Anemia of Chronic Disease (ACD)

At a Glance

Anemia of chronic disease (ACD) is second in frequency as a common cause of anemia, with iron deficiency anemia being the most frequent cause of anemia. In some clinical circumstances, such as in cancer clinics, ACD is the most common presentation. The chronic diseases most frequently associated with this type of anemia include chronic inflammatory disorders, chronic infections, neoplasms, and end-organ failure. Chronic inflammatory disorders can include diseases ranging from rheumatoid arthritis to inflammatory bowel disease. HIV-1 infections and other types of chronic infections are also known to be associated with this anemia. ACD also has an association with chronic liver disease, chronic kidney disease, and endocrinologic disorders. Typically, ACD occurs in older patients of both sexes with an apparent underlying chronic disease. However, age itself, especially after 85 years of age, is an indicator for this presentation.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The complete blood count (CBC) shows no pathognomonic findings in the peripheral blood of patients with ACD. The anemia is generally mild to moderate in nature. It is not associated with a compensatory increase in reticulocytes. The hemoglobin levels range from 7.0 to 11.0 g/dL, and the red blood cells (RBCs) vary little with a normal or slightly increased red cell distribution width (RDW), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC; MCH and MCHC) may be mildly decreased. The erythrocytes are normocytic and normochromic and the white blood cells (WBCs) and platelets do not show morphologic abnormalities.

There is no specific single test for ACD. The four most commonly used screening tests are serum iron, TIBC (transferrin), percent transferrin saturation, and serum ferritin. ACD shows a normal or decreased serum iron, decreased TIBC, transferring saturation greater than 10%, and increased serum transferrin. This compares to iron deficiency anemia, which has increased TIBC, decreased serum iron, transferrin saturation of 10-25%, and decreased serum ferritin. No further analyses for anemia are required with results that confirm ACD in patients with a known cause of chronic disease, unless it is suspected that there is an occurrence of neoplasia (leukemia, lymphoma, etc.) or other disease that may involve the bone marrow.

If a bone marrow examination is indicated, ACD typically shows morphologically normal bone marrow elements present in normal quantity. Sideroblasts are decreased, whereas storage iron is increased. Iron is especially prominent with Prussian blue stain in marrow macrophages. Depending on the underlying chronic disease, features such as granulomas and metastatic tumor may also be present in the bone marrow.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

A representative normal range for serum iron is 60-180 µg/dL. TIBC has a range of 240-410 µg/dL. Percent transferrin saturation is typically 20-50%. Serum iron concentrations can show wide diurnal variations with the highest levels in the morning. Oral iron therapy should be withdrawn 24 hours before the blood sample is drawn, and iron levels should be collected consistently at a designated time of day. Iron dextran administration may elevate plasma iron for several weeks after administration. When iron deficiency anemia and inflammatory disease coexist, serum ferritin levels may be in the normal range. Ferritin is an acute-phase reactant and may also increase with acute inflammation.

When examining the bone marrow, hemosiderin granules are typically seen in cells of reticuloendothelial origin. Siderblasts are found with a frequency of every third or fourth (×50) oil immersion field in normal bone marrow. Macrophages with a marked increase in storage iron and a reduced number of siderblasts combined with iron deficient erythroid precursors is a characteristic presentation for ACD.

What Lab Results Are Absolutely Confirmatory?

No single test is absolutely confirmatory for ACD. However, the presentation is common enough that most diagnoses can be made with the screening tests previously described combined with careful clinical review for chronic disease. Most patients with ACD can be clearly identified at the initial clinical presentation or over several clinical visits when this testing is performed along with a careful review of systems and patient history. As noted, a bone marrow examination is not typically required, unless additional indications, such as leukemia, are revealed in the clinical assessment.

What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?

Free erythrocyte protoporphyrin levels may serve as an ancillary test in patients with ACD. Because the iron available for hemoglobin synthesis is decreased, free erythrocyte protoporphyrin levels are elevated. However, it is not typically performed in the initial evaluation of this disease. Several other tests have been added recently as options for diagnosing ACD. Soluble serum transferrin receptor concentrations may provide additional information in distinguishing ACD from overt iron deficiency anemia. ACD will show normal to mildly increased levels of receptors, whereas iron deficiency shows a marked increase in receptors. Complicated patients with both ACD and iron deficiency anemia may be analyzed by serial examination of serum transferrin receptor concentrations to determine the effect of iron therapy.

A novel marker, called hepcidin, may also prove useful in the identification of patients with ACD. Hepcidin is a small peptide hormone of 25 amino acids discovered in the serum by Ganz and colleagues in 2000. Smaller hepcidin forms occur in urine. Hepcidin is tightly folded with four disulfide bonds and acts as the principal regulator of iron hemeostasis in vertebrates. Hepcidin interacts with the primary protein for iron absorption in the intestines, which functionally reduces iron absorption. Hepcidin activity is also partially responsible for iron sequestration in ACD, and levels are elevated in patients with renal failure. Mutations of hepcidin and hepcidin regulators can result in juvenile hemochromatosis. Most studies have been performed in animal models, and it is not certain yet how hepcidin urine and serum measurements may be most useful in the analysis of ACD.

What Factors, If Any, Might Affect the Confirmatory Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

There is no single test that will confirm the presence of ACD. Thus, the use of the four primary screening tests in concordance is essential in reviewing a patient's status for this disease. Also, an accurate review of the patient's history and clinical findings is essential in the search for related chronic conditions. Some types of chronic conditions are especially notable, including chronic renal failure, AIDS, and liver disease. The primary cause of anemia in chronic renal failures is decreased erythropoiesis secondary to decreased or nonfunctional erythropoietin. Cytopenia is a common abnormality in patients with AIDS. HIV-1 may invade bone marrow progenitor cells, resulting in suppression of hematopoiesis. The classic liver disease associated with ACD is that induced by alcoholism. It is proposed that ineffective liver function results in inadequate hematopoeisis and iron loss due to bleeding.

Because the standard CBC may not reflect significant anemia or morphologic changes, ACD may be overlooked. Also, the screening test results may be normal or only marginally abnormal. Probably a significant number of ACD cases are simply observed given that the primary clinical effort is to manage the predominant primary chronic disorder (e.g., neoplasia). It is important to note that, in most circumstances, transfusion is not required and is not appropriate for ACD, unless other causes for anemia are identified. Recent evidence suggests that some patients with ACD may respond to erythropoietin therapy. However, such therapy is expensive and may have hazards related to enhancing neoplasia for some types of cancers, such as breast cancer.

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