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Anemia, Chronic Disease
Christopher Lin-Brande, MD
Amy M. Davis, MD
image BASICS
DESCRIPTION
  • Otherwise known as anemia of chronic inflammation
  • During chronic systemic infection, inflammation, or malignancy, the production of proinflammatory mediators causes inhibition of erythropoiesis as well as the imbalance in iron homeostasis (1).
  • Anemia of chronic disease (ACD) is characterized as a normocytic, normochromic, hypoproliferative anemia and classically has low serum iron levels, elevated ferritin levels, and elevated total ironbinding capacity (TIBC) (1,2,3).
  • Anemia is typically mild to moderate with hemoglobin rarely <8 g/dL.
EPIDEMIOLOGY
Prevalence
ACD is the second most common anemia after iron deficiency anemia (IDA) due to the aging population and the high prevalence of chronic infections and inflammatory disorders in the United States (4).
ETIOLOGY AND PATHOPHYSIOLOGY
  • Production of red blood cells is decreased as a result of functional iron deficiency.
  • In general, the severity of the anemia will correspond with the severity of the underlying disease (1).
  • Proinflammatory cytokines such as interleukins (IL), tumor necrosis factor (TNF), bone morphogenic proteins (BMP), and interferons (IFN) create changes in iron homeostasis in several ways (1,4):
    • Dysregulating iron homeostasis
    • Diminishing proliferation as well as differentiation of red blood cell progenitor cells
    • Blunting the erythropoietic response
    • Increasing erythrocyte phagocytosis and apoptosis
  • Iron overload and the proinflammatory cytokines IL-1, IL-6, and BMP6 increase the production of the iron-regulating hormone hepcidin in hepatocytes, macrophages, and enterocytes (1,4).
    • Hepcidin binds to ferroportin causing internalization and degradation, which prevents efflux of iron from stores in macrophages and hepatocytes (reticuloendothelial cell iron blockade) and prevents iron absorption by duodenal enterocytes.
      • This results in low serum iron levels and inhibited erythropoiesis known as iron-restricted erythropoiesis.
    • As a result, iron delivery to erythroid progenitor cells within bone marrow is reduced and erythropoiesis is diminished, causing anemia.
  • Erythropoietin (EPO) production and the response to EPO by erythroid bone marrow is suppressed by proinflammatory cytokines such as IL-1,TNF-α, and IFN-γ (1).
  • Inflammatory cytokines may also cause erythrophagocytosis and oxidative damage, reducing RBC survival.
COMMONLY ASSOCIATED CONDITIONS
  • Chronic systemic diseases (2)
    • Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), sarcoidosis, temporal arteritis, inflammatory bowel disease (IBD), systemic inflammatory response syndrome (SIRS)
  • Hepatic disease or failure
  • Congestive heart failure or coronary artery disease
  • Chronic kidney disease (CKD)
  • Acute or chronic infections
    • Viral
      • HIV, HCV
    • Bacterial
      • Abscess, subacute bacterial endocarditis, tuberculosis, osteomyelitis
    • Fungal
    • Parasitic
  • Malignancies
  • Cytokine dysregulation (anemia of aging)
  • Hypometabolic states
    • Protein malnutrition, thyroid disease, panhypopituitarism, diabetes mellitus, Addison disease
image DIAGNOSIS
PHYSICAL EXAM
Physical exam findings are associated with the underlying condition.
DIFFERENTIAL DIAGNOSIS
  • IDA
  • Anemia of CKD
  • Drug-induced marrow suppression or hemolysis
  • Endocrine disorders
  • Thalassemia
  • Sideroblastic anemia
  • Dilutional anemia
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Hgb/Hct, MCV, reticulocyte count, ferritin, B12/folate, serum iron, TIBC
  • Hgb (1)
    • Typically, <13 g/dL in males or 12 g/dL in females
    • An Hgb of <8 g/dL typically suggests a concurrent secondary cause for the anemia.
  • Mean corpuscular volume (MCV)
    • Usually normal (80 to 100 fL), but microcytosis may be present with concurrent iron deficiency or long-standing disease (<25% of cases)
  • RBC morphology
    • Normocytic and normochromic
    • Increased protoporphyrin levels
  • Serum ferritin
    • Nonspecific acute phase reactant
    • Normal or slightly elevated (30 to 200 µg/L)
    • In CKD, ferritin can reach 800 µg/L.
    • Serum ferritin levels <30 µg/L suggests coexisting iron deficiency.
  • Serum iron levels
    • Low due to increased retention and decreased release from the RES
    • <50
  • TIBC
    • Extremely low
    • <300
  • Absolute reticulocyte count
    • Inappropriately low (reticulocyte index <20,000-25,000/µL) due to reduced erythropoiesis
  • Serum B12 and folate
    • Diminished due decreased absorption or lacking in diet

IDA

ACD

IDA+ACD

Iron

Low

Low

Low

Reticulocyte count

Low

Low

Low

Transferrin, TIBC

High

Low

Normal/high

Transferrin saturation

Low

Normal

Low

Ferritin

Low

Normal/high

Normal

sTfR index

High

Low

High

Hepcidin

Low

High

Normal

Inflammatory markers

Normal

High

High

Diagnostic Procedures/Other
  • Traditional gold standard: bone marrow biopsy with Prussian blue stainable iron combined with anemia, hypoferremia, and low TSAT (1,2,4)
    • Staining is qualitative and may not be accurate.
  • Reticulocyte Hgb concentration <28 pg (3)
  • Soluble transferrin receptor (sTfR) and the sTfR/log ferritin index (5)[A]
    • Ratio reflects erythropoiesis within bone marrow and differentiates among ACD, IDA, and ACD + IDA.
      • However, sTfR alone may have greater clinical value than the sTfR index because transferrin is not affected by chronic disease/inflammation, unlike ferritin.
  • Functional test: supplemental iron increase H/H in iron deficiency anemia and little effect on anemia of chronic disease
  • Although a known cause of anemia may be present, iron, B12, and folate deficiencies should be ruled out.
image TREATMENT
GENERAL MEASURES
  • Primary management should focus on the underlying cause of ACD (1,2,4).
    • Treatment of the primary disease will generally restore Hgb back to baseline.
  • In cases where primary treatment is not possible (e.g. terminal cancer, end-stage renal disease), additional treatment can be considered.
    • The two main forms of treatment are erythropoietin stimulating agents (ESAs) and transfusions.
    • ACD is frequently responsive to ESAs (epoetin-α, darbepoetin) in pharmacologic doses (6).
    • Replete iron to maximize ESA effectiveness.
    • Transfusion should only be initiated in severe anemia or acute symptoms.
  • Currently, no target Hgb exists but treatment to Hgb > 13 g/dL is associated with adverse outcomes (1).
  • Coexisting B12, or folate deficiency should be considered and corrected in severe cases of anemia (7)[B].
    • Reduced dietary intake of nutrients is common among patients who are chronically ill.
    • Patients who regularly undergo hemodialysis will often lose these during treatment.
P.47

MEDICATION
  • Erythropoietin-stimulating agents (ESAs)
    • Specifically approved for CKD, but there is evidence that they may also have applications in RA, IBD, HIV, and cancer
    • Indication for ESA therapy is an Hgb <10 g/dL (6)[C].
    • ESAs do not improve symptoms or outcomes in mild anemia of CHF (8)[A].
    • Do not use in certain cancers: breast, cervical, head and neck, lymphoid, and nonsmall cell lung cancers. Do not administer to patients with active malignancy not receiving curative therapy.
  • Epoetin-α (1,6,9)
    • Indications
      • Hgb <10 g/dL
      • Fatigue or exertional intolerance
      • CKD (eGFR <60 mL/min)
      • Anemia due to IBD, RA, hepatitis C
      • Chemotherapy in patients with specific malignancies (palliative therapy)
    • Dosing and schedule
      • Lowest effective dose to maintain a Hgb level generally between 10 and 12 g/dL (1,6,9)
      • CKD associated: Start 50 to 100 U/kg SC/IV 3 times per week.
    • Patients with cancer who are undergoing chemotherapy: 150 U/kg SQ 3 times per week or 40,000 units once a week.
    • Adverse affects:
      • Increased risk of cardiovascular complications, mortality, and thromboembolism
      • Pure red cell aplasia (decrease in Hgb, low reticulocyte count, normal WBC and platelets)
      • Risk of tumor progression in certain cancer patients
  • Darbepoetin-α
    • Long-acting, molecularly modified EPO preparation with a half-life 3 to 4 times longer than recombinant human EPO, reducing the frequency of injections to weekly or biweekly
    • Dosing and schedule
      • Administer SC/IV q1-2wk; hold if Hgb > 12 g/dL; IV route is preferred in hemodialysis patients.
    • Adverse affects
      • Similar to EPO
  • Epoetin-α or darbepoetin-α dose adjustments
    • Follow FDA-approved labeling.
    • Treatment beyond 6 to 8 weeks without appropriate rise of Hgb (>1 to 2 g/dL) is not recommended.
ADDITIONAL THERAPIES
  • Iron (6)
    • Indications
      • Coexisting iron deficiency
      • Resistance to EPO
    • Forms
      • Oral: ferrous sulfate. Poorly tolerated (GI side effects), incomplete absorption (due to hepcidin)
      • Intravenous: ferric gluconate. iron sucrose, iron dextran (potential allergic and anaphylactoid reactions), ferumoxytol
    • Adverse affects
      • May stimulate hepcidin production and exacerbate iron restriction
    • Benefits
      • Relatively safe
      • Inexpensive
      • May decrease ESA requirements (DRIVE study)
  • Transfusions
    • 1 to 2 U packed red blood cells (1)
    • Indications
      • Life-threatening/severe anemia: A “restrictive threshold” of Hgb 7 to 8 g/dL to guide transfusion in asymptomatic patients should be used (10)[A].
      • Patients with underlying cardiac or pulmonary disease, active ACS, elderly patients, or patients with acute bleeding or hemorrhagic shock may require transfusion at Hgb of higher threshold (>10 g/dL).
      • Symptomatic anemia (chest pain, SOB, reduced exercise capacity), and/or EKG changes
      • Lack of response to medical therapy
    • Possible adverse affects
      • Infection (HIV, hepatitis)
      • Volume overload
      • Transfusion reaction
    • Specific benefits
      • Rapid correction of anemia
    • When an infection occurs during EPO therapy, it is best to cease EPO therapy and rely on transfusion therapy instead until the infection is properly treated.
  • Future directions (1,4)
    • Antihepcidin antibodies, hepcidin-production inhibitors
    • Anti-BMP, anti-IL-6 antibodies
    • Ferroportin stabilizers
    • Vitamin D (lowers hepcidin)
    • Heparin (impairs hepcidin transcription)
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Referral to a hematologist is not always warranted.
Patient Monitoring
  • Hgb should not be increased > 11 to 12 g/dL because normalization of hemoglobin has been associated with higher mortality (9).
  • Baseline and periodic monitoring of transferrin saturation, and ferritin levels every 3 months may be of value (6).
PATIENT EDUCATION
Patients receiving medical therapy should be advised about the following possible risks:
  • Mortality, cardiovascular complications, thromboembolism, progression of cancer
PROGNOSIS
ACD does not typically progress.
REFERENCES
1. Gangat N, Wolanskyj AP. Anemia of chronic disease. Semin Hematol. 2013;50(3):232-238.
2. Cullis JO. Diagnosis and management of anaemia of chronic disease: current status. Br J Haematol. 2011;154(3):289-300.
3. Thomas DW, Hinchliffe RF, Briggs C, et al. Guidelines for the laboratory diagnosis of functional iron deficiency. Br J Haematol. 2013;161(5):639-648.
4. Nemeth E, Ganz T. Anemia of inflammation. Hematol Oncol Clin North Am. 2014;28(4):671-681.
5. Infusino I, Braga F, Dolci A, et al. Soluble transferrin receptor (sTfR) and sTfR/log ferritin index for the diagnosis of iron-deficiency anemia. A metaanalysis. Am J Clin Pathol. 2012;138(5):642-649.
6. Kidney Disease: Improving Global Outcomes Anemia Work Group. KDIGO Clinical practice guideline for anemia in chronic kidney disease. Kidney Inter Suppl. 2012;2(4):279-335.
7. Macciò A, Madeddu C, Gramignano G, et al. The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study. Haematologica. 2015;100(1):124-132.
8. Kansagara D, Dyer E, Englander H, et al. Treatment of anemia in patients with heart disease: a systematic review. Ann Intern Med. 2014;159(11):746-757.
9. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631-1634.
10. Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2012;(4):CD002042.
Additional Reading
  • Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339(9):584-590.
  • Fishbane S, Schiller B, Locatelli F, et al. Peginesatide in patients with anemia undergoing hemodialysis. N Engl J Med. 2013;368(4):307-319.
  • Macdougall IC, Provenzano R, Sharma A, et al. Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis. N Engl J Med. 2013;368(4):320-332.
  • Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019-2032.
  • Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;335(20):2085-2098.
  • Swedberg K, Young JB, Anand IS, et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013;368(13):1210-1219.
See Also
Iron Deficiency Anemia
Codes
ICD10
  • D63.8 Anemia in other chronic diseases classified elsewhere
  • D63.0 Anemia in neoplastic disease
  • D63.1 Anemia in chronic kidney disease
Clinical Pearls
  • ACD is the second most common anemia seen clinically.
  • One of the most common diagnostic problems is making the distinction between ACD, IDA, and combined ACD + IDA.
    • Iron level is usually nondiagnostic.
    • Use markers such as transferrin/TIBC, TSAT, and ferritin to distinguish. New markers are under development (hepcidin, sTfR, sTfR index).
  • IV iron should be given to all patients treated with ESAs.
  • Hemoglobin should be kept in low to normal range.