Highlights & Basics
- Anemia of chronic disease (ACD) is characterized by anemia and evidence of immune system activation.
- Anemia is mainly due to decreased red blood cell production; may be aggravated by shortened red blood cell survival.
- Commonly found in acute and chronic infections; autoimmune disorders; chronic diseases; malignancy; after major trauma, surgery, or critical illness; and among older adults.
- Physical examination findings are those of the underlying disorder.
- Therapeutic approach is primarily treatment of the underlying disorder, although treatment of the anemia itself is sometimes appropriate.
Quick Reference
History & Exam
Key Factors
systemic symptoms of underlying condition
absent history of bleeding
physical finding suggesting infection
physical finding suggesting neoplasm
physical finding suggesting autoimmune disorder
Other Factors
absent history of high alcohol intake
absent history of exposure to chemicals and radiation
absent history of drugs known to be associated with risk of anemia
absent history of poor nutrition
decreased exercise tolerance
shortness of breath with exercise
fatigue
pallor
Diagnostics Tests
1st Tests to Order
Hb
WBC and differential
platelet count
mean corpuscular volume (MCV)
mean corpuscular hemoglobin concentration (MCHC)
peripheral blood smear
serum ferritin
serum iron
total iron-binding capacity
transferrin saturation
absolute reticulocyte count
serum creatinine
Other Tests to consider
C-reactive protein (CRP)
erythrocyte sedimentation rate
serum B12
serum folate
thyroid function tests
LFTs
indirect and direct bilirubin
LDH
erythropoietin
hemoglobin electrophoresis
bone marrow biopsy
soluble transferrin receptor
ratio of soluble transferrin receptor to log ferritin
Treatment Options
acute
mild to moderate anemia (hemoglobin [Hb] 8 to 11 g/dL)
mild to moderate anemia (hemoglobin [Hb] 8 to 11 g/dL)
underlying disorder not responsive to treatment and anemia is symptomatic, or imposes additional risk
severe (Hb <8 g/dL) or life-threatening (Hb <6.5 g/dL) anemia
treatment of underlying disease and red blood cell (RBC) transfusion
treatment of underlying disease and erythropoiesis-stimulating agents (ESAs)
supplemental iron
Definition
Classifications
Underlying cause of inflammation
Vignette
Common Vignette 1
Common Vignette 2
Other Presentations
Epidemiology
Etiology
Pathophysiology
Diagnostic Approach
Symptoms and signs
Initial investigations
- Mild to moderate anemia that is either normocytic normochromic or microcytic hypochromic
- Otherwise normal red blood cell (RBC) morphology
- Normal or elevated serum ferritin
- Transferrin saturation <15%
Subsequent investigations
People with low MCV
- A systematic search for bleeding
- Soluble transferrin receptor (sTfR) assay (elevated in iron deficiency and normal in ACD)
- Ratio of sTfR to log ferritin (>2 in iron deficiency or coexisting iron deficiency and ACD but <1 in ACD alone)
- Bone marrow exam for evaluation of iron stores
People with normal MCV
People with elevated MCV
Bone marrow examination, if not previously performed to evaluate iron store
- Abnormalities on the blood smear are not consistent with the underlying disorder causing ACD (e.g., low granulocytes, low platelets, markedly increased platelets, nucleated RBC, other circulating precursor cells)
- LDH is elevated without other adequate explanation
- No other explanation for the anemia is apparent (a situation more often encountered in people ages >50 years, given the rising incidence of myelodysplasia and the various hematologic malignancies with age).
Risk Factors
History & Exam
Tests
Differential Diagnosis
Iron deficiency anemia
Differentiating Signs/Symptoms
- Signs and symptoms of anemia may be identical to those of anemia of chronic disease (ACD). Evidence of bleeding, or a compelling cause for poor iron absorption, may be found in iron deficiency, whereas these are absent in ACD.
Differentiating Tests
- Ferritin is typically low in iron deficiency and normal or elevated (>100 nanograms/mL) in anemia of chronic disease (ACD). A ferritin level of <15 nanograms/mL strongly suggests iron deficiency, although different thresholds have been used (30 or 50 nanograms/mL).
- The transferrin saturation is typically <20% in iron deficiency; a value of <5% makes iron deficiency very likely.
- Total iron-binding capacity is typically elevated in iron deficiency anemia (IDA) (>400 micrograms/dL) and reduced (<250 micrograms/dL) in ACD.
- Bone marrow iron is absent in IDA.
Differentiating Signs/Symptoms
- There may be no differentiating symptoms or signs.
Differentiating Tests
- Soluble transferrin receptor (sFTR) is normal to increased. Ratio of sTfR to log ferritin is high (>2) when IDA and ACD coexist.[38]
Anemia associated with chronic renal disease (erythropoietin deficiency)
Differentiating Signs/Symptoms
- Symptoms and signs may be identical to those of anemia of chronic disease (ACD).
- Patient more likely to present with conditions related to chronic renal disease (e.g., diabetes, hypertension, polycystic kidney disease).
- Patients with end-stage renal disease, including those on dialysis, may have ACD in addition to anemia of renal disease.
Differentiating Tests
- Serum creatinine is typically at least mildly elevated. Rarely, only creatinine clearance is reduced, as in early diabetic chronic kidney disease.
- When ACD coexists with anemia of renal disease, ferritin (absent in iron deficiency) should be higher than otherwise, and C-reactive protein and erythrocyte sedimentation rate should be elevated.
B12 deficiency (e.g., pernicious anemia)
Differentiating Signs/Symptoms
- History of diet poor in vitamin B12, inflammatory bowel disease, or gastric bypass surgery.[4]
- Posterior column symptoms and signs (e.g., ataxia, gait abnormalities) may be present.
- Occasionally may be other neurologic symptoms and signs (e.g., peripheral neuropathy).
Differentiating Tests
- Anemia is typically macrocytic (MCV >100 fL).
- Serum B12 is low (<200 picograms/mL).
Folate deficiency
Differentiating Signs/Symptoms
- History of diet poor in folate, inflammatory bowel disease, or heavy alcohol use.[4]
Differentiating Tests
- Anemia is macrocytic (MCV >100 fL).
- Low serum folate (<2.5 nanograms/mL).
- Red blood cell folate level <140 nanograms/mL.
Thalassemia
Differentiating Signs/Symptoms
- The patient is more likely to have a family history of thalassemia.
- More common in certain ethnic groups (Mediterranean, south Asian, or east Asian ancestry).
Differentiating Tests
- Mean corpuscular volume is low and mean corpuscular hemoglobin concentration is relatively normal in thalassemia trait, and Hb A2 is increased.
- Blood smear shows microcytosis and significant poikilocytosis.
Differentiating Signs/Symptoms
- Appropriate history of exposure to radiation, chemicals, or medication, especially having recently started to take a drug known to cause anemia.
Differentiating Tests
- Bone marrow exam may show incipient or fully developed aplastic anemia.
- Absolute reticulocyte count is typically low for the degree of anemia in hypoplastic and aplastic anemia.
Primary hematologic disorder (e.g., myelodysplasia, multiple myeloma, leukemia, lymphoma)
Differentiating Signs/Symptoms
- Bone pain, history of recent fracture, purpura, ecchymoses, lymphadenopathy, hepatomegaly, splenomegaly are all more likely with primary hematologic disorder than with anemia of chronic disease.
Differentiating Tests
- Mean corpuscular volume normal or mildly increased. CBC may show leukopenia, granulocytopenia, thrombocytopenia, leukocytosis, or thrombocytosis. Peripheral smear may show precursor cells. Lactate dehydrogenase may be increased.
Criteria
- Mild anemia: 11.0 to 12.9 g/dL Hb
- Moderate anemia: 8.0 to 10.9 g/dL Hb
- Severe anemia: <8.0 g/dL Hb
Treatment Approach
Initial treatment of patients with mild to moderate anemia (Hb 8 to 11 g/dL)
Symptomatic anemia: underlying disorder not responsive to treatment
- Observation (for patients with mild to moderate ACD)
- Red blood cell (RBC) transfusion; or ESA (for patients with symptomatic anemia that significantly impairs their quality of life, or with comorbidities in which a mild to moderate anemia imposes additional risk (e.g., heart failure, significant pulmonary disease, cerebral vascular disease).
RBC transfusion
ESAs
Initiating ESA therapy
- Intravenous iron for chemotherapy-associated anemia, given regardless of the iron status, with baseline and periodic iron studies
- Consideration of intravenous iron in patients with functional iron deficiency (ferritin 30 to 500 ng/mL and transferrin saturation <50%)[68]
Severe (Hb <8 g/dL) or life-threatening (Hb <6.5 g/dL) anemia
Treatment Options
mild to moderate anemia (hemoglobin [Hb] 8 to 11 g/dL)
treatment of underlying disease and observation
Comments
- The level of anemia correlates with the activity of the underlying disease, and treatment of the underlying disorder usually improves or abolishes the anemia.
- Patients with mild to moderate anemia of chronic disease and an underlying condition that cannot be treated, or is not responsive to therapy, despite correction of iron deficiency, can usually be managed with simple observation.
underlying disorder not responsive to treatment and anemia is symptomatic, or imposes additional risk
red blood cell transfusion
Comments
- Transfusion is considered when the patient has symptomatic anemia that significantly impairs their quality of life, or with comorbidities in which a mild to moderate anemia imposes additional risk (e.g., heart failure, significant pulmonary disease, cerebral vascular disease).
- The benefit of red blood cells (RBC) transfusion must always be weighed against its potentially significant risks, which include volume overload, transfusion reaction, acute hemolysis with shock, delayed hemolytic transfusion reaction, transfusion-associated acute lung injury, alloimmunization, and iron overload.[51]
erythropoiesis-stimulating agents (ESAs)
Primary Options
- epoetin alfa
40,000 units subcutaneously once weekly; if Hb has not increased by at least 1 g/dL after 4 weeks, dose may be increased to 60,000 units once per week if iron status satisfactory
- epoetin alfa
- darbepoetin alfa
200 micrograms subcutaneously once every 2 weeks; may increase dose to 300 micrograms once every 2 weeks
- darbepoetin alfa
Comments
- ESAs are considered when the patient has symptomatic anemia that significantly impairs their quality of life, or with comorbidities in which a mild to moderate anemia imposes additional risk (e.g., heart failure, significant pulmonary disease, cerebral vascular disease).
- The decision to prescribe an ESA is made in consult with a specialist and requires evaluation of the reported efficacy and adverse effects.
- Red blood cell transfusion may be required until benefits of ESA therapy manifest. Absence of a response to ESA treatment should prompt a search for an additional cause of anemia.
- ESAs may be considered for patients with CKD not on dialysis who have hemoglobin (Hb) levels <10 g/dL. For patients with CKD on dialysis, ESA therapy may be used when Hb levels are between 9 and 10 g/dL, to avoid levels falling below 9 g/dL. Decisions about starting treatment and dosing should be individualized.[51]
- Guidelines recommend considering ESAs for patients with chemotherapy-associated anemia who have Hb levels <10 g/dL.[63] [68] [85] The Food and Drug Administration (FDA) stipulates that ESAs should not be used in patients receiving treatment with curative intent because of the potential risks of increased tumor progression and reduced survival; this is reflected in the US guidance.[63] [68] If there are uncertainties about curative intent, RBC transfusion should be considered before ESA therapy.[63]
- For patients with chronic kidney diease (CKD) and cancer, use of ESAs may only be considered with caution and careful evaluation of the risks and benefits.[51] Patients receiving palliative chemotherapy may benefit from carefully dosed ESAs in preference to transfusion.[68] ESAs are not typically recommended for patients with CKD receiving curative cancer treatment, or with a history of cancer or stroke.[51]
- There have been reports that ESAs reduce overall survival and, in some cancer patients, shorten time to tumor progression. Increased mortality and worsened outcomes have been reported with higher target Hb levels (>11 to 12 g/dL).[69] While some subsequent studies found no association between ESA use and increased mortality, uncertainty remains.[65] [70] [71] [72] [73]
- ESAs are associated with cardiovascular adverse effects, including increased thrombotic events and hypertension. Risk factors for venous thromboembolism should be evaluated and blood pressure controlled before treatment with an ESA. Pure red cell aplasia due to development of neutralizing antibodies to erythropoietin has been reported rarely, but may be increased with some recombinant formulations.[68]
- ESAs should be used at the lowest dose sufficient to reduce the need for RBC transfusions. Treatment should be discontinued in patients with chemotherapy-induced anemia if there is no response to an ESA after 6 to 8 weeks. There is no benefit in switching to another ESA if the initial ESA has not been effective.[63]
supplemental iron
Primary Options
- sodium ferric gluconate complex
consult specialist for guidance on dose
- sodium ferric gluconate complex
- iron sucrose
consult specialist for guidance on dose
- iron sucrose
- iron dextran
consult specialist for guidance on dose
- iron dextran
Comments
- Intravenous iron is preferred to oral iron because it is associated with a more rapid achievement of target Hb and decreased ESA requirement compared with oral iron.[54] [55] [56] [57] Currently available intravenous iron formulations appear to be well-tolerated, with low risk of infusion reaction.[58] [59] [60] [61]
- One Cochrane review found evidence to suggest that intravenous ferric carboxymaltose may be more effective than intravenous iron sucrose for the treatment of iron deficiency in people with inflammatory bowel disease.[62]
- • Intravenous iron for chemotherapy-associated anemia, given regardless of the iron status, with baseline and periodic iron studies
- • Consideration of intravenous iron in patients with functional iron deficiency (ferritin 30 to 500 ng/mL and transferrin saturation <50%)National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hematopoietic growth factors [internet publication].https://www.nccn.org/professionals/physician_gls/default.aspx
- A trial of intravenous iron is recommended for patients with chronic kidney diease who are receiving ESA therapy.[51]
- Iron supplementation, alongside ESA treatment, may improve hemoglobin response and reduce RBC transfusion requirements. Baseline and periodic iron studies are recommended.[63]
- Test doses may need to be given before starting therapy.
severe (Hb <8 g/dL) or life-threatening (Hb <6.5 g/dL) anemia
treatment of underlying disease and red blood cell (RBC) transfusion
Comments
- Commencing treatment for the underlying condition is important as the level of anemia correlates with disease activity, and its treatment usually improves or abolishes the anemia.
- RBC transfusion may be effective in severe or life-threatening anemia, depending on comorbid conditions and rate of anemia development.[17]
- Likely benefits of transfusion need to be balanced against possible risks (e.g., volume overload, transfusion reaction, acute hemolysis with shock, delayed hemolytic transfusion reaction, transfusion-associated acute lung injury, alloimmunization, iron overload).[51]
- Decisions about starting treatment should be individualized; some patient subgroups may benefit from RBC transfusion to maintain higher hemoglobin concentrations.[68]
treatment of underlying disease and erythropoiesis-stimulating agents (ESAs)
Primary Options
- epoetin alfa
40,000 units subcutaneously once weekly; if Hb has not increased by at least 1 g/dL after 4 weeks, dose may be increased to 60,000 units once per week if iron status satisfactory
- epoetin alfa
- darbepoetin alfa
200 micrograms subcutaneously once every 2 weeks; may increased dose to 300 micrograms once every 2 weeks
- darbepoetin alfa
Comments
- Important pre-emptive therapy in patients who may require transfusions urgently but for whom they may be unacceptable, unavailable, or carry excessive risk (e.g., Jehovah's Witnesses, those with rare blood types, or those with multiple alloantibodies).
- Concurrent supplemental intravenous iron should also be considered.
- The decision to prescribe an ESA is made in consult with a specialist and requires evaluation of the reported efficacy and adverse effects.
- Red blood cell transfusion may be required until benefits of ESA therapy manifest. Absence of a response to ESA treatment should prompt a search for an additional cause of anemia.
- ESAs may be considered for patients with chronic kidney diease not on dialysis who have Hb levels <10 g/dL. For patients with CKD on dialysis, ESA therapy may be used when Hb levels are between 9 and 10 g/dL, to avoid levels falling below 9 g/dL. Decisions about starting treatment and dosing should be individualized.[51]
- Guidelines recommend considering ESAs for patients with chemotherapy-associated anemia who have Hb levels <10 g/dL.[63] [68] [85] The FDA stipulates that ESAs should not be used in patients receiving treatment with curative intent because of the potential risks of increased tumor progression and reduced survival; this is reflected in the US guidance.[63] [68] If there are uncertainties about curative intent, RBC transfusion should be considered before ESA therapy.[63]
- For patients with CKD and cancer, use of ESAs may only be considered with caution and careful evaluation of the risks and benefits.[51] Patients receiving palliative chemotherapy may benefit from carefully dosed ESAs in preference to transfusion.[68] ESAs are not typically recommended for patients with CKD receiving curative cancer treatment, or with a history of cancer or stroke.[51]
- There have been reports that ESAs reduce overall survival and, in some cancer patients, shorten time to tumor progression. Increased mortality and worsened outcomes have been reported with higher target Hb levels (>11 to 12 g/dL).[69] While some subsequent studies found no association between ESA use and increased mortality, uncertainty remains.[65] [70] [71] [72] [73]
- ESAs are associated with cardiovascular adverse effects, including increased thrombotic events and hypertension. Risk factors for venous thromboembolism should be evaluated and blood pressure controlled before treatment with an ESA. Pure red cell aplasia due to development of neutralizing antibodies to erythropoietin has been reported rarely, but may be increased with some recombinant formulations.[68]
- ESAs should be used at the lowest dose sufficient to reduce the need for RBC transfusions. Treatment should be discontinued in patients with chemotherapy-induced anemia if there is no response to an ESA after 6 to 8 weeks. There is no benefit in switching to another ESA if the initial ESA has not been effective.[63]
supplemental iron
Primary Options
- sodium ferric gluconate complex
consult specialist for guidance on dose
- sodium ferric gluconate complex
- iron sucrose
consult specialist for guidance on dose
- iron sucrose
- iron dextran
consult specialist for guidance on dose
- iron dextran
Comments
- Intravenous iron is preferred to oral iron because it is associated with a more rapid achievement of target Hb and decreased ESA requirement compared with oral iron.[54] [55] [56] [57] Currently available intravenous iron formulations appear to be well-tolerated, with low risk of infusion reaction.[58] [59] [60] [61]
- One Cochrane review found evidence to suggest that intravenous ferric carboxymaltose may be more effective than intravenous iron sucrose for the treatment of iron deficiency in people with inflammatory bowel disease.[62]
- • Intravenous iron for chemotherapy-associated anemia, given regardless of the iron status, with baseline and periodic iron studies
- • Consideration of intravenous iron in patients with functional iron deficiency (ferritin 30-500 ng/mL and transferrin saturation <50%)National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hematopoietic growth factors [internet publication].https://www.nccn.org/professionals/physician_gls/default.aspx
- A trial of intravenous iron is recommended for patients with CKD who are receiving ESA therapy.[51]
- Iron supplementation, alongside ESA treatment, may improve hemoglobin response and reduce RBC transfusion requirements. Baseline and periodic iron studies are recommended.[63]
- Test doses may need to be given before starting therapy.
Emerging Tx
Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor
Methoxy polyethylene glycol-epoetin beta
High-dose extended-interval epoetin alfa
Prevention
Primary Prevention
Follow-Up Overview
Prognosis
Monitoring
Complications
Citations
KDIGO Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl. 2012;2(4):279-335.[Full Text]
Bohlius J, Bohlke K, Castelli R, et al. Management of cancer-associated anemia with erythropoiesis-stimulating agents: ASCO/ASH clinical practice guideline update. J Clin Oncol. 2019 Apr 10;37(15):1336-51.[Abstract][Full Text]
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hematopoietic growth factors [internet publication].[Full Text]
Aapro M, Beguin Y, Bokemeyer C, et al. Management of anaemia and iron deficiency in patients with cancer: ESMO clinical practice guidelines. Ann Oncol. 2018 Oct 1;29(suppl 4):iv271.
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Key Articles
Referenced Articles
Guidelines
Diagnostic
Summary
Recommendations regarding preferred diagnostic studies in anemic adults and children with chronic kidney disease.Published by
Kidney Disease: Improving Global Outcomes
Published
2012
Treatment
Summary
A comprehensive overview of the use of hematopoietic growth factors.Published by
National Comprehensive Cancer Network
Published
2023
Summary
Recommendations for use of erythropoiesis-stimulating agents in patients with cancer.Published by
American Society of Clinical Oncology; American Society of Hematology
Published
2019
Summary
Evidence-based recommendations regarding the use of iron agents for anemia.Published by
Kidney Disease: Improving Global Outcomes
Published
2012
Summary
Guideline on the management of chemotherapy-induced anemia.Published by
European Society for Medical Oncology
Published
2018