February 01, 2013
3 min read

‘The anemia of chronic disease’: An outmoded diagnosis

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A 38-year-old lawyer has suffered from classic rheumatoid arthritis during the past 10 years.

During that time, her hematocrit and hemoglobin have fallen steadily from normal levels to recent values of 30% and 10 g/dL. Her serum iron is 22 mcg/dL, with a total iron binding capacity of 160 mcg/dL. Her serum ferritin is elevated at 800 ng/mL. Her reticulocyte count is 1%.

It is a safe bet that many — if not most — readers of HemOnc Today would conclude that this woman has “anemia of chronic disease.” That diagnosis certainly would be in keeping with contemporary teaching, as well as common usage in major medical textbooks and journals.

However, this designation is meaningless and misleading; therefore, it should be discarded.

A number of unrelated chronic ailments are regularly associated with normocytic, normochromic anemia (see Table). In contrast to the others on this list, the anemia due to chronic inflammation has a distinct and compelling pathophysiology. In these patients, iron homeostasis is deranged (see Figure). Increased amounts of iron are stored in duodenal enterocytes and in macrophages in the bone marrow, liver and spleen. Iron-laden macrophages engender elevated levels of ferritin in serum.

Table. Anemia associated with chronic disorders 

There is a block in the transfer of this excess iron from both enterocytes and macrophages to the plasma, resulting in low levels of serum iron. For unclear reasons, the level of total transferrin in the serum also is low. Because of this limitation in iron availability, erythropoiesis is somewhat “iron deficient.”

Erythroid precursors in the bone marrow have decreased amounts of cytoplasmic iron, and the red cells that enter the circulation are slightly smaller than normal. The suppression of red cell production results in a low reticulocyte index.

Because this block in iron utilization is subtle, the degree of anemia in patients with chronic inflammation is rarely severe. If patients with inflammatory disorders have hemoglobin of less than 8 g/dL, it is essential to look for additional contributors such as bleeding or hemolysis.

In the last 5 years, the pathogenesis of the anemia of chronic inflammation has been greatly clarified by the realization that plasma hepcidin levels are markedly increased, as a direct result of induction by inflammatory cytokines.

As shown in the Figure, hepcidin binds to ferroportin — a transport protein essential for the transit of iron out of cells — and blocks both iron absorption from the gut and the egress of iron from macrophages. This monkey wrench in the machinery of physiologic iron transit explains both increased storage iron and reduced levels of serum iron.

Anemia due to chronic inflammation has a distinct and compelling pathophysiology. In these patients, iron homeostasis is deranged. 

Figure 1. Anemia due to chronic inflammation has a distinct and compelling pathophysiology. In these patients, iron homeostasis is deranged.

Source: Image courtesy of H. Franklin Bunn, MD reprinted with permission.

As the Table indicates, chronic inflammation usually is due to infection, tumor or — as in this patient’s vignette — a connective tissue disorder. Anemia in patients with cancer is roughly proportional to the tumor burden and to its ability to trigger an inflammatory response. Some secrete inflammatory cytokines as part of their profile of aberrant gene expression. In others, impairment of oxygen or nutrient supply to the interior of the tumor can result in necrosis and an inflammatory response.

Of course, readers of HemOnc Today are well aware of factors other than inflammation that can aggravate anemia in patients with cancer. Blood loss is common in gastrointestinal malignancies. In tumors such as leukemias and lymphomas, as well as those that have metastasized to bone, red cell production is further compromised by direct marrow involvement. Less often, patients with cancer develop microangiopathic or autoimmune hemolytic anemia.

So let’s put “anemia of chronic disease” into the trash bin of outmoded diagnoses where it can keep company with consumption, dropsy and dementia praecox. The patient presented in brief at the beginning of this piece has the anemia of chronic inflammation.

For more information:

H. Franklin Bunn, MD, is research director for the hematology division of Brigham and Women’s Hospital in Boston. He also is a HemOnc Today Editorial Board member. He may be reached at Harvard Medical School, 1 Blackfan Circle, KARP Building — CHRB 05.215, Boston, MA 02115; email: bunn@calvin.bwh.harvard.edu.

Disclosure: Bunn reports no relevant financial disclosures.