Doctor123.org

Anemia of Chronic Disease (Anemia of Inflammation), Pediatric

Basics

Description

- 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.

- 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

- 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

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 beIron 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 destructionDiagnostic phlebotomy or other blood lossCytokine-mediated interference with erythropoietin signalingCytokine-mediated suppression of erythropoiesisCytokines 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 processInfections, both acute and chronicInflammatory diseaseCollagen vascular diseasesMalignanciesRenal 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 indicesNormocytic, 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 studiesLow plasma iron, with low total iron-binding capacityLow transferrin saturation by ironNormal 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 anemiaMild anisocytosisUsually normochromic, normocytic but can be hypochromic with microcytosisDecreased plasma ironDecreased iron-binding capacityNormal or slightly low transferrin saturationDecreased marrow sideroblastsNormal or elevated reticuloendothelial ironElevated free erythrocyte protoporphyrinNormal or elevated ferritinIncreased hepcidin
  • In iron deficiency:Decreased plasma ironIncreased iron-binding capacityDecreased transferrin saturationDecreased marrow sideroblastsDecreased reticuloendothelial ironIncreased free erythrocyte protoporphyrinDecreased serum ferritinDecreased hepcidin
  • In both iron deficiency and anemia of chronic disease:Decreased plasma ironDecreased transferrin saturationDecreased marrow sideroblastsElevated free erythrocyte protoporphyrinDecreased reticulocyte count
  • Tests that help differentiate iron deficiency from anemia of chronic disease:Iron-binding capacitySerum ferritinReticuloendothelial iron stain in marrowHepcidin level (although not available everywhere)

Treatment

General Measures

  • IronGenerally, 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 erythropoietinEffective, but indications for use are still not universally acceptedOften used in chronic renal failureHas been used in inflammatory bowel disease, with good resultsShould 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.