Basics
Description
Anemia that accompanies a variety of systemic diseases, with the common features of chronicity and inflammation. Anemia of chronic disease is more properly called anemia of inflammation (AI) and is the combined result of mildly increased destruction of RBCs, relative erythropoietin resistance, and iron-restricted erythropoiesis.
Pathophysiology
Typically mild to moderate anemia (Hgb 7-12 g/dL); develops in the setting of infection, inflammatory disorders, and some malignancies
- Deficient cellular iron in the setting of hepcidin excess (functionally inaccessible iron)
- Typically normochromic, normocytic but, if long-standing, can be hypochromic, microcytic (especially in children)
- Main mechanism appears to be
- Iron restriction (limited iron supply to erythropoiesis)
- Hepcidin is increased by interleukin 6 (IL-6) and causes depletion of the only known membrane iron transporter (ferroportin).
- These changes result in cellular inability to release stored iron and enterocyte inability to absorb iron because of inability to transport iron over cell membrane into bloodstream.
- Other factors contributing to anemia in various degrees include the following:
- Increased red cell destruction
- Diagnostic phlebotomy or other blood loss
- Cytokine-mediated interference with erythropoietin signaling
- Cytokine-mediated suppression of erythropoiesis
- Cytokines such as interleukin-1 (IL-1) and IL-6 can activate ferritin synthesis. The ferritin can lead to sequestration of iron, which eventually is converted into hemosiderin.
Etiology
Underlying disease process
Commonly Associated Conditions
- Underlying disease process
- Infections, both acute and chronic
- Inflammatory disease
- Collagen vascular diseases
- Malignancies
- Renal failure
- Anemia of chronic disease often coexists with other causes of anemia, including occult blood loss, hemolysis, dietary iron deficiency, and drug-related marrow suppression.
Diagnosis
Signs and Symptoms
- Various abnormal physical findings may be present, depending on the underlying chronic disease process.
- May have mild pallor but will not have signs of circulatory collapse
- Similar disease can be seen more acutely in the setting of anemia of critical illness (also part of AI).
History
Anemia develops over the 1st month of the underlying disease process and then remains fairly stable over time.
Physical Exam
- Mild pallor
- Mild tachycardia, may be inapparent at rest
- Very rarely more overt signs of anemia such as flow murmur, gallop, or hepatomegaly
- Physical findings of the underlying disease
Diagnostic Tests & Interpretation
If only the serum iron is obtained, without other iron studies, the child may be inappropriately diagnosed with iron deficiency.
Lab
- CBC with indices
- Normocytic, normochromic (can be microcytic, hypochromic when very long-standing) anemia with hematocrit rarely <20%
- Reticulocyte count usually in the normal range, but low for the level of anemia.
- Iron studies
- Low plasma iron, with low total iron-binding capacity
- Low transferrin saturation by iron
- Normal or high ferritin level
- Elevated free erythrocyte protoporphyrin
- Hemosiderin in bone marrow macrophages is increased if bone marrow aspiration is done and the aspirate is viewed with iron stains.
- Albumin and transferrin are both low.
- Acute-phase reactants such as C-reactive protein may be elevated.
- Hepcidin levels will be elevated.
Diagnostic Procedures/Other
Bone marrow aspiration is generally not indicated.
Differential Diagnosis
Anemia of chronic disease is often confused with iron deficiency anemia.
- In anemia of chronic disease:
- Mild to moderate anemia
- Mild anisocytosis
- Usually normochromic, normocytic but can be hypochromic with microcytosis
- Decreased plasma iron
- Decreased iron-binding capacity
- Normal or slightly low transferrin saturation
- Decreased marrow sideroblasts
- Normal or elevated reticuloendothelial iron
- Elevated free erythrocyte protoporphyrin
- Normal or elevated ferritin
- Increased hepcidin
- In iron deficiency:
- Decreased plasma iron
- Increased iron-binding capacity
- Decreased transferrin saturation
- Decreased marrow sideroblasts
- Decreased reticuloendothelial iron
- Increased free erythrocyte protoporphyrin
- Decreased serum ferritin
- Decreased hepcidin
- In both iron deficiency and anemia of chronic disease:
- Decreased plasma iron
- Decreased transferrin saturation
- Decreased marrow sideroblasts
- Elevated free erythrocyte protoporphyrin
- Decreased reticulocyte count
- Tests that help differentiate iron deficiency from anemia of chronic disease:
- Iron-binding capacity
- Serum ferritin
- Reticuloendothelial iron stain in marrow
- Hepcidin level (although not available everywhere)
Treatment
General Measures
- Iron
- Generally, no role for iron therapy unless there is coexisting iron deficiency anemia. However, recent studies in patients with renal disease have shown improved response to erythropoietin with coadministration of parenteral iron.
- Recombinant human erythropoietin
- Effective, but indications for use are still not universally accepted
- Often used in chronic renal failure
- Has been used in inflammatory bowel disease, with good results
- Should be used for more severe and symptomatic anemia in which the underlying disease is likely to be prolonged and difficult to treat
- Treatment should be directed at the underlying disease process.
Special Therapy
Transfusion of packed RBCs is sometimes indicated intermittently in severe anemia with hemodynamic compromise.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
Treatment of underlying disease process may promote slow resolution of associated anemia. Hematocrit increases ~6-8 weeks after start of recombinant human erythropoietin therapy; continues to rise over 6 months.
Complications
If severe, patients may be transfusion dependent and, thus, be at risk for complications associated with packed RBC transfusions.
Additional Reading
- Cullis J. Anaemia of chronic disease. Clin Med. 2013;13(2):193-196. [View Abstract]
- Ganz T. Molecular pathogenesis of anemia of chronic disease. Pediatr Blood Cancer. 2006;46(5):554-557. [View Abstract]
- Ganz T, Nemeth E. Iron sequestration and anemia of inflammation. Semin Hematol. 2009;46(4):387-393. [View Abstract]
- Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron, and erythropoiesis. Blood. 2000;96(3):823-833. [View Abstract]
Codes
ICD09
- 285.29 Anemia of other chronic disease
- 285.21 Anemia in chronic kidney disease
- 285.22 Anemia in neoplastic disease
- 282.9 Hereditary hemolytic anemia, unspecified
- 446.2 Hypersensitivity angiitis, unspecified
- 280.9 Iron deficiency anemia, unspecified
ICD10
- D63.8 Anemia in other chronic diseases classified elsewhere
- D63.1 Anemia in chronic kidney disease
- D63.0 Anemia in neoplastic disease
- D58.9 Hereditary hemolytic anemia, unspecified
- M35.9 Systemic involvement of connective tissue, unspecified
- D50.9 Iron deficiency anemia, unspecified
SNOMED
- 234347009 Anemia of chronic disorder (disorder)
- 49708008 Anemia of chronic renal failure (disorder)
- 191265009 Anemia in neoplastic disease (disorder)
- 22098000 Chronic idiopathic autoimmune hemolytic anemia (disorder)
- 398049005 Mixed collagen vascular disease (disorder)
- 87522002 Iron deficiency anemia (disorder)
FAQ
- Q: Does anemia that is associated with a chronic disease require further evaluation?
- A: If the anemia fits within the usual expectations for the patient's diagnosis, there is no need to pursue further investigation, except in specific cases. If there is an associated malignancy for which marrow metastasis is possible, a bone marrow aspirate and biopsy should be done. In conditions with malabsorption, nutritional deficiencies and blood loss should be ruled out.