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| {{Anemia of chronic disease}} | | {{Anemia of chronic disease}} |
| {{CMG}} {{AE}} {{OK}} | | {{CMG}} {{shyam}} {{AE}} {{OK}} {{Badria}} |
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| '''For patient information, click [[Anemia of chronic disease (patient information)|here]]''' | | '''For patient information, click [[Anemia of chronic disease (patient information)|here]]''' |
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| ==[[Anemia of chronic disease classification|Classification]]== | | ==[[Anemia of chronic disease classification|Classification]]== |
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| ==[[Anemia of chronic disease pathophysiology|Pathophysiology]]== | | ==[[Anemia of chronic disease pathophysiology|Pathophysiology]]== |
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| PATHOGENESIS
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| 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]:
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| ●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.)
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| ●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].
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| ●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.
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| ●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].
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| 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].
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| 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].
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| In support of these mechanisms are three clinical observations:
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| ●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'.)
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| ●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'.)
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| ●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].
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| 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].
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| 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.
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| Animal models of ACD — Animal models of ACD shed further light on the relative importance of hepcidin and IL-6 [36-47]:
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| ●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].
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| ●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.
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| ●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].
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| ●In a mouse model of sepsis, hepcidin gene deletion ameliorated anemia better than administration of erythropoietin [48].
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| The importance of interleukin (IL)-6 in this hepcidin pathway was shown by the following observations:
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| ●The effect of an injection of turpentine on liver hepcidin mRNA and serum iron was completely blunted in IL-6 knockout mice [49].
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| ●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].
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| ●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.
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| 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]:
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| ●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'.)
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| ●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].
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| ●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].
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| 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'.)
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| 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'.)
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| 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.
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| ==[[Anemia of chronic disease causes|Causes]]== | | ==[[Anemia of chronic disease causes|Causes]]== |
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| ==[[Anemia of chronic disease differential diagnosis|Differentiating Anemia of chronic disease from other Diseases]]== | | ==[[Anemia of chronic disease differential diagnosis|Differentiating Anemia of chronic disease from other Diseases]]== |
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| ==[[Anemia of chronic disease epidemiology and demographics|Epidemiology and Demographics]]== | | ==[[Anemia of chronic disease epidemiology and demographics|Epidemiology and Demographics]]== |
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| ==[[Anemia of chronic disease risk factors|Risk Factors]]== | | ==[[Anemia of chronic disease risk factors|Risk Factors]]== |
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| ==[[Anemia of chronic disease screening|Screening]]== | | ==[[Anemia of chronic disease screening|Screening]]== |
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| ==[[Anemia of chronic disease natural history, complications and prognosis|Natural History, Complications and Prognosis]]== | | ==[[Anemia of chronic disease natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| ==Diagnosis== | | ==Diagnosis== |
| [[Anemia of chronic disease diagnostic study of choice|Diagnostic study of choice]] | [[Anemia of chronic disease history and symptoms|History and Symptoms]] | [[Anemia of chronic disease physical examination|Physical Examination]] | [[Anemia of chronic disease laboratory findings|Laboratory Findings]] | [[Anemia of chronic disease x ray|X Ray]] | [[Anemia of chronic disease echocardiography and ultrasound|Echocardiography and Ultrasound]] | [[Anemia of chronic disease CT scan|CT scan]] | [[Anemia of chronic disease MRI|MRI]] | [[Anemia of chronic disease other imaging findings|Other Imaging Findings]] | [[Anemia of chronic disease other diagnostic studies|Other Diagnostic Studies]] | | [[Anemia of chronic disease diagnostic study of choice|Diagnostic study of choice]] | [[Anemia of chronic disease history and symptoms|History and Symptoms]] | [[Anemia of chronic disease physical examination|Physical Examination]] | [[Anemia of chronic disease laboratory findings|Laboratory Findings]] | [[Anemia of chronic disease x ray|X Ray]] | [[Anemia of chronic disease echocardiography and ultrasound|Echocardiography and Ultrasound]] | [[Anemia of chronic disease CT scan|CT scan]] | [[Anemia of chronic disease MRI|MRI]] | [[Anemia of chronic disease other imaging findings|Other Imaging Findings]] | [[Anemia of chronic disease other diagnostic studies|Other Diagnostic Studies]] |
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| ==Treatment== | | ==Treatment== |
| [[Anemia of chronic disease medical therapy|Medical Therapy]] | [[Anemia of chronic disease surgery|Surgery]] | [[Anemia of chronic disease primary prevention|Primary Prevention]] | [[Anemia of chronic disease seconday prevention|Secondary Prevention]] | [[Anemia of chronic disease cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Anemia of chronic disease future or investigational therapies|Future or Investigational Therapies]] | | [[Anemia of chronic disease medical therapy|Medical Therapy]] | [[Anemia of chronic disease surgery|Surgery]] | [[Anemia of chronic disease primary prevention|Primary Prevention]] | [[Anemia of chronic disease seconday prevention|Secondary Prevention]] | [[Anemia of chronic disease cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Anemia of chronic disease future or investigational therapies|Future or Investigational Therapies]] |
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| ==Case Studies== | | ==Case Studies== |
| [[Anemia of chronic disease case study one|Case #1]] | | [[Anemia of chronic disease case study one|Case #1]] |