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Anemia, Chronic Disease (ACD)

Description:
- Also known as anemia of chronic inflammation.
- Caused by proinflammatory mediators inhibiting erythropoiesis and disrupting iron homeostasis (1).
- Normocytic, normochromic, hypoproliferative anemia.
- Low serum iron, decreased TIBC, elevated ferritin.
- Mild to moderate anemia; hemoglobin rarely <8 g/dL.

Epidemiology

  • Second most common anemia after iron deficiency anemia (IDA).
  • Worldwide, up to 40% of anemias involve ACD, affecting >1 billion individuals.

Etiology and Pathophysiology

  • Decreased RBC production due to functional iron deficiency.
  • Three major pathways from proinflammatory cytokines:
  • Iron restriction
  • Suppressed erythropoietin (EPO) production
  • Reduced erythrocyte survival (2)
  • Hepcidin production increased by IL-1, IL-6, BMP6 (1).
  • Hepcidin binds ferroportin → internalization and degradation → inhibits iron efflux from macrophages and hepatocytes → reduces iron absorption in duodenum.
  • Hepcidin may directly limit erythropoiesis (2).
  • EPO production and marrow response suppressed by IL-1, TNF-α, IFN-γ (1).
  • Cytokines may cause erythrophagocytosis and oxidative RBC damage.

Risk Factors

  • Hepatic and renal disease
  • Chronic infections
  • Autoimmune diseases

General Prevention

  • Timely identification and treatment of underlying disease.

Commonly Associated Conditions

  • Chronic inflammatory diseases: RA, SLE, sarcoidosis, temporal arteritis, IBD
  • Cancer and hematologic malignancies
  • Hepatic disease/failure
  • CHF, coronary artery disease
  • CKD
  • Chronic obstructive lung disease
  • Acute or chronic infections (viral: HIV, HCV; bacterial: abscess, endocarditis, TB, osteomyelitis)
  • Malignancies
  • Cytokine dysregulation of aging
  • Hypometabolic states: protein malnutrition, thyroid disease, panhypopituitarism, diabetes, Addison disease

Diagnosis

History

  • Often incidental finding on CBC.
  • Symptoms mild, vague: fatigue, light-headedness, palpitations.
  • Cardiovascular symptoms possible at Hgb 10-11 g/dL.

Differential Diagnosis

  • Iron deficiency anemia (IDA)
  • Anemia of CKD
  • Drug-induced marrow suppression or hemolysis
  • Endocrine disorders
  • Thalassemia
  • Sideroblastic anemia
  • Dilutional anemia

Diagnostic Tests

Test ACD IDA ACD + IDA
Hemoglobin (Hgb) <13 men, <12 women Low Low
MCV Normal (80-100 fL) Low (<80 fL) Low
RBC Morphology Normocytic, normochromic Microcytic, hypochromic Mixed
Serum Ferritin Normal/high (>100 µg/L) Low (<30 µg/L) Normal/high
Serum Iron Low (<50) Low Low
Total Iron Binding Capacity Low (<300) High Normal/high
Reticulocyte Count Low Low Low
Soluble Transferrin Receptor (sTfR)* Low/normal High High
Hepcidin High Low Normal
Erythropoietin (EPO) Normal/high High High
Inflammatory Markers High Normal High

*sTfR: Soluble Transferrin Receptor

  • Bone marrow biopsy with Prussian blue stain is gold standard but limited by qualitative nature.
  • Reticulocyte hemoglobin concentration <28 pg helpful.
  • Hepcidin ELISA assay aids differentiation.
  • sTfR and sTfR/log ferritin index differentiate ACD, IDA, and combined ACD+IDA.
  • Rule out B12 and folate deficiencies.

Treatment

General Measures

  • Treat underlying condition (1).
  • Anemia typically resolves with primary disease treatment.
  • When primary treatment impossible (terminal cancer, ESRD), consider:
  • Erythropoiesis-stimulating agents (ESAs)
  • Blood transfusions

Medications

ESAs

  • Approved for CKD; some evidence in RA, IBD, HIV, some cancers (avoid in active malignancy not on curative therapy).
  • Indicated for Hgb <10 g/dL.
  • Not effective in mild CHF anemia.
Epoetin-α
  • Indications: Hgb <10, fatigue, CKD (eGFR <60), anemia in IBD, RA, hepatitis C, palliative chemo.
  • Dose: 50-100 U/kg SC/IV thrice weekly (CKD); 150 U/kg SC thrice weekly or 40,000 U weekly (chemo).
  • Adverse: cardiovascular risks, thromboembolism, pure red cell aplasia, tumor progression risk.
Darbepoetin-α
  • Long-acting EPO, half-life 3-4x longer than epoetin-α.
  • Dose: SC/IV every 1-2 weeks; hold if Hgb >12 g/dL.

  • Similar adverse effects as epoetin-α.

  • Discontinue if no Hgb rise after 6-8 weeks.

Iron Supplementation

  • Indicated in combined ACD + IDA.
  • Oral: ferrous sulfate (GI side effects, poor absorption).
  • IV: ferric gluconate, iron sucrose, iron dextran, ferumoxytol (allergic risks).
  • May stimulate hepcidin, worsening iron restriction but can reduce ESA needs.

Transfusions

  • For severe or life-threatening anemia.
  • Restrictive transfusion threshold: Hgb 7-8 g/dL in asymptomatic.
  • Higher threshold (>10 g/dL) for cardiac/pulmonary disease, active ACS, elderly, bleeding.
  • Risks: infection, volume overload, transfusion reaction.
  • Rapid anemia correction benefit.

Future Directions

  • Hepcidin antagonists
  • Anti-BMP, anti-IL-6 antibodies
  • Ferroportin stabilizers
  • Vitamin D (lowers hepcidin)
  • Heparin (impairs hepcidin transcription)

Ongoing Care

Follow-Up

  • Avoid raising Hgb >12 g/dL due to increased mortality risk.
  • Monitor transferrin saturation and ferritin every 3 months.

Diet

  • Balanced diet rich in fruits, vegetables, legumes, and iron.

Patient Education

  • Risks of medical therapies: mortality, cardiovascular complications, thromboembolism, cancer progression.

Complications

  • Anemia-related: mortality, cardiovascular complications, functional symptoms.
  • ESA-related: increased mortality, thromboembolism, cancer progression risk.

References

  1. Gangat N, Wolanskyj AP. Anemia of chronic disease. Semin Hematol. 2013;50(3):232-238.
  2. Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019;133(1):40-50.
  3. Karlsson T. Evaluation of hepcidin ELISA assay for differential diagnosis of iron deficiency anemia and anemia of inflammation. J Inflamm (Lond). 2017;14:21.

Additional Reading

  • Besarab A, Bolton WK, Browne JK, et al. Effects of normal vs low hematocrit in cardiac disease with hemodialysis and epoetin. N Engl J Med. 1998;339(9):584-590.

See Also

  • Anemia, Iron Deficiency

ICD10 Codes

  • D63.1 Anemia in chronic kidney disease
  • D63.8 Anemia in other chronic diseases classified elsewhere

Clinical Pearls

  • ACD is second most common clinical anemia.
  • Distinguishing ACD from IDA and combined ACD+IDA is a frequent diagnostic challenge.
  • Iron levels alone are usually nondiagnostic.
  • Use transferrin/TIBC, TSAT, sTfR, sTfR index, hepcidin, and ferritin for differentiation.
  • Maintain Hgb in low to normal range; avoid repletion beyond 12 g/dL.