with ACD not only
have a reduced concentration of erythropoietin for the degree of
anaemia but the developing red blood cells are less sensitive to the
available erythropoietin.
Most patients with chronic kidney disease are anaemic caused by
the ACD but also from significantly reduced erythropoietin secretion
by the kidney.
2.3. Shortened red cell survival
Inflammatory cytokines, especially IFNγ, can impair proliferation
of erythroid precursors, induce apoptosis, and induce free radical for-
mation by neighbouring macrophages which damages erythrocytes 1.
This results in a mildly shortened lifespan of red cells. Under normal
circumstances the bone marrow would respond to a shortened red
cell lifespan by an increase in red cell production. In patients with
ACD such an increase is inhibited by the mechanisms described
above.
3. Clinical investigation
As Cavill et al 14 highlight, ACD is an overlooked and undertreated
condition and patients with ACD provide the same diagnostic chal-
lenge as a pyrexia of unknown origin (PUO) caused to physicians in
previous decades. ACD is not a diagnosis but a stimulus to determine
the underlying cause. The underlying cause may be obvious but in the
authors' experience it is the patients without an apparent diagnosis
who will be referred to a haematology or other clinic. It is important
to confirm a diagnosis of ACD and exclude other possible explana-
tions for the anaemia such as haematinic deficiency, blood loss, haemo-
lysis, endocrine disorders such as hypothyroidism and hypogonadism
and primary bone marrow disorders such as myelodysplasia. Occult
bleeding is an occasional diagnosis in patients thought to have ACD
and this should always be considered.
The diagnosis of patients referred to our clinic with unexplained
ACD is rarely a primary haematological disorder such as lymphoma
and myeloma probably because such patients have already had these
diagnoses considered and usually excluded.
During the past few years patients with ACD referred to the authors'
clinics have eventually had diagnoses made of chronic infection (e.g.
bacterial endocarditis and human immunodeficiency virus infection),
67
malignancy (e.g. renal cell carcinoma, ovarian cancer) and autoimmune
disease.
Anaemia caused by chronic kidney disease is common but usually
apparent from the basic screening tests of renal function. However, it
is important to remember that the glomerular filtration rate (GFR) is
a function not only of the plasma creatinine but also the patient's
age, sex and body weight. Thus a plasma creatinine of 140 μmol/l
in a 50 year old male weighing 100 kg produces a calculated GFR
of 77 mL/min. The same creatinine in an 85 year old woman weigh-
ing 50 kg gives a GFR of 20 mL/min. An unusual patient seen recently
had a diagnosis of ACD with raised inflammatory markers for many
years with no explanation despite intensive and thorough investigation.
Her body mass index was 37 kg/m 2. Adipocytes release inflammatory
cytokines15 so it was concluded that obesity was the probable cause
of her ACD.
In a patient with ACD a careful history and examination should be
undertaken followed by appropriate investigations to search for an
underlying chronic illness. Consideration should be given to screen-
ing for the illnesses described above, amongst others, and radiological
imaging is very important in the absence of a diagnosis particularly
where inflammatory markers are also increased.
Despite appropriate investigation some patients will have no
detectable cause for their anaemia identified.
4. Laboratory Investigation
An anaemia in a patient with a chronic disease cannot be assumed
to be ACD as other causes such as iron deficiency, megaloblastic anae-
mia and haemolysis are also common and may co-exist. The main
purpose of investigation is to confirm the diagnosis and rule out
other possibly easily correctable causes of anaemia.
Classically, ACD presents with a mild to moderate, normocytic, nor-
mochromic anaemia. Haemoglobin levels are usually above 8 g/dL 1 and
mean cell volume (MCV) and mean cell haemoglobin (MCH) are usually
within the normal range. However, in more advanced disease the MCH
and MCV may fall reflecting the inadequacy of iron supply. The reticulo-
cyte count is low, reflecting inadequate erythropoiesis and the red cell
distribution width (RDW) is often normal, although this is not always
the case16.
An assessment of iron status is important in order to distinguish
ACD from iron deficiency (IDA), although the two may co-exist. This
should begin with a history looking for a cause of iron deficiency
(bleeding, malabsorption and dietary insufficiency). Serum ferritin
may not be helpful as inflammation and intracellular iron accumula-
tion (as occurs in ACD) stimulates ferritin synthesis. However, true
iron deficiency is indicated if the serum ferritin level is low 8. Serum
iron concentration and transferrin saturation are low in both ACD
and IDA. In IDA this reflects true iron deficiency but in ACD this
reflects lack of iron in the blood stream (hypoferremia).
Because the serum ferritin, serum and transferrin may not reliably
distinguish between ID and ACD other laboratory parameters have
been investigated to try and help make this distinction. Commercial
assays are available that measure soluble transferrin receptor. This
is a truncated fragment of the membrane receptor which is in equilib-
rium with soluble transferrin receptor in the plasma. Transferrin re-
ceptor expression is increased in iron deficient states whereas in
ACD, concentrations are normal as inflammatory cytokines negatively
affect transferrin receptor expression. However, this assay has not
been standardised and in practice it has not proved particularly use-
ful 17. Indeed, in patients in whom the distinction between iron defi-
ciency and ACD is difficult measurement of the serum transferrin
receptor concentration only showed a specificity of 84% and positive
predictive value of 58% 18. The sTfR/log ferritin ratio has also been
proposed as a tool to differentiate between IDA and ACD with a
ratio of b1 suggesting ACD and >2 suggesting iron deficiency +/−
ACD. However, again, sensitivity and specificity are poor and
68 S.L. Davis, T.J. Littlewood / Blood Reviews 26 (2012) 65–71
corrections must be made in inflammatory states 8. A bone marrow
aspirate stained with Perls stain is the gold standard for assessing
iron stores. However, a bone marrow aspirate is invasive and uncom-
fortable and has to be performed by trained personnel.
In ACD and IDA changes in haemoglobin concentration are a late
manifestation of the failure of an iron supply to developing red
blood cells. One of the earliest changes which occur is a fall in
the haemoglobin content of reticulocytes. The reticulocyte haemo-
globin content (CHr) provides an indication of the iron supply to
developing red cells within the last 48 h and so provides a very
early indication of iron deficiency. The percentage of hypochromic
red cells (%HYPO) represents the percentage of iron deficient red
cells in the circulation which reflects the development of iron defi-
ciency over a longer time frame (20–120 days) 8. Many laboratory
analysers can be fairly easily adapted to measure CHr and %HYPO.
CHr is also useful in assessing response to iron therapy as levels re-
turn to normal within 4 days 8.
Hepcidin plays a key role in the pathogenesis of ACD and elevat-
ed hepcidin levels have been found in a wide variety of chronic dis-
eases, including inflammatory bowel disease, infections, myeloma
and non-hodgkin lymphoma 17. Theurl et al. 19, using a rat model,
also showed that serum hepcidin concentrations are elevated in
ACD but significantly lower in co-existing ACD and IDA. Until re-
cently a widely available method for measuring plasma hepcidin
didn't exist. However, mass spectrometry 20 and ELISA methods 21
are now available. These may provide a useful marker for defining
ACD but caution will need to be applied, as patients with co-
existing IDA may still be misdiagnosed. Alternatively, it may be
that the main niche for hepcidin levels will be in differentiating
between ACD and ACD + IDA. Further studies will need to be per-
formed before it becomes a routine diagnostic test.
Other investigations that may be useful in ACD include C-reactive
protein (CRP) and erythrocyte sedimentation rate (ESR). These not
only confirm inflammation/infection but give an idea of the degree
of erythroid inhibition by cytokines. Serum erythropoetin level can
give an indication of the marrow stimulus but must be interpreted
in combination with the haemoglobin concentration.
A comparison of laboratory tests in anaemia of chronic disease and
iron deficiency is shown in Table 2.
5. Rationale for treatment
There are three main reasons for correcting the anaemia of chronic
disease. Firstly, long term anaemia can cause organ damage. For ex-
ample, lack of systemic oxygen delivery causes a compensatory in-
crease in cardiac output and can lead to left ventricular hypertrophy
and eventual failure. Secondly, anaemia has been shown to worsen
Table 2
Comparison of laboratory parameters in anaemia of chronic disease and iron deficiency
anaemia.
Laboratory Anaemia of chronic Iron deficiency ACD and IDA
parameter disease anaemia
Haemoglobin ≥8 g/dL May be lower May be lower
than 8 g/dL than 8 g/dL
MCV/MCH Normal/mild ↓ ↓ ↓
Serum iron ↓ ↓ ↓
sTfR Normal/mild ↓ ↑ Normal/↑
sTfR/log ferritin ratio ↓ ↑ ↑ concerns as well as cost. The ASCO/ASH take a more pragmatic ap-
Ferritin Normal/↑ ↓ Normal
Serum hepcidin ↑ ↓ Normal
CHra ↓ ↓ ↓
CRP/ESR ↑ Normal ↑
MCV = mean cell volume, MCH = mean cell haemoglobin, sTfR = soluble transferrin
receptor, CHr = reticulocyte haemoglobin content, CRP = C-reactive protein, ESR =
erythrocyte sedimentation rate
a
Does not differentiate between IDA and ACD but allows early identification of iron
depleted erythropoiesis
prognosis in a variety of chronic illnesses including cancer, chronic
kidney disease and congestive heart disease 2. In patients with HIV,
anaemia is independently associated with increased mortality 22.
Thirdly, it can negatively impact on patient's quality of life. Fatigue
is a significant symptom that affects economic productivity 14 and in-
deed, in cancer patients, has been shown to be a more significant
problem than other cancer related symptoms such as pain and nau-
sea 23. Correction of anaemia can improve quality of life in patients
with cancer 24. However, concerns about the safety of erythropoiesis
stimulating agents (ESAs) in various clinical settings have restricted
their use.
6. Treatment
6.1. Treatment of underlying disease
The degree of anaemia is often a reflection of the underlying dis-
ease process. Therefore, initial treatment should be directed at the
causative disease. This is often sufficient in cases of mild anaemia
caused by diseases such as HIV and rheumatoid arthritis 17. For
patients with diseases that can't be reversed, such as chronic kidney
disease or patients with cancer being treated with chemotherapy al-
ternative strategies are often necessary.
6.2. Erythropoiesis stimulating agents (ESAs) for anaemia correction
As discussed by Cullis, 2011 17, the current mainstay of treatment
in ACD consists of ESAs and iron therapy. As outlined above, an inad-
equate erythropoietin response to the degree of anaemia and reduced
sensitivity of erythrocyte precursors to erythropoietin, due to circu-
lating cytokines, are important mechanisms in ACD. ESAs are believed
to overcome these defects.
The main evidence for use of ESAs in ACD comes from two main
patient groups: ESAs have been used in patients with malignancy
and in patients with chronic kidney disease since the 1980s. In pa-
tients receiving chemotherapy for cancer, approximately 75% will be-
come anaemic during the course of their treatment and ESAs can
improve the haemoglobin concentration in around 50% of these pa-
tients 25. Indeed, several meta-analyses have shown benefit for ESAs
in increasing haemoglobin levels and reducing the need for blood
transfusions 26,27. This has also been shown to equate to improved
quality of life 28 but does not confer a survival benefit 29. In 2002, the
growing evidence led to the American Society of Clinical Oncology
(ASCO) and American Society of Hematology (ASH) publishing a
joint guideline for the use of epoetin in adults with chemotherapy-
induced anaemia 30. This was last revised in 2010, and the most recent
updates have reflected the growing safety concerns surrounding ESAs
in patients with cancer 31. These include the risk of thromboembolic
events, increased mortality, tumour progression and stroke and
have led to the Food and Drug Administration (FDA) in the United
States to limit indications for ESA use to patients receiving chemo-
therapy for palliative intent. The National Institute of Clinical Excel-
lence (NICE) also issued guidance on the use of ESAs in cancer-
treatment induced anaemia 32. They recommend that they should
only be used in women receiving platinum based chemotherapy for
ovarian cancer with a haemoglobin of ≤8 g/dL or patients who can-
not receive blood transfusions. This restricted use again reflects safety
proach and recommend ‘that for patients undergoing chemotherapy
with a haemoglobin concentration b10 g/dL, clinicians should discuss
the potential harms (thromboembolism, shorter survival) and bene-
fits (decreased transfusions) of ESAs and compare those with poten-
tial harms (serious infections, immune-mediated adverse reactions)
and benefits (rapid haemoglobin improvement) of RBC transfusions.’
Glaspy et al. 33, performed a meta-analysis of 60 studies with more
than 15,000 cancer patients and failed to show a reduced survival
 S.L. Davis, T.J. Littlewood / Blood Reviews 26 (2012) 65–71
rate or tumour progression in the patients treated with ESAs. There-
fore, further research into this area remains important.
Doctors treating patients for the anaemia associated with chronic
kidney disease have developed extensive experience and expertise in
the use of ESAs since the pioneering work of Winearls and Esbach dur-
ing the 1980s 34,35. Up to 95% of patients respond to ESAs36 but there is
also concern that they may have a deleterious effect. The CHOIR
(Correction of Hemoglobin and Outcomes in Renal Insufficiency)
study37 showed a higher cardiovascular event rate, with no improve-
ment in quality of life, in patients with a target Hb of 13.5 g/dL as op-
posed to 11.3 and the TREAT38 (Trial to Reduce Cardiovascular Events
with Aranesp Therapy) study showed a higher risk of stroke in patients
with diabetes and chronic kidney disease using ESAs. Recent NICE guid-
ance, 2011 39 is still strongly in favour of ESAs. They recommend that
physicians should consider treating anaemia in chronic kidney disease
if they are symptomatic or their Hb is≤ 11 g/dL and ESAs should be of-
fered to patients who are likely to benefit in terms of quality of life and
physical function. NICE recommends that haemoglobin levels should
not be corrected to normal and instead recommend that physicians
aim for a HB between 10 and 12 g/dL in adults.
A Cochrane review into the use of ESAs in chronic heart failure 40
showed that they were associated with an improvement in left ven-
tricular function, exercise tolerance and improved quality of life. Hos-
pital admissions and mortality were also reduced and they found no
apparent effect on stroke, myocardial infarction, hypertension or
thromboembolic events. There is also evidence that ESAs have a ben-
eficial effect in HIV, inflammatory bowel disease and rheumatoid
arthritis 17.
However in the authors experience patients with these disorders
are rarely treated with ESAs.
The authors support the recommendations set out by the FDA and
ASH/ASCO for the use of ESAs in ACD. These centre around using the
lowest possible dose of an ESA that will gradually increase haemoglo-
bin concentration to a level that avoids the need for transfusion and
maintaining haemoglobin levels under 12 g/dL to reduce the risk of
cardiovascular events. It is also prudent to avoid use of ESAs in pa-
tients at risk of thromboembolic disease and to be more cautious in
patients with cancer as this is the group with the highest rate of
adverse events.
6.3. ESAs plus intravenous iron
In patients with chronic kidney disease it was noted that a number
of factors would inhibit the response to treatment with an ESA. These
included infection, inflammatory disorders and the development of
true or functional iron deficiency. The pathophysiology of functional
iron deficiency is similar to that of the ACD. In functional iron defi-
ciency iron is present in the stores but release of iron from macro-
pahges to developing red blood cells is blocked by the impact of
hepcidin. Randomised trials in patients with CKD treated with an
ESA showed that intravenous iron was superior to oral iron in achiev-
ing and maintaining a haemoglobin response 41 and that patients trea-
ted with the intravenous iron required a much smaller ESA dose.
In patients with anaemia secondary to cancer seven randomised
trials have been reported in full comparing intravenous with oral
iron or placebo in ESA treated patients. All the trials bar one showed
a significant improvement in the haemoglobin response when intra-
venous iron was used and other benefits seen in some but not all of
the studies included a reduction in transfusion requirements and a re-
duction in the dose of ESA needed to maintain the haemoglobin
response 42–48.
It is unsurprising that oral iron is unhelpful in patients with ACD as
these patients are likely to have high hepcidin levels and therefore re-
duced absorption of iron from the intestine. The only time that oral
iron may be useful is if IDA and ACD co-exist as oral iron will then
be absorbed.
69
6.4. Intravenous iron alone for the treatment of ACD
As intravenous iron enhances the response to treatment with ESAs
in patients with CKD and the anaemia of cancer it is possible that
treatment with intravenous iron alone may be beneficial in these
patients.
A fascinating study was reported recently on the use of intravenous
iron versus placebo in patients with New York stage 2 and 3 heart
failure. 50% of patients in the intravenous iron treated group reported
a functional improvement compared to 28% in the placebo group 49.
In patients with cancer two small studies have been reported on
intravenous iron alone in the treatment of anaemia in patients with
gynaecological malignancy treated with chemotherapy 50,51. Both
studies showed an improvement in haemoglobin and a reduction in
transfusion need in the treatment group but larger randomised stud-
ies are required and these are underway.
6.5. ESA preparations
There are a number of ESAs available. In the United Kingdom, prob-
ably the best known are darbepoetin (Aranesp©) and epoetin alfa
(Eprex©).Both are licenced for use in symptomatic anaemia associat-
ed with chronic kidney disease and in adult patients with non-
myeloid malignancies receiving chemotherapy. Neither have a licence
for use in other causes of the anaemia of chronic disease. They can be
given subcutaneously or intravenously. It is recommended that a sus-
tained haemoglobin concentration of >12 g/dL is avoided and once
the desired haemoglobin concentration is reached the dose is reduced.
Poorly controlled hypertension and previous history of hypersensitiv-
ity to any of the products are contraindications and side effects include
injection site pain, hypertension, stroke, convulsions, thromboembol-
ic events and rashes. Antibody mediated pure red cell aplasia has also
been reported after treatment with subcutaneous eprex.
Intravenous iron preparations include cosmofer©, venofer© and
ferinject©. The most significant adverse reaction with intravenous
iron is anaphylaxis. This is rare occurring in 0.6–0.7% of doses and
almost exclusively with high molecular weight iron dextrose 14. The
newer iron preparations are much safer and serious adverse reactions
are rare 52.
6.6. The future
An increase in the plasma concentration of hepcidin is a key find-
ing which has helped us to understand the pathogenesis of ACD. The
discovery of this and the understanding of the bone morphogenetic
protein signalling pathway, which controls hepcidin expression, has
elucidated several targets to reduce hepcidin levels and therefore im-
prove anaemia in chronic illnesses. Hepcidin neutralising antibody is
effective in a mouse model of ACD 53 making hepcidin antagonists one
area for development. Inhibitors of BMP signalling also decrease hep-
cidin and dorsomorphin is a small molecule that has been shown to
do this in mice 54. Anti-cytokines therapy may also be helpful. In pa-
tients with Castleman disease, who have dysregulated production of
IL-6, it has been shown that the anti-IL-6 receptor antibody, tocilizu-
mab, reduces hepcidin levels and improves anaemia 55 and this agent
may be useful in ACD. It is likely that over the next decade several
agents targeting hepcidin will be available for use in humans and
this may revolutionise the treatment of ACD.
7. Conclusions
Anaemia of chronic disease is common and causes significant mor-
bidity and mortality, including reduced quality of life for patients.
During the last decade the mechanisms behind anaemia of chronic
disease have become much clearer making it an exciting and evolving
field. The discovery of hepcidin is allowing the development of new
70 S.L. Davis, T.J. Littlewood / Blood Reviews 26 (2012) 65–71
diagnostic tests, such as hepcidin assays, which will make the diagno-
sis of ACD easier and treatments specifically targeting the hepcidin/
BMP pathway are also under development.
8. Practice points
• A search for an underlying cause should be performed in a patient
presumed to have ACD if no cause is obvious
• It is important to confirm the diagnosis of ACD and exclude other
causes of anaemia
• Iron deficiency should be excluded
• Apart from treatment of the underlying disease the main stay of
treatment includes erythropoiesis stimulating agents (ESAs) and
intravenous iron
• If ESAs are used the lowest dose should be used that will increase
the Hb to a level that avoids the need for a transfusion but keeps
the Hb b12 g/dL
9. Research agenda
• The use of serum hepcidin concentration in ACD or to distinguish
between ACD and ACD + IDA
• Do ESAs have any effect on tumour progression or reduced survival
in cancer patients?
• Larger randomised controlled trials into the use of intravenous iron
alone in ACD
• Developing agents that antagonise hepcidin and the BMP signalling
pathway
Conflict of interest statement
Timothy J Littlewood has received fees for attendance at advisory
boards and for giving talks from companies manufacturing erythro-
poiesis stimulating agents and intravenous iron.
Sarah Davis has no conflicts of interest
References
[1] Weiss G, Goodnough LT. Anaemia of chronic disease. N Engl J Med 2005;352:
1011–23.
[2] Nissenson MD, Goodnough LT, Dubois RW. Anemia: not just an innocent bystander?
Arch Intern Med 2003;163:1400–4.
[3] 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:
2214–21.
[4] Krause A, Nietz S, Magert HJ, Schultz A, Forssmann WG, Schultz-Knappe P, et al.
LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial
activity. FEBS Lett 2000;480:147–50.
[5] Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide
synthesized in the liver. J Biol Chem 2001;276:7806–10.
[6] Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol
2009;122:78–86.
[7] Brasse-Lagnel C, Karim Z, Letteron P, Bekri S, Bado A, Beaumont C. Intestinal DMT1
cotransporter is down-regulated by hepcidin via proteasome internalization and
degradation. Gastroenterol 2011;140:1261–71.
[8] Goodnough LT, Nemeth E, Ganz T. Detection, evaluation and management of iron-
restricted erythropoiesis. Blood 2010;116:4754–61.
[9] Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, et al. IL-6 medi-
ates hypoferremia of inflammation by inducing the synthesis of the iron regulato-
ry hormone hepcidin. J Clin Invest 2004;113:1271–6.
[10] Lee P, Peng H, Gelbart T, Wang L, Beutler E. Regulation of hepcidin transcription
by interleukin-1 and interleukin-6. Proc Natl Acad Sci U S A 2005;102:1906–10.
[11] Maes K, Nemeth E, Roodman GD, Huston A, Esteve F, Freytes C, et al. In anemia of
multiple myeloma, hepcidin is induced by increased bone morphogenetic protein
2. Blood 2010;116:3635–44.
[12] Jelkmann W. Proinflammatory cytokines lowering erythropoietin production. J
Interferon Cytokine Res 1998;18:555–9.
[13] Faquin WC, Schneider TJ, Goldberg MA. Effect of inflammatory cytokines on hyp-
oxia induced erythropoietin production. Blood 1992;79:1987–94.
[14] Cavill I, Auerbach M, Bailie GR, Barrett-Lee P, Beguin Y, Kaltwasser P, et al. Iron
and the anaemia of chronic disease: a review and strategic recommendations.
Curr Med Res Opin 2006;22:731–8.
[15] Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance.
Gastroenterologica 2007;132:2169–80.
[16] Marsh WL, Bishop JW, Darcy TP. Evaluation of red cell distribution width (RDW).
Hematol Pathol 1987;1:117–23.
[17] Cullis J. Diagnosis and management of anaemia of chronic disease: current status.
Br J Haematol 2011;154:289–300.
[18] Mast AE, Blinder MA, Gronowski AM, Chumley C, Scott MG. Clinical utility of the
soluble transferrin receptor and comparison with serum ferritin in several popu-
lations. Clin Chem 1998;44:45–51.
[19] Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, et al. Regulation of iron
homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic
and therapeutic implications. Blood 2009;113:5277–86.
[20] Murphy AT, Witcher DR, Luan P, Wroblewski VJ. Quantitation of hepcidin from
human and mouse serum using liquid chromatography tandem mass spectrome-
try. Blood 2007;110:1048–54.
[21] Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M. Immunoassay for human
hepcidin. Blood 2008;112:4292–7.
[22] Belperio PS, Rhew DC. Prevalence and outcomes of anemia in individuals with
human immunodeficiency virus: a systematic review of the literature. Am J Med
2004;116(S):27–43.
[23] Vogelzang NJ, Breitbart W, Cella D, Curt GA, Groopman JE, Horning SJ, et al. Pa-
tient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a
tripart assessment survey. The Fatigue Coalition. Semin Hematol 1997;34:4–12.
[24] Littlewood TJ, Bajetta E, Nortier JWR, Vercammen E, Rapoport B. Effects of epoetin
alfa on hematological parameters and quality of life in cancer patients receiving
nonplatinum chemotherapy: results of a randomized, double-blind, placebo-
controlled trial. J Clin Oncol 2001;19:2865–74.
[25] Clifford R, Littlewood T. Increased efficacy of anaemia treatment in cancer. Eur
Haematol 2010;4:8–10.
[26] Bohlius J, Langensiepen S, Schwarzer G, Seidenfeld J, Piper M, Bennet C, et al.
Erythropoietin for patients with malignant disease. Cochrane Database Syst Rev
2004;CD003407.
[27] Seidenfeld J, Piper M, Aronson N. Systematic review of controlled trials on eryth-
ropoietin to support evidence-based guidelines. Oncology 2002;16:171–88.
[28] Littlewood T. Epoetin alfa (Eprex) and quality of life. Curr Med Res Opin
2005;21(S2):S1–2.
[29] Wilson J, Yao GL, Raftery J, Bohlius J, Brunskill S, Sandercock J, et al. A systematic
review and economic evaluation of epoetin alfa, epoetin beta and darbopoetin
alfa in anaemia associated with cancer, especially that attributable to cancer treat-
ment. Health Technol Assess 2007;11:1–202.
[30] Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Benentt CL, Cella D, et al. Use of epoe-
tin 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;20:4083–107.
[31] Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, et al. American
Society of Clinical Oncology/American Society of Hematology clinical practice
guideline update on the use of epoetin and darbopoetin in adult patients with
cancer. J Clin Oncol 2010;28:4996–5010.
[32] Epoetin alfa, epoetin beta and darbepoetin alfa for cancer treatment-induced
anaemia. Natl Inst Health Clin Excell 2008.
[33] Glapsy J, Crawford J, Vanstenkiste J, Henry D, Rao S, Bowers P, et al. Erythropoieses-
stimulating agents in oncology: a study level meta-analysis of survival and other
safety outcomes. Br J Cancer 2010;102:301–15.
[34] Winearls GC, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of
human erythropoietin derived from recombinant DNA on the anemia of patients
maintained by chronic hemodialysis. Lancet 1986;2:1175–8.
[35] Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the
anemia of end-stage renal disease with recombinant human erythropoietin. Re-
sults of a combined phase I and II clinical trial. N Eng J Med 1987;316:73–8.
[36] Clinical Practice Guidelines for anemia of chronic kidney disease: update 2001.
Am J Kidney Dis 2001;37(S1):S182–238.
[37] Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. Correction of ane-
mia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085–98.
[38] Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al. A
trial of darbepoietin alfa in type 2 diabetes and chronic kidney disease. N Engl J
Med 2009;361:2019–32.
[39] Anaemia management in people with chronic kidney disease. Natl Inst Health
Clin Excel 2011.
[40] Ngo K, Kotecha D, Walters JAE, Manzano L, Palazzuoli A, van Veldhuisen DJ, et al.
Erythropoiesis-stimulating agents for anaemia in chronic heart failure patients.
Cochrane Database Syst Rev 2010;CD007613.
[41] Silverberg DS, Iaina A, Peer G, et al. Intravenous iron supplementation for the
treatment of the anemia of moderate to severe chronic renal failure patients not
receiving dialysis. Am J Kidney Dis 1996;27(2):234–8.
[42] Hedenus M, Birgegård G, Näsman P, Ahlberg L, Karlsson T, Lauri B, et al. Addition
of intravenous iron to epoetin beta increases hemoglobin response and decreases
epoetin dose requirement in anemic patients with lymphoproliferative malignan-
cies: a randomized multicenter study. Leukemia 2007;21:627–32.
[43] Auerbach M, Ballard H, Trout JR, Mcilwain M, Ackerman A, Bahrain H, et al. Intra-
venous iron optimizes the response to recombinant human erythropoietin in can-
cer patients with chemotherapy-related anemia: a multi-center, open-label,
randomized trial. J Clin Oncol 2004;22:1301–7.
[44] Bastit L, Vandebroek A, Altintas S, Gaede B, Pintér T, Suto TS, et al. Randomized,
multicenter, controlled trial comparing the efficacy and safety of darbepoetin
alpha administered every 3 weeks with or without intravenous iron in patients
with chemotherapy-induced anemia. J Clin Oncol 2008;26:1611–8.
[45] Pedrazzoli P, Farris A, Del Prete S, Del Gaizo F, Ferrari D, Bianchessi C, et al.
Randomized trial of intravenous iron supplementation in patients with
 S.L. Davis, T.J. Littlewood / Blood Reviews 26 (2012) 65–71
chemotherapy-related anemia without iron deficiency treated with darbepoietin
alpha. J Clin Oncol 2008;26:1619–25.
[46] Henry DH, Dahl NV, Auerbach M, Tchekmedyian S, Laufman LR. Intravenous ferric
gluconate significantly improves response to epoetin alfa versus oral iron or no
iron in anemic patients with cancer receiving chemotherapy. Oncologist
2007;12:231–42.
[47] Auerbach M, Silberstein PT, Webb RT, Averyanova S, Ciuleanu TE, Shao J, et al.
Darbepoetin alfa 300 or 500 γg every 3 weeks with or without intravenous iron
in patients with chemotherapy-induced anaemia. Am J Hematol 2010;85:655–63.
[48] Steensma DP, Sloan JL, Dakhil SR, Dalton R, Kahanic SP, Prager DJ, et al. Phase I.I.I.
randomized study of the effects of parenteral iron, oral iron, or no iron supple-
mentation on the erythropoietic response to darbepoetin alfa for patients with
chemotherapy-induced anaemia. J Clin Oncol 2011;29:97–105.
[49] Anker SD, Colet JC, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al.
Ferric carboxymaltose in patients with heart failure and iron deficiency. N Eng J
Med 2009;361:2436–48.
71
[50] Kim YT, Kim SW, Yoon BS, Cho HJ, Nahm EJ, Kim SH, et al. Effect of intravenously
administered iron sucrose on the prevention of anemia in the cervical cancer
patients treated with concurrent chemoradiotherapy. Gynecol Oncol 2007;105:
199–204.
[51] Dangsuwan P, Manchana T. Blood transfusion reduction with intravenous iron in
gynaecologic patients receiving chemotherapy. Gynecol Oncol 2010;116:522–5.
[52] Auerbach M, Henry D. Parenteral iron therapy-taking the rust off. Haematology
2010:338–47 Dece 2010.
[53] Nemeth E. Targeting the hepcidin–ferroportin axis in the diagnosis and treatment
of anemias. Adv Haematol 2010:750643 Epub 2009 Dec 24.
[54] Yu PB, Hong CC, Sachidanandan C, Babitt JL, Deng DY, Hoyng SA, et al. Nat Chem
Biol 2008;4:33–41.
[55] Song SN, Tomosugi N, Kawabata H, Ishikawa T, Nishikawa T, Yoshizaki K.
Down-regulation of hepcidin resulting from long term treatment with an
anti-IL-6 receptor antibody (tocilizumab) improves anaemia of inflammation
in multicentric Castleman disease. Blood 2010;116:3627–34.