Anemia of Chronic Disease - Inflammation - UpToDate

25/11/2018 Anemia of chronic disease/inflammation - UpToDate
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Anemia of chronic disease/inflammation
Authors: Stanley L Schrier, MD, Clara Camaschella, MD

Section Editor: William C Mentzer, MD
Deputy Editor: Jennifer S Tirnauer, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2018. | This topic last updated: Nov 16, 2018.
INTRODUCTION — The anemia of chronic disease (ACD, also called the anemia of inflammation, anemia of chronic inflammation, or hypoferremia of
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 chronic kidney disease, severe trauma, diabetes mellitus, anemia of older adults, and
in those with acute or chronic immune activation. The anemia is typically normochromic, normocytic, hypoproliferative, and mild in degree.
The pathogenesis, laboratory findings, and treatment of ACD will be reviewed here. An overview of the approach to the adult patient with anemia is
presented separately. (See "Approach to the adult with anemia".)
PATHOGENESIS
Overview — ACD is thought to primarily reflect a reduction in red blood cell (RBC) production by the bone marrow, with a component due to mild
shortening of RBC survival [1,2]. A number of factors are thought to contribute to this hypoproliferative state [3,4]:
● Hepcidin-induced alterations in iron metabolism, including reduced absorption of iron from the gastrointestinal tract and trapping of iron in
macrophages. This results in reduced plasma iron levels (hypoferremia), making iron unavailable for new hemoglobin synthesis [5-7]. (See
'Hepcidin' below.)
● Inability to increase erythropoiesis in response to anemia. Serum erythropoietin (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 within the bone marrow [3,8,9].
● A relative decrease in EPO production. The inverse relationship between hematocrit levels and serum EPO seen in most anemic conditions
(figure 1) is not maintained in ACD [7]. As an example, patients with ACD have lower levels of EPO than do patients with iron deficiency and a
similar degree of anemia.
● A minor component of ACD is due to decreased red cell survival. Shortening of red cell life span may occur in cases of acute inflammation
characterized by increased macrophage activity [10,11].
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A large number of conditions have been associated with ACD, including infections, inflammatory disorders, malignancy, trauma, diabetes mellitus,
aging, and acute or chronic immune activation [10,12-16].
The role of cytokines — Why the above-noted changes occur is becoming increasingly understood. It has been suggested that the underlying
inflammatory medical condition causes the release of cytokines such as the interleukins (eg, IL-1 and IL-6) and tumor necrosis factor (TNF-alpha) by
activated monocytes; these cytokines unleash a cascade including the secretion of interferon (IFN)-beta and IFN-gamma by T lymphocytes [17,18].
The decreased bone marrow responsiveness to erythropoietin is mediated by inflammatory cytokines, especially IL-1 beta and TNF-alpha [10], which
may induce apoptosis of red cells precursors as well as downregulation of erythropoietin receptors on progenitor cells. Cytokines may also decrease
erythropoietin expression by renal cells [13,19,20]. In vitro treatment of cultured cells with proinflammatory cytokines can also alter ferritin and
transferrin receptor expression and iron-responsive protein activity, inducing iron retention in macrophages [6]. However, iron metabolism in ACD is
mainly altered via overproduction of hepcidin [21].
Several observations support this paradigm:
● Treatment of patients with rheumatoid arthritis or inflammatory bowel disease using an anti-TNF-alpha antibody led to a reduction in IL-6 and
hepcidin levels, a decrease in the proportion of apoptotic red cell precursors, and an improvement in anemia [9,22-26].
● Treatment of children with systemic juvenile idiopathic arthritis (formerly called systemic onset juvenile rheumatoid arthritis or Still's disease) using
the anti-IL-6 receptor antibody tocilizumab resulted in clinical improvement along with significant, profound reduction in C-reactive protein levels
and reduced incidences of anemia, thrombocytosis, and hyperferritinemia [27].
● Doses of the erythropoiesis-stimulating agent darbepoetin required to reverse anemia in pre-dialysis older adult patients were higher in the
presence of elevated levels of IL-6 and TNF-alpha [28].
● Administration of IFN-gamma to experimental animals (or stimulation of IFN-gamma production in vivo) causes most of the characteristic
abnormalities of ACD [3,29-32].
Hepcidin — As noted above, hepcidin, a component of the innate immune response to infection, appears to be most directly involved in iron
availability [33,34]. Evidence from transgenic mouse models and human genetic disorders 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 [35], secondary to its
effect on internalization and degradation of the iron export protein ferroportin (see "Regulation of iron balance", section on 'Hepcidin'). The complex
relationships between hepcidin and different types of infections have been reviewed [36].
One effect of hepcidin is to remove non-transferrin-bound iron (NTBI; a form of extracellular iron) from the circulation. This reduction in extracellular
iron is thought to reduce dissemination of bacteria [37]. NTBI is essential for certain bacteria such as Vibrio vulnificus and siderophilic Yersinia
enterocolitica; iron-loaded patients are especially susceptible to infection with these organisms [38]. Hepcidin is induced during Gram negative
pneumonia.
Animal models of ACD — Animal models of ACD shed further light on the relative importance of hepcidin and IL-6 [39-50]:
● In one study, a single injection of turpentine induced an acute sixfold increase in liver hepcidin mRNA and a twofold decrease in serum iron [41].
The latter effect was completely blunted in hepcidin-deficient mice [42].
● In a study performed in mice, ACD was induced via injection of heat-killed bacteria, resulting in iron-deficient erythropoiesis and resistance to
treatment with supraphysiologic doses of an erythropoiesis-stimulating agent (ESA, darbepoetin) [43,44]. Treatment of the anemic animals with
either a mouse-antihuman or a fully-human antibody to hepcidin corrected the hypoferremia and restored responsiveness to ESA.
● Ablation of hepcidin in hepcidin knockout mice ameliorates ACD caused by heat-killed Brucella abortus and allows faster recovery compared with
controls [39]. Similarly, mice deficient in erythroferrone, an erythropoiesis-driven regulator of iron homeostasis that mediates the suppression of
hepcidin, develop a more severe anemia with higher hepcidin levels and lower serum iron concentrations [45].
● In a mouse model of sepsis, hepcidin gene deletion ameliorated anemia better than administration of erythropoietin [51].
The importance of interleukin (IL)-6 in this hepcidin pathway was shown by the following observations:
● The effect of an injection of turpentine on liver hepcidin mRNA and serum iron was completely blunted in IL-6 knockout mice [52].
● 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 [52].
● ACD caused by heat-killed Brucella abortus in IL-6 knockout mice was milder and recovered faster than in controls, but with differences compared
with Hamp (hepcidin) knockout mice [39], supporting a distinct role for both IL-6 and hepcidin in ACD [40]. IL-6 negatively interferes with the
erythropoietin response while hepcidin only decreases iron availability.
Clinical studies — Increased hepcidin production, increased urinary excretion of hepcidin, and increased serum levels of prohepcidin and hepcidin
have been noted in patients with infections, malignancy, or inflammatory states (as evidenced by C-reactive protein levels >10 mg/dL) [7,33,53,54].
Examples of the available data include the following [7,52,54-63]:
● The use of the anti-IL-6 receptor antibody tocilizumab reduced the hepcidin levels in patients with Castleman disease, a disorder characterized by
a clinical picture similar to that seen in ACD, including high levels of both IL-6 and hepcidin [58]. Such treatment resulted in progressive
normalization of iron-related parameters and symptomatic improvement [59]. (See "HHV-8-negative/idiopathic multicentric Castleman disease",
section on 'IL-6 inhibitors'.)
● In patients with ACD, production of hepcidin has been detected in circulating monocytes as an autocrine mechanism to increase macrophage iron
sequestration [7,60]. Hepcidin mRNA levels were significantly correlated with serum IL-6 concentrations and were associated with decreased
expression of ferroportin as well as increased monocyte iron retention [60].
● Hepcidin plasma levels were significantly higher in 65 patients with Hodgkin lymphoma than in controls and showed a positive correlation with IL-6
levels [54]. Hepcidin and IL-6 levels were significantly higher in those with more aggressive disease characteristics (eg, stage IV disease,
presence of B symptoms, International Prognostic Score >2). (See "The Reed-Sternberg cell and the pathogenesis of Hodgkin lymphoma",
section on 'Cytokine responses'.) Increased hepcidin levels have also been documented in patients with multiple myeloma [61], inflammatory
bowel disease [62], and Castleman disease [59,63].
These studies suggest that IL-6 is required for the induction of hepcidin and hypoferremia during inflammation in both animals and humans (figure 2),
although hepcidin can also be upregulated by the cytokine IL-1 [64]. While the molecular mechanisms responsible for this activation are only partially
understood, IL-6 appears to be involved in regulation of hepcidin levels through the JAK/STAT-3 signaling pathway (figure 3) [65-67]. (See "Regulation
of iron balance", section on 'Hepcidin'.)
Hepcidin assays — Assays to measure serum hepcidin are not yet routinely available for clinical use. It is possible that in the future hepcidin levels
might aid in the differential diagnosis of iron deficiency anemia alone or in combination with other tools [68]. Potential uses of hepcidin measurements
have been proposed [69]. Lack of standardization of the available assays remains a major limitation, although efforts to harmonize the different tests
are ongoing [70]. (See "Regulation of iron balance", section on 'Hepcidin'.)
In one study, measurement of hepcidin-25 levels by mass spectrometry was proposed as a potential tool for differentiating ACD from iron deficiency
anemia [71]. The use of a hepcidin-25 cutoff of ≤4 nmol/L allowed the differentiation of iron deficiency anemia from the anemia of chronic disease
(ACD, alone or in the presence of iron deficiency), but not the discrimination of ACD from ACD in the presence of iron-restricted erythropoiesis.
EPIDEMIOLOGY — ACD is considered the second most common cause of anemia worldwide, after iron deficiency [10]. However, detailed statistics
on its prevalence are not available. Often the anemia in individuals with inflammatory diseases is complex and multifactorial, and it may be challenging
to separate out the component due to ACD. This is especially true in patients with diabetes. Examples of the prevalence of ACD in various
inflammatory states include the following:
● Anemia is observed in 33 to 60 percent of patients with rheumatoid arthritis [72]. (See "Hematologic manifestations of rheumatoid arthritis",
section on 'Anemia'.)
● Cancer-related anemia occurs in more than 30 percent of the cases at diagnosis [73]; the rate reached 63 percent in an observational study on
888 consecutive cancers [74]. However, cancer-related anemia is multifactorial and includes types of anemia other than ACD (eg, iron deficiency
anemia). Anemia is even more common in hematologic malignancies as lymphoma and multiple myeloma [75]. (See "Hematologic complications
of malignancy: Anemia and bleeding".)
● ACD accounts for about one-third of the cases of anemia of the elderly because of concomitant inflammatory conditions or chronic kidney
diseases. (See "Anemia in the older adult".)
CLINICAL PRESENTATION
Typical presentation — The typical patient with ACD presents with a known underlying chronic condition that contains an inflammatory component.
While these were initially described as being infectious (eg, active pulmonary tuberculosis), inflammatory (eg, rheumatoid arthritis), or malignant (eg,
Hodgkin lymphoma), other chronic conditions have been shown to have an inflammatory component and share some or all of the features of ACD.
These include the following [10,12-16].
● Malignancy – (See "Hematologic complications of malignancy: Anemia and bleeding" and "Role of erythropoiesis-stimulating agents in the
treatment of anemia in patients with cancer".)
● HIV infection – (See "Hematologic manifestations of HIV infection: Thrombocytopenia and coagulation abnormalities" and "Hematologic
manifestations of HIV infection: Anemia".)
● Rheumatologic disorders – (See "Hematologic manifestations of systemic lupus erythematosus", section on 'Anemia of chronic disease' and
"Hematologic manifestations of rheumatoid arthritis", section on 'Anemia of chronic disease'.)
● Inflammatory bowel disease – (See "Nutrient deficiencies in inflammatory bowel disease".)
● Castleman disease – (See "HHV-8-associated multicentric Castleman disease", section on 'Clinical features'.)
● Heart failure – (See "Approach to anemia in adults with heart failure", section on 'Increased circulating cytokines and the anemia of
inflammation'.)
● Older adults – (See "Anemia in the older adult", section on 'Inflammation'.)
● Renal insufficiency – A generalized increase in the inflammatory response may occur in patients with decreased renal function. (See
"Inflammation in renal insufficiency", section on 'Inflammation and kidney disease'.)
● Chronic obstructive pulmonary disease – A subset of patients with chronic obstructive pulmonary disease, estimated at approximately 50
percent, have laboratory findings consistent with ACD (eg, anemia, elevated levels of C-reactive protein, IL-6, interferon-gamma, and serum
erythropoietin), suggesting the presence of background infection or inflammation [18,76]. (See "Chronic obstructive pulmonary disease: Definition,
clinical manifestations, diagnosis, and staging".)
Symptoms in such patients are those of the underlying disease, rather than the anemia, which is usually only mild to moderate in degree, compatible
with the patient's often limited lifestyle.
Acute variant of ACD — Acute event-related anemia, such as that occurring after surgery, major trauma, myocardial infarction, or sepsis, a condition
called the "anemia of critical illness," shows many of the features of ACD (ie, low serum iron, high ferritin, blunted response to EPO), presumably
secondary to tissue damage and acute inflammatory changes [77,78]. It appears to be an acute variant of ACD and is also characterized by shortened
red blood cell (RBC) survival [10,79,80].
A mouse model of the acute variant of ACD has been created using injections of lipopolysaccharide and zymosan. These animals develop anemia
along with increased messenger RNA levels for both IL-6 and hepcidin [81].
In a series of 92 consecutive patients admitted for sepsis, hepcidin levels at admission were high, increased with the number of systemic inflammatory
response syndrome (SIRS) criteria, and correlated with both IL-6 levels and the subsequent decrease in hemoglobin over the following days [82].
Similarly, in a series of 150 patients with severe trauma, urinary hepcidin levels were extremely high on admission, hepcidin was positively correlated
with the Injury Severity Score (ISS) and the duration of anemia, and negatively correlated with hypoxia [83].
Since the underlying mechanisms are similar, anemia of acute and chronic inflammatory disorders may be considered together under the general term
"anemia of inflammation" [10,13].
LABORATORY FINDINGS
General findings — Anemia in ACD is of variable severity. Many patients have a mild anemia, with a hemoglobin concentration of 10 to 11 g/dL. The
anemia is usually normocytic and normochromic; it is microcytic and hypochromic in less than 25 percent of the cases, in which case the mean
corpuscular volume (MCV) is rarely less than 70 fL [2,10] (table 1). The mean corpuscular hemoglobin (MHC) is normal or low in a proportion of cases,
similar to the MCV, and the red cell distribution width (RDW) is normal to increased. There are not significant changes in the mean corpuscular
hemoglobin concentration (MCHC).
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 red blood cell (RBC) production. (See "Approach to the adult with anemia",
section on 'Reticulocyte count'.)
The anemia may be accompanied by an elevation in cytokines (eg, IL-6, interferon-gamma) as well as acute phase reactants (eg, fibrinogen,
erythrocyte sedimentation rate, C-reactive protein, ferritin, haptoglobin, factor VIII) [84,85]. (See "Acute phase reactants", section on 'Clinical use'.)
Iron studies — The serum iron concentration and transferrin level (also measured as total iron binding capacity, TIBC) are both low and the transferrin
saturation (TSAT) is usually normal or low-normal. The latter two findings help to distinguish ACD from iron deficiency anemia, in which the transferrin
level is increased and TSAT is low (table 1).
However, approximately 20 percent of patients with ACD have a TSAT in the iron deficiency range (as low as 10 percent). In most patients, the effect
of hepcidin to block the release of iron from macrophages is responsible for the low serum iron levels and low TSAT (figure 2 and figure 4). (See
"Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Iron studies (list of available tests)'.)
Individuals with an inflammatory condition that is being treated with a tumor necrosis factor (TNF) inhibitor may have an increase in TSAT (into the
normal range) and a reduction in ferritin, which may reflect iron stores more accurately. The mechanism is thought to be reduced hepcidin and
restoration of more physiologic iron availability. (See 'The role of cytokines' above.)
The serum ferritin concentration, which is usually normal or elevated in ACD, is a poor index of iron stores in chronic inflammatory diseases since
ferritin is also an acute phase reactant (table 2). In addition, the destruction of hepatic or splenic tissue due to the primary disease may release
relatively large amounts of ferritin into the circulation. (See "Acute phase reactants" and "Causes and diagnosis of iron deficiency and iron deficiency
anemia in adults", section on 'Patients with inconclusive initial testing or comorbidities'.)
Soluble transferrin receptor — Measurement of the soluble transferrin receptor (sTfR; also called circulating transferrin receptor or serum transferrin
receptor) provides a quantitative measure of total erythropoietic activity, since its concentration in serum is directly proportional to the erythropoietic
rate and inversely proportional to tissue iron availability. Accordingly, sTfR is normal in patients with ACD, while it is increased in those with iron
deficiency anemia (IDA). This subject is discussed in depth separately. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in
adults", section on 'Diagnostic evaluation'.)
The biologic principle is that in iron deficiency states, cellular membrane transferrin receptor density increases, with the result that truncated forms of
sTfR appear in the serum in increased amounts. Measurement of sTfR can distinguish between IDA and ACD [86-89].
sTfR - ferritin index — Calculation of the ratio of sTfR (expressed as mg/L) to ferritin (expressed as mcg/L), or the ratio of sTfR to the logarithm (to
the base 10) of the ferritin concentration may also be useful for distinguishing between ACD and IDA (figure 5). (See "Causes and diagnosis of iron
deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)
This ratio is effective in making this distinction since the numerator (sTfR) is increased in IDA and normal in ACD, while the denominator (ferritin or log
ferritin) is decreased in IDA and normal to increased in ACD. Specifically, a sTfR/log ferritin ratio (TfR-ferritin index) <1 suggests the diagnosis of ACD,
while a ratio >2 suggests the presence of IDA [10,90]. Those with the combination of IDA and ACD will also have a TfR-ferritin index >2.
Peripheral blood smear — The red cells in patients with ACD are normocytic and normochromic in over 75 percent of cases. Stigmata of the
underlying disorder may be present on the peripheral smear, such as leukocytosis with a "left shift" in infection, the presence of leukemic or malignant
cells, or leukopenia/lymphocytopenia in those with cancer or acute or chronic disorders involving the immune system. (See "Approach to the patient
with neutrophilia" and "Evaluation of the peripheral blood smear", section on 'Worrisome findings' and "Approach to the child with lymphocytosis or
lymphocytopenia", section on 'Lymphocytopenia'.)
Bone marrow studies — Examination of the bone marrow for its content and distribution of iron is instructive, although this examination is not
performed routinely in patients with suspected ACD. In the most classical presentation of ACD, bone marrow macrophages contain normal or
increased amounts of storage iron, reflecting reduced export of iron from macrophages due to the action of hepcidin. In addition, erythroid precursors
show decreased or absent staining for iron (ie, decreased numbers of sideroblasts), reflecting reduced availability of iron for red cell production (picture
1) [91].
DIAGNOSIS
Suspecting the diagnosis — ACD is suspected in a patient with an acute or chronic infectious process, inflammatory disorder, or malignant condition
who has a mild to moderate normocytic, normochromic, hypoproliferative (ie, no evidence for an increased erythropoietic rate) anemia. (See 'Clinical
presentation' above.)
In many cases, the underlying disorder (eg, rheumatoid arthritis, inflammatory bowel disease) leading to ACD has already been diagnosed. However,
when iron studies consistent with the diagnosis of ACD have been obtained and the underlying disorder is unclear, further clinical and laboratory
evaluation of the patient is required. While the list is not exhaustive, candidate conditions commonly leading to ACD are listed above along with the
appropriate UpToDate reviews dealing with these diagnoses. (See 'Typical presentation' above.)
If the patient has criteria for ACD but a known underlying cause is not immediately apparent, the clinician needs to review the patient’s medical record
for information concerning past diagnoses, timing of onset of the anemia, and whether or not age- and gender-appropriate cancer screening has been
performed. A complete history and physical examination and routine laboratory testing for renal and hepatic disease is also warranted at this time.
Making the diagnosis — There is no one test that will reliably make the diagnosis of ACD. Rather, a "pattern" of abnormalities serves to make this
diagnosis. Accordingly, ACD is most likely when all of the following are present (note: normal ranges may differ among laboratories) (see 'Laboratory
findings' above):
● Low serum iron (Normal: 60 to 150 mcg/dL or 0.6 to 1.5 mg/L; 11 to 27 microM/L)
● Normal to low serum transferrin (total iron binding capacity) (Normal: 300 to 360 mcg/dL or 3 to 3.6 mg/L; 54 to 64 microM/L)
● Low transferrin saturation
● Normal to increased serum ferritin (Normal: 40 to 200 ng/mL or 40 to 200 mcg/L; 90 to 449 picoM/L)
● Elevated erythrocyte sedimentation rate (Normal: 0 to 20 mm/hour [men], 0 to 30 mm/hour [women]) or elevated C-reactive protein (Normal:
<3 mg/L for most subjects)
The following test results may be helpful in diagnosing ACD when the above test results are equivocal:
● Reduced reticulocyte response for the degree of anemia (calculator 1)
● Normal soluble transferrin receptor (sTfR) level (Normal: 2.2 to 5 mg/L)
● Normal sTfR/ferritin ratio (figure 5) (see 'sTfR - ferritin index' above)
An elevated hepcidin level would also be helpful, although assays to measure serum hepcidin are not yet widely available. (See 'Hepcidin assays'
above.)
DIFFERENTIAL DIAGNOSIS
Concomitant iron deficiency — For those patients who qualify for the diagnosis of ACD, as described immediately above, the major differential is
whether the patient has ACD alone or ACD with concomitant iron deficiency anemia (ACD/IDA).
● Measurement of soluble transferrin receptor levels (sTfR) and/or the sTfR-ferritin index appears to be the most effective way to distinguish
between ACD and ACD/IDA; sTfR and the sTfR-ferritin index are normal in uncomplicated ACD, while both are elevated when IDA is also present
[92]. (See 'Soluble transferrin receptor' above.)
● Evaluation of the percentage of hypochromic red cells and reticulocyte hemoglobin content may help in the identification of true iron deficient
erythropoiesis in patients with ACD [93,94]. As an example, in two studies, a reticulocyte hemoglobin content (ret-He) <26 pg/cell was a stronger
predictor of iron deficiency and IDA than routine iron studies (eg, serum iron, transferrin, transferrin saturation, ferritin, sTfR. In guidelines for
functional iron deficiency [95], a ret-He cutoff >25 pg/cell may help in distinguishing between iron deficiency and ACD, although there is some
overlap when iron deficiency is mild. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Findings on
CBC'.)
● While bone marrow examination is not required for most patients in whom ACD is suspected, in difficult cases the diagnosis can often be
established by bone marrow examination. Findings in the most common disorders include:
• ACD – Bone marrow macrophages contain normal to increased iron, while erythroid precursors show decreased to absent amounts of iron
(ie, decreased to absent sideroblasts) (picture 1).
• Iron deficiency – Stainable iron is absent from both macrophages and erythroid precursors. (See "Causes and diagnosis of iron deficiency
and iron deficiency anemia in adults", section on 'Differential diagnosis'.)
• Myelodysplastic syndromes – Single or multi-lineage dysplastic changes with or without increased number of sideroblasts, including ring
forms, are commonly seen in patients with myelodysplasia (picture 2). (See "Clinical manifestations and diagnosis of the myelodysplastic
syndromes", section on 'Pathologic features' and "Sideroblastic anemias: Diagnosis and management", section on 'Diagnostic approach'.)
• Sideroblastic anemias – The diagnostic hallmark of congenital or acquired sideroblastic anemia is the presence of ring sideroblasts on bone
marrow examination (picture 3). The amount of iron in bone marrow macrophages is strikingly increased due to ineffective erythropoiesis.
Single or multi-lineage dysplastic changes are not seen. Evaluation of sideroblastic anemias, including genetic testing, is presented
separately. (See "Sideroblastic anemias: Diagnosis and management" and "Clinical manifestations and diagnosis of the myelodysplastic
syndromes", section on 'MDS with ring sideroblasts'.)
● Serum erythropoietin (EPO) levels are lower in ACD than in patients with IDA and comparable degrees of anemia [7]. However, serum EPO levels
in anemic subjects scatter too broadly to be of diagnostic use in distinguishing IDA from ACD [96]. This is illustrated in the figure, which shows that
the correlation between EPO levels and hematocrit is semi-logarithmic, with wide scatter of EPO levels for any particular level of hematocrit (figure
1).
● If the distinction between ACD and ACD/IDA cannot be made by laboratory tests alone, one may monitor the response to a short trial (eg, four to
six weeks) of oral iron supplementation.
Other candidate disorders — As mentioned above, the anemia in ACD is commonly normocytic and normochromic, and hypoproliferative and other
blood cell lines are not affected.
● The most common disorders with a similar presentation are chronic kidney disease (CKD) and anemia in the older adult, although some of these
patients may also have an underlying component of inflammation. (See "Inflammation in renal insufficiency" and "Anemia in the older adult",
section on 'Inflammation'.)
● Several endocrine disorders, including hyperthyroidism, hypothyroidism, panhypopituitarism, and primary and secondary hyperparathyroidism
may also present with a normocytic, normochromic hypoproliferative anemia. They are diagnosed via the accompanying endocrine signs,
symptoms, and hormone assays.
For patients with more severe anemia (eg, hemoglobin concentration <8 g/dL) along with hypochromic and microcytic red cells, the differential
diagnosis is wider (table 3). The most common conditions, which need to be excluded, include IDA, the thalassemic disorders, sideroblastic anemias,
and the sideroblastic variants of the myelodysplastic syndrome [97]. A further discussion for distinguishing among the various causes of a microcytic
anemia is presented separately; although, of these conditions, only IDA is associated with low serum iron levels. (See "Microcytosis/Microcytic
anemia", section on 'Causes of microcytosis'.)
TREATMENT ISSUES
Initial approach — The preferred initial therapy for ACD is correction of the underlying disorder. (See 'Underlying disorder' below.)
Other complicating factors (eg, blood loss, deficiencies of iron, folate, and/or vitamin B12) should be treated, if present, and may obviate the need for
blood transfusions or an erythropoiesis-stimulating agent (eg, erythropoietin, darbepoetin). (See "Approach to the adult with anemia".)
Red blood cell transfusions or use of an erythropoiesis-stimulating agent may be necessary for those with severe, symptomatic anemia. (See
"Indications and hemoglobin thresholds for red blood cell transfusion in the adult".)
● Most patients with ACD have mild anemia that produces no symptoms, being compatible with the patient's often limited lifestyle. It has been
suggested that ACD is a biologically adaptive response in which, for example, low serum iron levels serve to inhibit the growth of iron-requiring
microorganisms [98].
● Some patients have more severe anemia, leading to impaired function and an impaired quality of life [12,99]. Since ACD can complicate the
course of aging-related disorders, its presence has considerable importance, since anemia negatively influences the outcome of several
associated disorders [100,101]. (See "Anemia in the older adult" and "Evaluation of health-related quality of life (HRQL) in patients with a serious
life-threatening illness".)
Underlying disorder — Typically, the underlying disorder(s) responsible for ACD will be known to the patient and the clinician. Therapy for the
underlying disorder should be pursued, with the specific interventions depending on the clinical status of the patient and the available therapeutic
options.
The degree to which ACD responds to treatment of the underlying disorder may depend on several factors, including whether the inflammatory
component is controlled and the presence of other contributing factors. As an example, in patients with diabetes, improved glucose control may not
lead to resolution of ACD, because it may not correct concomitant renal insufficiency or inflammatory changes.
In other cases, treatment of the underlying disorder may be more effective in improving the anemia. As examples:
● If the anemia is due to underlying malignancy, successful treatment with surgery, chemotherapy, and/or radiation therapy may, in the long term,
lead to improvement in the anemia. However, anemia may be transiently or permanently exacerbated by the myelosuppressive effects of
chemotherapy and radiation. Treatment of cancer-associated anemia is discussed in depth separately. (See "Role of erythropoiesis-stimulating
agents in the treatment of anemia in patients with cancer".)
● If the anemia is due to an underlying disorder with a major inflammatory component (eg, rheumatoid arthritis, Castleman disease), treatment of
the inflammatory disorder with a disease-modifying antirheumatic drug (DMARD) may lead to improvement in the anemia. (See "Initial treatment
of rheumatoid arthritis in adults", section on 'DMARD therapy' and "HHV-8-negative/idiopathic multicentric Castleman disease", section on 'IL-6
inhibitors'.)
In the rare case in which an underlying disorder is not obvious in a patient with ACD, a search for inflammatory disorders such as inflammatory bowel
disease and possibly malignancy should be pursued. It is best to start with age-appropriate health screening and evaluations directed at any patient
symptoms. The aggressiveness of the search should be determined by the clinicians familiar with the patient’s symptoms, severity of the anemia, and
other relevant information.
Erythropoietin — Measurement of the plasma erythropoietin (EPO) concentration may be helpful in patients with ACD who have symptomatic anemia
and/or who have not responded to treatment of their underlying disorder and continue to have symptomatic anemia requiring treatment.
● Patients with cancer, rheumatoid arthritis, or AIDS who have EPO levels <500 mU/mL (although some authors suggest a cutoff of 100 mU/mL)
may respond to the administration of an erythropoiesis-stimulating agent (ESA) [102-106]. (See 'Pathogenesis' above and "Hematologic
manifestations of rheumatoid arthritis", section on 'Anemia'.)
● Advice for the use of EPO or darbepoetin in patients with malignancy is presented separately. (See "Role of erythropoiesis-stimulating agents in
the treatment of anemia in patients with cancer", section on 'ESAs: efficacy, side effects, and clinical use'.)
EPO can be given once per week, while darbepoetin has an effectiveness equal to that of EPO when given once every two or three weeks.
Supplemental iron should be given in all patients receiving EPO or darbepoetin in order to maintain a transferrin saturation ≥20 percent and a serum
ferritin ≥100 ng/mL. Such use of erythropoiesis-stimulating agents is considered "unlabeled or investigational" in the United States and may not be
reimbursed.
Because our aim is to obtain a short-range response to the anemia while an investigation is underway to determine the underlying cause of the ACD,
we prefer the use of EPO rather than darbepoetin.
Dosage — Although one of the hallmarks of ACD is a reduced erythropoietic response to both endogenous as well as exogenous EPO, high doses
of EPO may overcome this hyporesponsiveness. (See 'Pathogenesis' above and "Hematologic manifestations of rheumatoid arthritis", section on
'Anemia'.)
Two treatment options are available.
● Standard dosing of EPO is a starting dose of 100 to 150 units/kg subcutaneously three times weekly along with supplemental iron. Responders
may show a rise in the hemoglobin concentration of at least 0.5 g/dL by two to four weeks [105,107]. If there is no elevation in the hemoglobin
concentration by six to eight weeks, the regimen can be intensified to daily therapy or 300 units/kg three times weekly. It is not worthwhile to
continue EPO in patients who do not have a clinically meaningful response by 12 weeks [105].
● An alternative treatment schedule is to employ 30,000 to 40,000 units of EPO given SQ once per week, a single dose that is numerically
equivalent to a dose of 140 to 190 units/kg three times per week for a 70 kg person [108]. This dose can be increased to 60,000 units if there is no
response (ie, hemoglobin rise <1 g/dL) at four weeks.
For ease of use and to minimize inconvenience to the patient, we prefer the latter of these two schedules.
● This simplified, well-tolerated dosing regimen has also been recommended for treatment of the anemia associated with HIV infection. (See
"Hematologic manifestations of HIV infection: Anemia" and "Hematologic manifestations of HIV infection: Thrombocytopenia and coagulation
abnormalities".)
● There is conflicting evidence regarding the benefits versus risks of using EPO in critically ill patients. This subject is discussed separately. (See
"Use of blood products in the critically ill", section on 'RBC alternatives'.)
Adverse side effects of EPO treatment in patients with ACD have not been rigorously studied, although there is considerable information available on
adverse side effects of EPO in patients with cancer-related anemia. Accordingly, potential adverse side effects are minimized by initiating treatment
when the patient’s hemoglobin is <10 g/dL and stopping treatment with EPO when hemoglobin levels reach 12 g/dL. (See "Role of erythropoiesis-
stimulating agents in the treatment of anemia in patients with cancer", section on 'ESAs: efficacy, side effects, and clinical use'.)
Darbepoetin — Although darbepoetin has had limited use in the treatment of ACD in humans, it is capable of reversing anemia due to chronic
inflammatory disease in experimental animals [109]. A dose of darbepoetin equivalent to the above-noted dose of erythropoietin is in the range of 60 to
100 mcg/week, or 300 mcg every three weeks. However, since we are looking for a rapid, short-term response of the anemia, darbepoetin, with its
prolonged half-life, may result in excessive and prolonged stimulation. Accordingly, we prefer EPO for this purpose.
Supplemental iron — To achieve and maintain 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 [110]. Intravenous iron is more effective than oral iron. Two factors associated with increased hepcidin production in ACD limit the
availability of oral iron preparations to achieve these levels (see 'Hepcidin' above). These are:
● Suboptimal intestinal absorption of oral iron preparations is expected when hepcidin levels are increased.
● Subjects with ACD have functional iron deficiency due to hepcidin-mediated inhibition of the transfer of iron from macrophages to the developing
erythron [68]. Such functional iron deficiency cannot be overcome with oral preparations but does respond to the use of parenteral iron
preparations.
Accordingly, if the patient has not responded to treatment with oral iron preparations, with or without EPO, intravenous iron should be administered
before considering the patient to be a nonresponder. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with
cancer", section on 'Iron monitoring and supplementation'.)
Transfusion — Transfusion of packed red cells is appropriate when the patient with ACD develops symptomatic anemia and the clinician believes that
there is insufficient time for the patient to respond either to treatment of the underlying condition or to respond to treatment with an erythropoiesis-
stimulating agent. The use of transfusion in such settings as well as the trigger hemoglobin level for such treatment are discussed separately. (See
"Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Overview of our approach'.)
Investigational agents — Studies are underway using agents capable of altering/inhibiting the function of hepcidin (eg, hepcidin antagonists) and the
hepcidin receptor (ferroportin) in order to alleviate the various disorders of iron metabolism associated with increased levels of hepcidin, including ACD
[111-116]. (See 'Hepcidin' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Anemia in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics
patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient
might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade
reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Anemia of chronic disease (The Basics)")
SUMMARY AND RECOMMENDATIONS
● When to suspect the diagnosis of ACD – The anemia of chronic disease (ACD) is suspected in a patient with a chronic infectious, inflammatory,
or malignant condition who has a mild to moderate normocytic, normochromic hypoproliferative anemia. The presence of laboratory findings
consistent with ACD in a patient with no obvious underlying condition should initiate a search for the cause. (See 'Typical presentation' above and
'Suspecting the diagnosis' above.)
● Making the diagnosis of ACD – Appropriate initial studies for patients with suspected ACD include the following (see 'Laboratory findings'
above):
• Complete blood count, reticulocyte percentage, white blood cell and platelet counts
• Serum iron studies (ie, serum iron, total iron binding capacity [transferrin], ferritin)
• Serum creatinine and estimated glomerular filtration rate (eGFR)
• Measurement of acute phase reactants (eg, sedimentation rate, C-reactive protein)
ACD is most likely when all of the following are present (see 'Making the diagnosis' above):
• Low serum iron
• Normal to low serum transferrin (total iron binding capacity)
• Normal to increased serum ferritin
• Elevated erythrocyte sedimentation rate and/or C-reactive protein
● Differential diagnosis – Although the differential diagnosis of mild to moderate anemia is wide, the following conditions should be considered
(see 'Differential diagnosis' above):
• Hypoproliferative anemias (eg, renal disease, endocrine disorders).
• Iron deficiency anemia (IDA).
• Thalassemia.
• Sideroblastic anemias, including inherited disorders and sideroblastic myelodysplastic syndrome/myeloproliferative syndrome variants. (See
"Sideroblastic anemias: Diagnosis and management".)
● Coexisting iron deficiency – Coexisting iron deficiency may be seen in patients with ACD. Its presence is suggested by the finding of low serum
ferritin levels, absence of stainable iron on bone marrow aspiration/biopsy, an increased soluble transferrin receptor (sTfR)/ferritin index, and/or a
response to administration of oral or intravenous iron. (See 'Concomitant iron deficiency' above.)
● Treatment – Most patients with ACD have mild anemia that produces no symptoms, being compatible with the patient's often limited lifestyle.
Accordingly, treatment should be limited to those with symptomatic anemia.
• First-line therapy in ACD is directed at treatment of the underlying cause. (See 'Underlying disorder' above.)
• For most patients with ACD who do not have an underlying malignancy and who have symptomatic anemia and a hemoglobin <10 g/dL, we
suggest use of an erythropoiesis-stimulating agent (ESA) at the same time as the underlying cause is being sought and treated (Grade 2C).
Observational evidence suggests that response to an ESA is most likely to occur only if the erythropoietin level is less than 500 international
units/L. (See 'Erythropoietin' above.)
Use of an ESA for the treatment of anemia in patients with malignancy and for the treatment of anemia in those infected with HIV are
discussed separately. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'ESAs:
efficacy, side effects, and clinical use' and "Hematologic manifestations of HIV infection: Anemia" and "Hematologic manifestations of HIV
infection: Thrombocytopenia and coagulation abnormalities".)
We prefer the use of EPO over darbepoetin because a short-term response is preferred.
In order to achieve maximal response, supplemental iron should be administered, as needed, to maintain a transferrin saturation of ≥20
percent, and a serum ferritin level of ≥100 ng/mL. Intravenous iron is more effective than oral iron. (See 'Treatment issues' above.)
• Red blood cell transfusion is only warranted when patients with ACD develop symptomatic anemia despite treatment of the underlying cause
and administration of an ESA with intravenous iron, or when waiting for such a response is not a viable clinical option. (See 'Transfusion'
above.)
• Evidence supporting the decision to treat patients with highly symptomatic anemia and a hemoglobin level between 10 and 12 g/dL is indirect.
This decision should be made based on clinical judgment, consideration of the risks and benefits of ESAs and blood transfusions, and patient
preference. (See 'Initial approach' above and "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer",
section on 'Summary and recommendations' and "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section
on 'Overview of our approach'.)
Use of UpToDate is subject to the Subscription and License Agreement.
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107. González-Barón M, Ordóñez A, Franquesa R, et al. Response predicting factors to recombinant human erythropoietin in cancer patients
undergoing platinum-based chemotherapy. Cancer 2002; 95:2408.
108. Cazzola M, Beguin Y, Kloczko J, et al. 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.
109. Coccia MA, Cooke K, Stoney G, et al. Novel erythropoiesis stimulating protein (darbepoetin alfa) alleviates anemia associated with chronic
inflammatory disease in a rodent model. Exp Hematol 2001; 29:1201.
110. 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.
111. Fung E, Nemeth E. Manipulation of the hepcidin pathway for therapeutic purposes. Haematologica 2013; 98:1667.
112. Poli M, Asperti M, Naggi A, et al. Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo. Blood 2014;
123:1564.
113. Schmidt PJ, Fleming MD. Modulation of hepcidin as therapy for primary and secondary iron overload disorders: preclinical models and
approaches. Hematol Oncol Clin North Am 2014; 28:387.
114. van Eijk LT, John AS, Schwoebel F, et al. Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in
humans. Blood 2014; 124:2643.
115. Zhao N, Zhang AS, Enns CA. Iron regulation by hepcidin. J Clin Invest 2013; 123:2337.
116. Boyce M, Warrington S, Cortezi B, et al. Safety, pharmacokinetics and pharmacodynamics of the anti-hepcidin Spiegelmer lexaptepid pegol in
healthy subjects. Br J Pharmacol 2016; 173:1580.
Topic 7149 Version 37.0
GRAPHICS
Serum erythropoietin levels in anemia
This graph indicates the exponential relationship between serum erythropoietin

levels (EPO, milliUnits/mL, logarithmic scale) and venous hematocrit (percent,
linear scale) in normal and anemic subjects without renal or chronic diseases.
EPO was assayed by either bioassay or radioimmunoassay.
Data from: Erslev AJ, Wilson J, Caro J. Erythropoietin titers in anemic, nonuremic
patients. J Lab Clin Med 1987; 109:429.
Graphic 53916 Version 3.0
Mechanism for the anemia of chronic disease
A proposed mechanism for the anemia of chronic disease (ACD) is shown here. In the
presence of infection, inflammation, or malignancy, the macrophage is stimulated to produce
interleukin-6 (IL-6) and interleukin-1 beta (IL-1β), which induce the production of hepcidin by
the liver. Hepcidin, in turn, through its interaction with the iron export protein ferroportin,
inhibits iron absorption from the gastrointestinal tract and decreases release of iron from
macrophages. Both effects lead to the reduced plasma iron levels (hypoferremia) characteristic
of ACD. Inflammatory cytokines such as IL-1β and TNF-α reduce erythropoietin production
and the efficiency of erythropoiesis, which are also components of ACD.
Hepcidin regulatory pathways
Schematic representation of mechanisms activating hepcidin transcription.

Central part - BMP6 and BMP2 activate type I and II receptors, interacting with the co-
receptor hemojuvelin on hepatocyte plasma membrane. This triggers the phosphorylation of
SMAD1/5/8, which interacts with SMAD4; the transcriptional SMAD complex translocates to
the nucleus to activate transcription via the HAMP gene, which encodes hepcidin. ERFE can
negatively regulate BMP6.
Left side (potential role of HFE and TfR2) - HFE binds TfR1 in competition with Tf-Fe 2. High
Tf-Fe 2 levels displace HFE, which is then free to bind TfR2. It is hypothesized that the HFE-
TfR2 complex activates hepcidin, but the molecular mechanisms are unclear (indicated by
the question mark).
Right side - IL-6, increased in inflammation, interacts with its receptor (IL-6R) to
phosphorylate STAT3, which in turn interacts with the HAMP promoter to activate hepcidin
transcription.
TfR1: transferrin receptor 1; Tf-Fe2: diferric transferrin; HJV: hemojuvelin; BMP6: bone
morphogenetic protein 6; BMP2: bone morphogenetic protein 2; BMPRI-II: bone morphogenetic
protein type I and II receptors; IL-6: interleukin 6; IL-6R: IL-6 receptor; HAMP: hepcidin antimicrobial
peptide.
Laboratory findings in iron deficiency anemia, thalassemia, and anemia of chronic disease/inflammation
Anemia of chronic
Test Iron deficiency anemia Alpha or beta thalassemia
disease/inflammation
Complete blood count
Hemoglobin Decreased Decreased Decreased
Mean corpuscular volume (MCV) Decreased Decreased Normal to decreased
Red cell distribution width (RDW) Increased Increased or normal Normal to increased
Red blood cell count Decreased Increased or normal Decreased
Iron studies
Serum iron Decreased Normal or increased Decreased
Total iron-binding capacity (TIBC); Increased Normal Decreased

transferrin
Transferrin saturation Decreased Normal Decreased
Serum ferritin Decreased Normal or increased Increased
Erythrocyte protoporphyrin* Increased Normal or increased Increased
Soluble transferrin receptor* Increased Increased Normal
Reticulocyte hemoglobin equivalent Decreased Decreased Normal

(Ret-he or CHr)
C-reactive protein Normal Normal Increased
Refer to UpToDate topics on anemia for further details of the evaluation and interpretation. Refer to UpToDate topic on iron deficiency anemia for early changes
associated with iron deficiency (before anemia develops).
* Not used in the routine evaluation of anemia.
Interactions between hepcidin and ferroportin
This figure illustrates the iron export function of ferroportin in macrophages. This
function (in blue, A) is regulated, in part, by the iron regulatory protein hepcidin (red
circle), which binds to ferroportin (B), causing the complex to be internalized and
degraded (C), preventing iron export. When hepcidin is in excess, dietary iron absorption
is decreased by blocking iron export from intestinal brush border cells; iron export from
macrophages is also blocked, leading to hypoferremia. When hepcidin levels are
deficient, as in hereditary hemochromatosis, iron absorption proceeds without effective
inhibition, leading to iron overload. Two types of ferroportin mutation are known. In one,
ferroportin's iron export function is reduced, leading to accumulation of iron in
macrophages and low transferrin saturation (D). In the second, hepcidin binding to
ferroportin is impaired (E), leading to uncontrolled iron absorption.
Redrawn after Andrews N. Ferroportin hemochromatosis - One molecule, two diseases. The
Hematologist 2005; 2:1.
Conditions associated with increased serum ferritin
Condition
Pattern Management implications
(examples)
Iron overload Progressive/cumulative increase in ferritin over Close monitoring with iron removal once there is evidence of excess tissue
time, eventually causing organ damage if not deposition (eg, from MRI) or the ferritin level exceeds a certain threshold (eg,
Hereditary
treated. TSAT will be high (typical value >45%). >1000 ng/mL). Phlebotomy is often used in individuals without anemia; iron
hemochromatosis
chelation is used for individuals with anemia.
Transfusional iron
overload
Ineffective erythropoiesis
(eg, thalassemia)
Massive cell/tissue death Rapid rise in ferritin to very high levels (eg, Aggressive therapy for the underlying condition is usually indicated. Ferritin level
>3000 ng/mL), usually in the setting of acute may be a useful marker of disease activity.
HLH
illness with immune dysregulation. TSAT will not
Cancer
be increased (typical value <45%).
Liver failure
Inflammatory block Chronic, modest increase in ferritin May be helpful in distinguishing ACD from iron deficiency, but ferritin by itself is
(approximately two to three times normal). a poor indicator of iron stores in the setting of chronic inflammation. A search for
Anemia of chronic
Ferritin is an acute phase reactant. TSAT will not the cause may be indicated if not immediately apparent (eg, infection). Therapy
inflammation/ACD (eg,
be increased (typical value <45%). is directed to the underlying condition.
diabetes, cancer, chronic
infection, autoimmune
disorders)
Anemia of renal failure
Chronic liver disease
Ferritin is a marker of iron stores, but it may also be elevated as an acute phase reactant or due to massive cell and tissue death, especially in the liver and in
the setting of hemophagocytosis. The absolute ferritin level cannot be interpreted in isolation and should not be the sole basis for treatment decisions. The
pattern of ferritin increase (progressive, acute/marked increase, or chronic mild elevation) as well as the patient's underlying condition must be incorporated in
the evaluation.
TSAT: transferrin saturation; MRI: magnetic resonance imaging; HLH: hemophagocytic lymphohistiocytosis; ACD: anemia of chronic disease.
Transferrin receptor-ferritin index in anemic patients
This figure shows the transferrin receptor-ferritin index (TfR-F index), the ratio
of the serum TfR to the logarithm (base 10) of the serum ferritin in iron
deficiency anemia (IDA, red circles), anemia of chronic disease (ACD, green
squares) and those with both conditions (IDA/ACD, blue triangles). Median
values are indicated by the horizontal bars. A value of ≤1.0 suggests ACD, while
values ≥2 suggest IDA or IDA/ACD.
Reproduced with permission from: Punnonen K, Irjala K, Rajamaki A. Serum

transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency.
Blood 1997; 89:1052. Copyright © 1997 American Society of Hematology.
Anemia of chronic disease - bone marrow iron stain
Section of a bone marrow aspirate taken from a patient with the anemia of chronic
disease. The slide has been stained for iron (Prussian blue reaction) and
counterstained with safranin to show nuclear detail. Note the increased iron staining
within the voluminous cytoplasm of macrophages (thick black arrows), while there
is no staining for iron within the cytoplasm of red blood cell precursors (thin black
arrows). This pattern (abundant iron in macrophages and reduced to absent iron in
red cell precursors) is quite typical for the anemia of chronic disease, and contrasts
with iron deficiency, in which iron is absent from both macrophages and red cell
precursors, while normal subjects demonstrate iron in macrophages and red cell
precursors.
Slide provided by Stanley L Schrier, MD.
Ring sideroblasts in refractory anemia with ring

sideroblasts (RARS)
Prussian blue stain of the bone marrow in a patient with refractory anemia and
ring sideroblasts (RARS). Blue-stained ferritin iron deposits in the mitochondria
of erythroid precursors form an apparent ring around the nucleus (see arrows).
Courtesy of Stanley L Schrier, MD.
Bone marrow - ring sideroblasts
Upper panel: bone marrow aspirate stained with Prussian blue to show red cell
precursors with numerous iron- positive granules surrounding the nucleus, in
some cases forming a complete ring (arrows). Lower panel: Electron micrograph
of a single erythroblast with iron-laden (electron dense deposits) mitochondia
(red arrows) clustered near its nucleus.
Courtesy of Sylvia Bottomley, MD.
Causes of microcytic anemia (mean corpuscular volume less than 80 fL)
Hereditary disorders
Defects of globin synthesis
Thalassemia syndromes
Thalassemic hemoglobinopathies (eg, hemoglobin [Hb]E, Hb Lepore)
Defects of iron metabolism

Iron refractory iron deficiency anemia (IRIDA)*
Divalent metal transporter (DMT)1 mutations*
Atransferrinemia*
Sideroblastic anemia
Acquired disorders
Iron deficiency anemia
Myelodysplastic syndrome (MDS) with acquired thalassemia*
Sideroblastic anemias due to drugs or toxins (lead poisoning, alcohol, drugs)
Copper deficiency (some cases)
Zinc deficiency
The two most common causes of microcytosis are shown in red type.
* Very rare cause of microcytosis.
Contributor Disclosures
Stanley L Schrier, MD Nothing to disclose Clara Camaschella, MD Grant/Research/Clinical Trial Support: Vifor Pharma [Iron deficiency anemia
(Use of ferric carboxymaltose)]. William C Mentzer, MD Equity Ownership/Stock Options: Johnson & Johnson [Anemia (Erythropoietin)]. Jennifer S
Tirnauer, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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Anemia of chronic disease/inflammation

Authors: Stanley L Schrier, MD, Clara Camaschella, MD

Several observations support this paradigm:

● Inflammatory bowel disease – (See "Nutrient deficiencies in inflammatory bowel disease".)

● Older adults – (See "Anemia in the older adult", section on 'Inflammation'.)

● Low transferrin saturation

● Reduced reticulocyte response for the degree of anemia (calculator 1)

● Normal soluble transferrin receptor (sTfR) level (Normal: 2.2 to 5 mg/L)

● Normal sTfR/ferritin ratio (figure 5) (see 'sTfR - ferritin index' above)

Two treatment options are available.

SUMMARY AND RECOMMENDATIONS

• Serum creatinine and estimated glomerular filtration rate (eGFR)

• Measurement of acute phase reactants (eg, sedimentation rate, C-reactive protein)

• Low serum iron

• Normal to low serum transferrin (total iron binding capacity)

• Normal to increased serum ferritin

• Elevated erythrocyte sedimentation rate and/or C-reactive protein

• Hypoproliferative anemias (eg, renal disease, endocrine disorders).

• Iron deficiency anemia (IDA).

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Topic 7149 Version 37.0

Serum erythropoietin levels in anemia

This graph indicates the exponential relationship between serum erythropoietin

Graphic 53916 Version 3.0

Mechanism for the anemia of chronic disease

Graphic 78381 Version 3.0

Hepcidin regulatory pathways

Schematic representation of mechanisms activating hepcidin transcription.

Graphic 64022 Version 3.0

Complete blood count

Hemoglobin Decreased Decreased Decreased

Mean corpuscular volume (MCV) Decreased Decreased Normal to decreased

Red blood cell count Decreased Increased or normal Decreased

Serum iron Decreased Normal or increased Decreased

Total iron-binding capacity (TIBC); Increased Normal Decreased

Transferrin saturation Decreased Normal Decreased

Serum ferritin Decreased Normal or increased Increased

Erythrocyte protoporphyrin* Increased Normal or increased Increased

Soluble transferrin receptor* Increased Increased Normal

Reticulocyte hemoglobin equivalent Decreased Decreased Normal

C-reactive protein Normal Normal Increased

* Not used in the routine evaluation of anemia.

Graphic 65701 Version 6.0

Interactions between hepcidin and ferroportin

Graphic 66578 Version 3.0

Conditions associated with increased serum ferritin

Graphic 115294 Version 1.0

Transferrin receptor-ferritin index in anemic patients

Reproduced with permission from: Punnonen K, Irjala K, Rajamaki A. Serum

Graphic 79053 Version 2.0

Anemia of chronic disease - bone marrow iron stain

Slide provided by Stanley L Schrier, MD.

Graphic 70226 Version 2.0

Ring sideroblasts in refractory anemia with ring

Courtesy of Stanley L Schrier, MD.

Graphic 65887 Version 5.0

Bone marrow - ring sideroblasts

Courtesy of Sylvia Bottomley, MD.

Graphic 62536 Version 2.0

Causes of microcytic anemia (mean corpuscular volume less than 80 fL)

Defects of iron metabolism