Hematology

Anemia of chronic inflammation

Anemia of chronic inflammation

What every physician needs to know:

The anemia of inflammation is a common cause of anemia found in those with cancer, chronic infection, and rheumatological conditions, among others. The diagnosis of the anemia of inflammation is often difficult, and is primarily one of exclusion. Treatment should be focused on the underlying condition, though exogenous erythropoietin can be effective.

Are you sure your patient has anemia of inflammation? What should you expect to find?

Because of its chronicity, association with only a mild anemia (hemoglobin approximately 10g/dl), and the presence of other underlying conditions, the symptoms directly attributable to the anemia of inflammation are typically mild.

The anemia of inflammation is typical microcytic or normocytic, and not associated with other abnormalities in the blood (with the exception of occasional leukocytosis and thrombocytosis seen with inflammation).

Iron studies typically show low serum iron, low total iron binding capacity (TIBC), and an elevated percentage saturation. Ferritin is often elevated.

An underlying inflammatory condition should be present (see "Which individuals are most at risk for developing anemia of chronic inflammation?").

A complete physical exam and standard serological work-up should be performed to exclude vitamin deficiency, erythropoietin deficiency, and/or a paraproteinemia. Typically a bone marrow exam should not be necessary, but may be required to exclude other causes of anemia or to diagnose an underlying inflammatory condition.

Beware of other conditions that can mimic anemia of inflammation:

Other conditions that can mimic anemia of inflammation

Other conditions that can mimic anemia of inflammation are iron deficiency, erythropoietin deficiency, and myelodysplastic disorders. However, the classic triad of low serum iron and transferrin levels, with a normal or elevated ferritin, should lead one to suspect the anemia of inflammation.

Which individuals are most at risk for developing anemia of inflammation:

Although this anemia is most associated with classic inflammatory conditions (for example, cancer, infection, rheumatological disorders), other conditions such as heart failure and diabetes have been described as also leading to the anemia of inflammation.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

There is no single set of laboratory results that definitively rules in or rules out the diagnosis of anemia of inflammation. Iron studies (low serum iron, low TIBC, and elevated ferritin) in the setting of a mild microcytosis are typical.

Serum erythropoietin may be elevated, but often not as elevated as in those with other forms of anemia (for example, iron deficiency).

Erythrocyte sedimentation rate is often elevated, though mild elevations may be seen in any anemia.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of anemia of inflammation?

While imaging studies are typically not helpful, they may be necessary to undercover an underlying inflammatory condition that is causing the anemia, and may be helpful to rule out other causes of anemia.

If you decide the patient has anemia of inflammation, what therapies should you initiate immediately?

If it is thought that the anemia is severe enough to cause symptoms, and often those with the anemia of inflammation have additional comorbid conditions which may make any anemia more symptomatic, transfusion may be necessary.

More definitive therapies?

The most effective therapy is to reverse the underlying cause of inflammation, although this may be difficult.

Exogenous erythropoietin has been demonstrated to be effective in a majority of patients, and may improve quality of life. There are limited data that erythropoietin therapy may be more effective with iron supplementation. However the risks of erythropoietin use in those with cancer, particularly those undergoing chemotherapy, must be considered. The use of erythropoietin may be counter-productive in other patient populations as well; the target hemoglobin should not be above 10g/dl.

What other therapies are helpful for reducing complications?

There are no other specific treatments known to be useful. Rather, addressing the underlying inflammatory condition as soon as possible is the preferred approach.

What should you tell the patient and the family about prognosis?

Typically, the anemia of inflammation is mild. Although this anemia may be a poor prognostic indicator for some conditions (for example, heart failure), the anemia per se is typically not directly related to morbidity or mortality.

What if scenarios.

The most common pitfall in the diagnosis and treatment of the anemia of inflammation is when one is diagnosed with this condition without consideration of other causes, specifically myelodysplastic conditions, mild aplastic anemia, or erythropoietin deficiency due to renal disease. The suspicion of the anemia of inflammation should trigger an evaluation for the underlying inflammatory condition, if not otherwise known.

Pathophysiology

The pathophysiology of the anemia of inflammation is complicated and multi-factorial.

To various degrees, this anemia is caused by:

  • Shortened life-span of the erythrocyte

  • A relative erythropoietin deficiency

  • Poor response to the erythropoietin present

  • Hampered erythroid differentiation

  • Very abnormal iron utilization

Inflammatory cytokines, particularly tumor necrosis factors (TNFs) and interleukin 6 (IL-6) are thought to play a major role in all of these defects. More recently, the role of the peptide hormone hepcidin has been emphasized as one of the leading causes of the anemia of inflammation. Hepcidin, which is elevated in inflammatory conditions due to cytokines, inhibits iron transport out of the reticuloendothelial cells, gut cells, and macrophages, and thus makes iron unavailable to the erythrocyte.

What other clinical manifestations may help me to diagnose anemia of inflammation?

A complete physical exam is required to search for underlying inflammatory conditions that could be causing the anemia of inflammation, and other conditions which could mimic the anemia of inflammation.

Special care should be paid to fever patterns, inflammation in the joints, lymphadenopathy, splenomegaly, and a loss of vibratory sense that may be seen with B12 deficiency.

Stool should be examined for occult blood, and age appropriate cancer screening should be performed.

What other additional laboratory studies may be ordered?

In the future, a test for hepcidin may be helpful for cases which are difficult to diagnose.

What’s the evidence?

Sasu, BJ, Cooke, KS, Arvedson, TL. "Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia". Blood. vol. 115. 2010. pp. 3616-24.

[This study points the way to possible use of hepcidin modulation to manage anemia.]

Roy, CN, Mak, HH, Akpan, I. "Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation". Blood. vol. 109. 2007. pp. 4038-44.

[Proof of the concept of the role of hepcidin in anemia of inflammation.]

Bohlius, J, Wilson, J, Seidenfeld, J. "Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients". J Natl Cancer Inst. vol. 98. 2006. pp. 708-14.

[A study suggesting that erythropoietin may have some, although limited utility in anemia of inflammation.]
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