Anemia of chronic disease: Year of the Zebra

Anemia of chronic disease refers to a low red blood cell, or RBC, count that may be associated with many chronic disease states like infections, malignancy, diabetes, or autoimmune disorders. The disease used to be called anemia of chronic inflammation because the underlying cause anemia is the continuous inflammation generated by chronic disease, which impairs iron metabolism and, in turn, RBC production. The anemia itself is usually mild and it’s the second most common type of iron deficiency anemia. 

RBCs are produced in the bone marrow, in response to erythropoietin - which is a molecule secreted by the kidneys in response to low levels of oxygen in the blood. Taking a closer look at our RBCs, we can see they’re loaded with millions of copies of the same exact protein called hemoglobin, which binds to oxygen and turns our RBCs into little oxygen transporters that move oxygen to all the tissues in our body. Zooming in even closer, each hemoglobin molecule is made up of four smaller heme molecules, which have iron right in the middle. Oxygen binds to the iron, so each hemoglobin molecule can bind four molecules of oxygen. In addition, iron is also an important part of proteins like myoglobin, which delivers and stores oxygen in muscles; and mitochondrial enzymes like cytochrome oxidase, which help generate ATP.

Now, we get the iron required for RBC production from our diet. Following breakdown of food in the stomach, iron is released, and then it’s absorbed in the small intestine - specifically, the duodenum. Inside the duodenal cells, iron molecules bind to a protein called ferritin, which temporarily stores the iron.  When iron is needed in the body, some iron molecules are released from ferritin and transported into the blood, where they bind to an iron transport protein called transferrin that carries iron to various target tissues and releases them there.

Now, the mechanisms that underlie anemia of chronic disease are complex and still under investigation. In general, the disease mechanism is a two fold process; decreased RBC lifespan and decreased RBC production. 

Shortened RBC lifespan is a result of direct cellular destruction via toxins from cancer cells, viruses, or bacterial infections. Decreased RBC production is a bit more complex and involves several mechanisms. 

The most important one, and the one that most researchers agree upon, involves dysregulation of iron homeostasis and the signals that control RBC production. In chronic disease states, chemical messengers called cytokines mediate this pathologic process in the kidney, immune system, and the GI tract.

Two cytokines called TNF-α and IFN-γ inhibit the production of erythropoietin in the kidney, which subsequently prevents RBC production in the bone marrow. Additionally, TNF-α  promotes RBC degradation in macrophages via phagocytosis, and IF-γ increases the expression of a protein channel called divalent metal transporter one on the surface of macrophages. This channel serves as a pathway for iron to enter the macrophage at increased rates, so less iron is available for the production of hemoglobin.

Another cytokine called IL-10 mediates the expression of increased ferritin receptors on the surface of macrophages, which then sequesters even more iron.