Anemia of chronic disease
| Anemia of chronic disease | |
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Differentiating Anemia of chronic disease from other Diseases | |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]
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Synonyms and keywords: Anemia of inflammation.
Overview
Historical Perspective
Classification
Pathophysiology
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].
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]. As an example, IFN-gamma, when given to experimental animals, or when its formation is stimulated in vivo, can produce the picture of ACD with most of the abnormalities noted above [3,19-22].
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 [13,23,24]. 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 [25].
In support of these mechanisms are three clinical observations:
●Treatment of patients with rheumatoid arthritis using an anti-TNF-alpha antibody led to a reduction in IL-6 levels, a decrease in the proportion of apoptotic red cell precursors, and an improvement in anemia [9,26,27]. (See "Hematologic manifestations of rheumatoid arthritis", section on 'Anemia of chronic disease' and "Acute phase reactants", section on 'The acute phase response'.)
●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 [28]. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis", section on 'Laboratory findings'.)
●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 [29].
Hepcidin — One acute phase protein that appears to be most directly involved in iron metabolism is hepcidin, which appears to be a component of the innate immune response to acute infection [30,31]. 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 [32], 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 [33].
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 [34]. 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 [35]. 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 [36-47]:
●In one study, a single injection of turpentine induced an acute sixfold increase in liver hepcidin mRNA and a twofold decrease in serum iron [38]. The latter effect was completely blunted in hepcidin-deficient mice [39].
●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) [40,41]. 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 [36]. 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 [42].
●In a mouse model of sepsis, hepcidin gene deletion ameliorated anemia better than administration of erythropoietin [48].
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 [49].
●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 [49].
●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 [36], supporting a distinct role for both IL-6 and hepcidin in ACD [37]. IL-6 negatively interferes with the erythropoietin response while hepcidin only decreases iron availability.
Studies in human subjects — 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) [7,30,50,51]. Examples of the available data include the following [7,49,51-60]:
●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 [55]. Such treatment resulted in progressive normalization of iron-related parameters and symptomatic improvement [56]. (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 [7,57]. 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 [57].
●Hepcidin plasma levels were significantly higher in 65 patients with Hodgkin lymphoma than in controls and showed a positive correlation with IL-6 levels [51]. 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 [58], inflammatory bowel disease [59], and Castleman disease [56,60].
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 [61]. 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) [62-64]. (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 [65]. Potential uses of hepcidin measurements have been proposed [66]. Lack of standardization of the available assays remains a major limitation, although efforts to harmonize the different tests are ongoing [67]. (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 [68]. 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.
Causes
Differentiating Anemia of chronic disease from other Diseases
Epidemiology and Demographics
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 [69]. (See "Hematologic manifestations of rheumatoid arthritis", section on 'Anemia'.)
●Cancer-related anemia occurs in more than 30 percent of the cases at diagnosis [70]; the rate reached 63 percent in an observational study on 888 consecutive cancers [71]. 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 [72]. (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".)
Risk Factors
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: 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 [18,73]. (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 [74,75]. It appears to be an acute variant of ACD and is also characterized by shortened red blood cell (RBC) survival [10,76,77].
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 [78].
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 [79]. 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 [80].
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].
Screening
Natural History, Complications and Prognosis
Diagnosis
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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) [81,82]. (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 percent saturation of transferrin (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)'.)
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 [83-86].
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 [10,87]. 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) [88].
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.)
Treatment
Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies
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 [95].
●Some patients have more severe anemia, leading to impaired function and an impaired quality of life [12,96]. 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 [97,98]. (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) [99-103]. (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 [102,104]. 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 [102].
●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 [105]. 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", section on 'Recombinant human erythropoietin'.)
●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 [106]. 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 [107]. 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 [65]. 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 [108-113]. (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".)
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