Anemia of Inflammation

Background

• Anemia of inflammation (also called anemia of chronic disease) refers to a mild-to-moderate reduction in hemoglobin level (anemia) associated with an acute or chronic inflammatory condition (see World Health Organization definitions of anemia).
• Iron-restricted erythropoiesis is a state in which delivery of iron to erythroid precursors is impaired, regardless of the level of iron stores and includes iron deficiency anemia (reduced iron stores) and anemia of inflammation (normal or increased iron stores).
• Functional iron deficiency occurs as a result of insufficient iron for incorporation into erythroid precursors despite adequate body iron stores, and includes anemia of inflammation and erythropoiesis-stimulating agent (ESA) therapy, when iron availability and increased iron requirements for erythropoiesis are imbalanced.
• Anemia of inflammation is the second most common anemia worldwide, after iron deficiency anemia, and the most common cause of anemia in hospitalized patients.
• Causes include autoimmune disease, inflammatory bowel disease, infections, aging, chronic kidney disease, cancer, and heart failure.
• Inflammatory mediators increase the expression of the peptide hormone hepcidin, which results in sequestration of iron in hepatocytes and tissue macrophages, disruption of red blood cell production, and a hypoproliferative normocytic, normochromic anemia.
• Symptoms and signs, if present, are usually referable to the underlying inflammatory condition.

Evaluation

• No uniform diagnostic criteria for anemia of inflammation have been established.
• Perform blood tests to detect anemia and inflammation, and to rule out iron deficiency anemia or identify coexisting iron deficiency anemia.
  • Perform a complete blood count (CBC) with differential, and a reticulocyte count. Consider anemia of inflammation if:
    • the CBC shows normocytic, normochromic anemia (anemia may become microcytic and hypochromic as disease progresses)
    • the reticulocyte count is low
  • Perform iron studies including serum ferritin and transferrin, and consider soluble transferrin receptor level.
    • Ferritin ≥ 30 mcg/L suggests anemia of inflammation with or without coexisting iron deficiency anemia.
    • Ferritin < 30 mcg/L suggests iron deficiency anemia.
    • A soluble transferrin receptor index (ratio of soluble transferrin receptor/log [ferritin concentration]) that is < 1 suggests anemia of inflammation, an index that is ≥ 2 suggests iron deficiency anemia alone or coexisting with anemia of inflammation.
  • Consider measuring markers of inflammation such as C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) in addition to the CBC.
    • Elevated CRP or ESR, leukocytosis, or thrombocytosis suggests anemia of inflammation with or without coexisting iron deficiency anemia.
    • Consider iron deficiency anemia or other causes of anemia if inflammatory markers are absent.
• Additional tests that may help differentiate anemia of inflammation from iron deficiency anemia:
  • serum hepcidin concentration - a high level suggests anemia of inflammation, a normal level suggests anemia of inflammation with coexisting iron deficiency, a low level suggests iron deficiency anemia alone.
  • reticulocyte hemoglobin content (CHr) assay - a CHr that is < 28 pg suggests functional iron deficiency.
• If needed, perform additional testing to rule out other causes of normocytic anemia, such as renal insufficiency, hemolysis, and primary bone marrow disorders.

Management

• Treat the underlying cause of inflammation, if possible.
• Anemia of inflammatory bowel disease (IBD):
  • Provide iron supplementation for all patients with IBD and absolute iron deficiency and those with ulcerative colitis and anemia (Strong recommendation).
  • Administer ESA treatment to patients with anemia of inflammation with an insufficient response to IV iron despite optimized IBD therapy with a target Hb level not above 12 g/dL (120 g/L) (Strong recommendation).
• Anemia of chronic kidney disease (CKD):
  • Iron therapy:
    • For adult patients with anemia not receiving iron or ESA therapy, consider a trial of IV iron if an increase in Hb concentration without starting ESA treatment is desired, and transferrin saturation (TSAT) is ≤ 30% and ferritin is ≤ 500 mcg/L) (Weak recommendation).
    • For adult patients on ESA therapy who are not receiving iron supplementation, consider a trial of IV iron if an increase in Hb concentration or a decrease in ESA dose is desired, and TSAT is ≤ 30% and ferritin is ≤ 500 mcg/L (Weak recommendation).
    • For children with CKD and anemia, oral iron (or IV iron for children with hemodialysis-dependent CKD) is recommended:
      • when TSAT is ≤ 20% and ferritin is ≤ 100 mcg/L if the patient is not receiving iron or ESA therapy (Strong recommendation)
      • to maintain TSAT > 20% and ferritin > 100 mcg/L if the patient is receiving ESA therapy but not already on iron supplementation (Strong recommendation)
  • Erythropoiesis-stimulating agents (ESAs):
    • Use ESA therapy with great caution, if at all, in CKD patients with an active malignancy (in particular when a cure is the anticipated outcome), a history of stroke, or a history of malignancy (Strong recommendation).
    • For adult dialysis-dependent CKD patients, consider using ESA therapy when the hemoglobin (Hb) concentration is between 9 and 10 g/dL (90-100 g/L) to avoid having the Hb concentration fall below 9 g/dL (90 g/L) (Weak recommendation).
    • For adult CKD patients not on dialysis:
      • consider not starting ESA therapy if the Hb concentration is ≥ 10 g/dL (≥ 100 g/L) (Weak recommendation)
      • consider initiation of ESA therapy if the Hb concentration is < 10 g/dL (< 100 g/L), taking into account the rate of hemoglobin decrease, the prior response to iron therapy, the risk of transfusion requirement, the risks of ESA therapy, and the presence of anemia symptoms (Weak recommendation)
  • See also Anemia of chronic kidney disease.
• Anemia of cancer:
  • Consider IV or oral iron supplementation in patients with absolute iron deficiency (ferritin < 30 mcg/L and TSAT < 20%) (Weak recommendation).
  • Consider IV iron plus ESA in patients with functional iron deficiency receiving ESA (ferritin 30-500 mcg/L and TSAT < 50%) (Weak recommendation).
  • IV or oral iron should not be administered in the absence of iron deficiency (ferritin > 800 mcg/L or TSAT ≥ 50%) (Weak recommendation).
  • Consider ESAs for patients with cancer and CKD, and patients receiving palliative treatment (Weak recommendation).
  • Do not use ESAs in patients receiving myelosuppressive chemotherapy with curative intent, in patients not receiving therapy or palliative treatment, or those on nonmyelosuppressive therapy (Weak recommendation).
  • Consider ESAs for the remainder of patients with anemia on myelosuppressive chemotherapy without other identifiable causes of anemia (Weak recommendation).
  • See also Anemia of cancer
• Anemia of heart failure:
  • Consider IV ferric carboxymaltose in symptomatic patients with heart failure with reduced ejection fraction and iron deficiency to ease heart failure symptoms and to improve exercise capacity and quality-of-life (Weak recommendation)
  • Do not use erythropoiesis-stimulating agents in patients with mild-to-moderate anemia and heart failure or coronary heart disease (Strong recommendation).
• The decision to offer a blood transfusion is not based on hemoglobin level alone, but on an assessment of individual patient characteristics, the severity of anemia, the presence and severity of comorbidities, and the clinical judgement of the clinician.
• Guideline recommendations vary on the Hb level cutoff which should trigger a transfusion. A transfusion is not considered beneficial when the Hb concentration is > 10 g/dL (100 g/L), but may be considered when the Hb concentration is < 6-7 g/dL (60-70 g/L).