Anemia of Chronic Disease - Anemia of Inflammation

Anemia of chronic disease (ACD), also known as anemia of inflammation (AI), is a functional anemia of iron-restricted erythropoiesis related to chronic diseases, such as infections, autoimmune diseases, cancer, and end-organ failure.   ACD/AI is the second most common form of anemia after iron deficiency anemia (IDA) and the most common form of anemia in hospitalized or critically ill patients.   Testing for ACD/AI includes standard blood parameter measurements, a peripheral blood smear, iron studies, testing to exclude other possible diagnoses, and in some cases, bone marrow biopsy.  ACD/AI testing should be interpreted in the appropriate clinical context.  Treatment for ACD/AI entails treatment of the underlying disease or disorder; however, this is often not feasible.  Iron therapy and erythropoiesis-stimulating agents may be used to alleviate anemia and thereby improve patient quality of life.   

Quick Answers for Clinicians

Which laboratory tests can be used to distinguish between anemia of chronic disease/anemia of inflammation and iron deficiency anemia?

Iron indices are complicated in the face of inflammation, and may be further confounded by concomitant anemia of chronic disease/anemia of inflammation (ACD/AI) and iron deficiency anemia (IDA). In both ACD/AI and IDA, insufficient functional iron is available for erythropoiesis. In IDA, mean corpuscular volume (MCV) is often (although not always) reduced, whereas MCV is usually normal in ACD/AI. Similarly, cells are often hypochromic in IDA, whereas they are frequently normochromic in ACD/AI.  Total iron binding capacity (TIBC) and soluble transferrin receptor levels are increased in IDA, but normal or decreased in ACD/AI. Both serum iron and transferrin saturation (Tsat) are decreased in both IDA and ACD/AI.     See Laboratory Testing to Distinguish Between ACD/AI and IDA table, below.

What are special testing considerations for patients with inflammatory conditions that affect iron status?

Anemia of chronic disease/anemia of inflammation (ACD/AI) is a common complication in many conditions that affect iron status, including inflammatory bowel disease (IBD) and chronic kidney disease (CKD). IBD leads to problems in iron and vitamin absorption, and thus may result in ACD/AI with concomitant iron deficiency anemia and megaloblastic anemia. Normocytic anemia is also frequently observed in CKD. Anemia in CKD results primarily from decreased erythropoiesis, and may be exacerbated by hemolysis, iron deficiency, hemorrhage, medication toxicity, chronic infections, and other factors ; patients with CKD may therefore demonstrate simultaneous ACD/AI and iron deficiency. Regular anemia workups are recommended for both patient populations. For more information on laboratory testing for anemia in patients with IBD or CKD, see the Iron Deficiency Anemia topic.

What differentiates testing in anemia of critical illness from testing in anemia of chronic disease/anemia of inflammation?

Anemia of critical illness can be severe and develops rapidly, often within a few hours or days,  resulting in a limited time frame for testing. Although further study is required, this rapid onset of anemia may result from reduced red blood cell production and survival,  as well as iatrogenic factors such as blood loss due to phlebotomy and medication.  Anemia of critical illness is treated via transfusion; to determine which patients require transfusion, a hemoglobin threshold of 70 g/L is recommended.  In patients with some conditions (eg, sepsis, traumatic brain injury, and cardiovascular disease), a higher hemoglobin threshold to trigger transfusion may be appropriate. 

What is the laboratory testing strategy for anemia of aging?

Anemia is a risk factor for morbidity, mortality, and other unfavorable outcomes in patients ≥65 years of age.  The prevalence of anemia in older adults increases with age, exceeding 20% in patients ≥85 years of age.  Given the potential for adverse outcomes, the evaluation of anemia in elderly adults is especially important if surgery or other procedures that may result in blood loss are planned. Furthermore, anemia in older adults is often associated with an underlying chronic condition, and iron indices may not be typical of younger adults.  Some experts recommend assessing iron status via serum ferritin or transferrin saturation (Tsat) tests following a finding of low hemoglobin. In patients who are iron deficient, consider evaluation for gastrointestinal malignancy and oral iron supplementation. In patients with replete iron stores, testing for chronic kidney disease (CKD) and vitamin deficiency is recommended, as well as assessment for other chronic or inflammatory conditions. 

Indications for Testing

Patients with hemoglobin (Hb) levels at least 2 standard deviations below the mean for age and sex (see Anemia) and a chronic or inflammatory condition should be evaluated for ACD/AI. Conditions in which ACD/AI is common include chronic infection, autoimmune disease, cancer, acute infection, chronic pulmonary obstructive disease, pulmonary arterial hypertension, obesity, chronic liver disease, and certain forms of heart disease. 

Laboratory Testing

Once anemia is confirmed, red blood cell (RBC) counts and morphology from a CBC can be used to further classify anemia. In general, ACD/AI presents as a normocytic anemia (cells have a normal mean corpuscular volume [MCV]), but may be microcytic in up to 25% of cases. A reticulocyte count is also recommended to assess bone marrow response to anemia and rule out conditions in which this response is elevated, such as hemolytic anemia.  Patients with anemia, a normal or low MCV, and a low corrected reticulocyte count or reticulocyte production index should be evaluated for ACD/AI.

Initial Evaluation

Iron Studies

Serum ferritin and total iron binding capacity (TIBC) are first-line tests to evaluate iron stores. Serum iron indices are complicated in ACD/AI: iron is sequestered, leading to ample stores, but is not made available for erythropoiesis.  Soluble transferrin receptor testing may also be useful.  IDA and ACD/AI may occur together, complicating diagnosis.   

Laboratory Testing to Distinguish Between ACD/AI and IDA
Parameter ACD/AI IDA
Serum iron Low to normal Low
TIBC Low High
Tsat Low Very low (<10%)
Serum ferritin High Low
Serum transferrin receptor Normal to slightly high High
MCV Normal Low
MCHC Normal Low
RDW Normal to slightly high High
Bone marrow iron High Low
Adapted from Kjeldsberg, 2010

MCHC, mean corpuscular hemoglobin concentration; RDW, red blood cell distribution width; Tsat, transferrin saturation

Ancillary Testing

Erythrocyte protoporphyrin is increased in ACD/AI, but not in conditions of abnormal heme synthesis, and thus may be useful in distinguishing ACD/AI from diseases such as thalassemia minor.  Serum and urine hepcidin levels may be increased in ACD/AI.  Although ongoing research in hepcidin testing is promising, there is no standardized or approved hepcidin assay, and this testing is not currently recommended for diagnosis of ACD/AI.   

Monitoring

Monitoring in ACD/AI depends on the treatment administered. Treatment of the underlying cause of inflammation often resolves anemia in patients with ACD/AI, which can be confirmed with a CBC (including measurements of Hb and hematocrit as well as serum ferritin and Tsat. 

ARUP Lab Tests

Initial Testing

Detect anemia; calculate MCV, MCHC, RDW

Assess bone marrow response to anemia

Evaluate iron stores

Calculate Tsat

Testing to Differentiate Between ACD/AI and IDA

Determine transferrin receptor levels

Ancillary Testing

Distinguish between ACD/AI and conditions of abnormal heme synthesis

Medical Experts

Contributor

Pearson

Lauren N. Pearson, DO, MPH
Assistant Professor of Clinical Pathology, University of Utah
Laboratory Director for ARUP at University of Utah Health and Huntsman Cancer Institute
Laboratory Director, South Jordan and Sugarhouse Health Center Clinical Laboratories

References

Resources from the ARUP Institute for Clinical and Experimental Pathology®