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{{Anemia of chronic disease}}
{{Anemia of chronic disease}}
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==Overview==
==Overview==
The primary goal in the treatment of [[anemia]] of chronic disease is to treat the underlying [[disease]] itself. [[Iron|Supplemental iron]] is recommended, as needed, to keep the [[transferrin]] saturation of above 20 percent and a [[serum]] [[ferritin]] level of above 100 ng/mL. [[Intravenous therapy|Intravenous]] [[iron]] is more effective than [[Oral|oral supplementaion.]] Stable patients can be administered synthetically prepared [[erythropoiesis]]-stimulating agent such as [[erythropoietin]] or [[darbepoietin]]. It is important to give [[oral]] [[iron]] supplementation to all the patients receiving [[erythropoietin]] or [[darbepoetin]], in order to maintain a t[[Transferrin|ransferrin]] [[saturation]] more than 20 percent and a [[serum]] [[ferritin]] more than 100 ng/mL. In case of severe [[disease]], [[blood transfusion]] is recommended. If the case is underlying [[malignancy]], [[chemotherapy]] or [[radiotherapy]] may transiently exacerbate [[anemia]] due to [[Bone marrow suppression|myelosuppressive]] effects, but in the long term, it leads to improvement. If the cause is [[Inflammatory|inflammatory disorder]], such as [[rheumatoid arthritis]] the management of the disease with a [[disease-modifying antirheumatic drug]] [[DMARD|(DMARD]]) improves the [[anemia]] significantly.
==Medical Therapy==
==Medical Therapy==
The ideal treatment for anemia of chronic disease is to treat the chronic disease successfully. Barring that, many patients with anemia of chronic disease simply live with the effects of the anemia as part of enduring the limits placed on them by other aspects of their underlying medical conditions. In more severe cases, [[transfusions]] or several versions of commercially-produced [[erythropoietin]] can be helpful in some circumstances; both approaches are costly.
The primary goal in the treatment of [[anemia]] of chronic disease is to treat the underlying [[disease]] itself.<ref name="pmid18695181">{{cite journal |vauthors=Zarychanski R, Houston DS |title=Anemia of chronic disease: a harmful disorder or an adaptive, beneficial response? |journal=CMAJ |volume=179 |issue=4 |pages=333–7 |date=August 2008 |pmid=18695181 |pmc=2492976 |doi=10.1503/cmaj.071131 |url=}}</ref>
 
*If the cause is underlying [[malignancy]], [[chemotherapy]] or [[radiotherapy]] may transiently exacerbate [[anemia]]  due to [[Bone marrow suppression|mylesuppressive]] effects, however in the long term, it leads to improvement.  
Initial approach — The preferred initial therapy for ACD is correction of the underlying disorder. (See 'Underlying disorder' below.)
*If the cause is [[Inflammatory|inflammatory disorder]], such as [[rheumatoid arthritis]] the management of the disease with a [[disease-modifying antirheumatic drug]] [[DMARD|(DMARD]]) improves the [[anemia]] significantly.<ref name="pmid2589399">{{cite journal |vauthors=Cash JM, Sears DA |title=The anemia of chronic disease: spectrum of associated diseases in a series of unselected hospitalized patients |journal=Am. J. Med. |volume=87 |issue=6 |pages=638–44 |date=December 1989 |pmid=2589399 |doi= |url=}}</ref>
 
*If the root cause of [[anemia]] is not found, a detailed search for [[Inflammatory|inflammatory disorders]] such as [[inflammatory bowel disease]] and [[malignancy]] should be carried.  
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'.)
==== Supplemental iron ====
*[[Iron|Supplemental iron]] is recommended, as needed, to keep the [[transferrin]] saturation of above 20 percent and a [[serum]] [[ferritin]] level of above 100 ng/mL.<ref name="pmid15051778">{{cite journal |vauthors=Auerbach M, Ballard H, Trout JR, McIlwain M, Ackerman A, Bahrain H, Balan S, Barker L, Rana J |title=Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial |journal=J. Clin. Oncol. |volume=22 |issue=7 |pages=1301–7 |date=April 2004 |pmid=15051778 |doi=10.1200/JCO.2004.08.119 |url=}}</ref>
*A variety of oral iron formulations can be used, such as ferrous sulfate.


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.)
==== Intravenous iron ====
*[[Intravenous therapy|Intravenous]] [[iron]] is more effective than [[Oral|oral supplementation]].
*[[Intestinal]] absorption of [[iron]] is greatly reduced due to [[hepcidin]] activity at [[Intestinal|intestinal lining]].
*[[Hepcidin]]-induced entrapment of [[iron]] can be managed with [[parenteral]] iron infusions.
*A variety of IV iron formulations can be used, such as iron sucrose, iron dextran, or ferric carboxymaltose.


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".)
==== Erythropoietin ====
In the case of a patient who does not respond to [[oral]] iron, [[parenteral]] iron infusions [[erythropoietin]] should be considered.<ref name="pmid8049455">{{cite journal |vauthors=Spivak JL |title=Recombinant human erythropoietin and the anemia of cancer |journal=Blood |volume=84 |issue=4 |pages=997–1004 |date=August 1994 |pmid=8049455 |doi= |url=}}</ref>
*Stable patients can be administered synthetically prepared [[erythropoiesis]]-stimulating agent such as [[erythropoietin]].<ref name="pmid11953880">{{cite journal |vauthors=Lind M, Vernon C, Cruickshank D, Wilkinson P, Littlewood T, Stuart N, Jenkinson C, Grey-Amante P, Doll H, Wild D |title=The level of haemoglobin in anaemic cancer patients correlates positively with quality of life |journal=Br. J. Cancer |volume=86 |issue=8 |pages=1243–9 |date=April 2002 |pmid=11953880 |pmc=2375336 |doi=10.1038/sj.bjc.6600247 |url=}}</ref>
*[[Erythropoietin]] can be given once per week, while [[darbepoetin]] should be administered once every two or three weeks.
*It is important to give [[oral]] [[iron]] supplementation to all the patients receiving [[erythropoietin]] or [[darbepoetin]], in order to maintain a t[[Transferrin|ransferrin]] [[saturation]] more than 20 percent and a [[serum]] [[ferritin]] more than 100 ng/mL.  


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.
==== Blood Transfusion ====
*In case of severe [[disease]], [[blood transfusion]]  is recommended.
*Blood transfusions, if performed frequently, can result in iron overload and circulatory overload.


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.)
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Latest revision as of 06:59, 2 December 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

Overview

The primary goal in the treatment of anemia of chronic disease is to treat the underlying disease itself. Supplemental iron is recommended, as needed, to keep the transferrin saturation of above 20 percent and a serum ferritin level of above 100 ng/mL. Intravenous iron is more effective than oral supplementaion. Stable patients can be administered synthetically prepared erythropoiesis-stimulating agent such as erythropoietin or darbepoietin. It is important to give oral iron supplementation to all the patients receiving erythropoietin or darbepoetin, in order to maintain a transferrin saturation more than 20 percent and a serum ferritin more than 100 ng/mL. In case of severe disease, blood transfusion is recommended. If the case is underlying malignancy, chemotherapy or radiotherapy may transiently exacerbate anemia due to myelosuppressive effects, but in the long term, it leads to improvement. If the cause is inflammatory disorder, such as rheumatoid arthritis the management of the disease with a disease-modifying antirheumatic drug (DMARD) improves the anemia significantly.

Medical Therapy

The primary goal in the treatment of anemia of chronic disease is to treat the underlying disease itself.[1]

Supplemental iron

  • Supplemental iron is recommended, as needed, to keep the transferrin saturation of above 20 percent and a serum ferritin level of above 100 ng/mL.[3]
  • A variety of oral iron formulations can be used, such as ferrous sulfate.

Intravenous iron

Erythropoietin

In the case of a patient who does not respond to oral iron, parenteral iron infusions erythropoietin should be considered.[4]

Blood Transfusion

  • In case of severe disease, blood transfusion is recommended.
  • Blood transfusions, if performed frequently, can result in iron overload and circulatory overload.

References

  1. ↑ Zarychanski R, Houston DS (August 2008). "Anemia of chronic disease: a harmful disorder or an adaptive, beneficial response?". CMAJ. 179 (4): 333–7. doi:10.1503/cmaj.071131. PMC 2492976. PMID 18695181.
  2. ↑ Cash JM, Sears DA (December 1989). "The anemia of chronic disease: spectrum of associated diseases in a series of unselected hospitalized patients". Am. J. Med. 87 (6): 638–44. PMID 2589399.
  3. ↑ Auerbach M, Ballard H, Trout JR, McIlwain M, Ackerman A, Bahrain H, Balan S, Barker L, Rana J (April 2004). "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. 22 (7): 1301–7. doi:10.1200/JCO.2004.08.119. PMID 15051778.
  4. ↑ Spivak JL (August 1994). "Recombinant human erythropoietin and the anemia of cancer". Blood. 84 (4): 997–1004. PMID 8049455.
  5. ↑ Lind M, Vernon C, Cruickshank D, Wilkinson P, Littlewood T, Stuart N, Jenkinson C, Grey-Amante P, Doll H, Wild D (April 2002). "The level of haemoglobin in anaemic cancer patients correlates positively with quality of life". Br. J. Cancer. 86 (8): 1243–9. doi:10.1038/sj.bjc.6600247. PMC 2375336. PMID 11953880.


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