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New Treatments for Anemia of Chronic Disease

The definition of anemia of chronic disorders is that this is a hypo-proliferative anemia and it accompanies a variety of chronic non-hematological conditions, such as infections, malignancies, immunologic disorders and chronic traumatic disorders. All of these conditions have in common an inflammatory response to the underlying disorder. That’s the sine qua non and prerequisite for this diagnosis. This is the most common anemia that we see in hospitalized adults in the United States. Now worldwide, malaria and probably some other causes would outnumber this, but in the United States this is the most common cause of anemia that we see. It’s typically a mild anemia.

Now what kind of chronic conditions can be associated with the anemia of chronic disorders? There are a number of chronic infections that are associated with this condition, such as tuberculosis, lung abscess, endocarditis, fungal infections, AIDS, and the list can go on and on. There are noninfectious inflammatory conditions associated with the anemia of chronic disorders and these can include rheumatic arthritis, rheumatic fever, systemic lupus erythematosus, regional enteritis, ulcerative colitis and various types of vasculitides. Malignancies are typically associated with the inflammatory response and these can range from non-metastatic carcinomas.

What is the etiology of the anemia of chronic disorders? Well, we know there is an underlying inflammatory process, but we still don’t really know the precise mechanism of this anemia but we have some clues and some windows into it. One is that there is a moderately shortened erythrocyte life span. The survival is moderately reduced to the 60-90 day range, instead of the normal 90-120 day range. This is possibly secondary to increased phagocytosis by macrophages and splenic activity. It’s interesting that if you take the patient’s red blood cells and give them to a normal recipient the red blood cell survival tends to be normal. The anemia of chronic disorders is associated with distinctively altered iron metabolism. The inflammatory response is associated with a decreased serum iron concentration and a decreased total iron-binding capacity, and decreased serum transferrin concentration.

Inflammatory cytokines have been linked to this condition. In the inflammatory response there is increased production of tumor necrosis factor alpha, interleukin 1, and interferon gamma. Both tumor necrosis factor alpha and interleukin 1 lead to reduced serum iron concentrations and a shift of iron into the storage form in the bone marrow. There is also some evidence that these cytokines can inhibit erythropoietin production. Interleukin 1 itself is one of the stimulators of interferon gamma production by T lymphocytes and both tumor necrosis factor alpha and interferon gamma have been shown to suppress erythropoiesis. So that in this condition of the anemia of chronic inflammation you have a moderate reduction in red blood cell survival, you have a shift of iron into storage form from active form, and you have a certain degree.

To make the diagnosis of the anemia of chronic disorders; first of all you exclude other forms of anemia. You exclude iron deficiency, B12 folate deficiency, hemoglobinopathies, immune hemolytic anemias, etc. and then you confirm that there is a hypo-proliferative anemia, i.e. the reticulocyte count is not increased, the LDH is not increased. You find consistent iron metabolism measurements and you find the setting of an underlying chronic inflammatory.

How do you demonstrate that there is a hypo-proliferative anemia? It’s pretty basic but it’s good to review some of these basic matters. One, the reticulocyte count is not increased. Two, the heptoglobin is not reduced, the indirect bilirubin is normal and the LDH is normal. All of these features tend to support a hypo-proliferative anemia that you would then document with a bone marrow biopsy. But it’s not necessary to make the diagnosis, usually in this condition. You find consistent iron metabolism measurements. These include a low serum iron, a low total iron binding capacity, a low transferrin concentration, low iron saturation of transferrin, a normal

I’d like to take this opportunity to return a little bit to the pattern of iron metabolism and the common laboratory measures that we see in the anemia of chronic disorders and compare it to what we see in normal and iron deficiency. Because I think this tends to be what we deal with chronically in the wards and what I would expect the Board to deal with this issue of how we distinguish the anemia of chronic disorders from iron deficiency of various degrees. First of all, let’s review again normal iron metabolism. In this schema, which was developed by

Then let’s look at iron metabolism in iron deficiency. First of all, as iron deficiency develops - say somebody develops a small colorectal cancer and they begin to lose a little bit of iron every day - first of all, before frank iron deficiency develops all you have is a reduction in the iron stores. So that your body is geared to maintain the functional iron compartment and the red cells circulating in the blood and the muscles and parenchymal cells in the liver, and if there is a small chronic blood loss it’s going to take it out of stores in the spleen and the bone marrow, or in the macrophages of the liver. In this early stage of iron depletion or loss of iron, the only

In contrast to this setting we have the iron metabolism in the anemia of chronic disorders, and now we are going to contrast what happens to chronic inflammatory stimulus, to the body’s iron compartments, and to the body’s red blood cell compartments to that of the chronic depletion of iron. So in this setting what is similar to iron deficiency anemia is that we have a reduction in functional iron in the circulating red blood cells. But what we have here is we have an expansion of the storage iron in the liver and the bone marrow. We have a slight expansion of storage iron in the Kupffer cells of the liver. So we have a shift. Basically what we have done.

Here are the clinical indicators of iron status. The plasma ferritin concentration is greater than 50, and indeed usually tends to be greater than even 100 to 200, although it can be in the normal range. That’s different from iron deficiency. What’s similar to iron deficiency is that we have a low transferrin saturation. This is also similar to iron deficiency; we have an elevated red blood cell protoporphyrin concentration, but this is in distinction to iron deficiency; we have.

Okay, how about the therapy of the anemia of chronic disorders? Most patients have a self-limited anemia that needs no specific therapy and the treatment should be directed to the underlying inflammatory disorder. We need to diagnose this disorder and provide treatment for it. In fact, there is some indication that the inflammatory response and the mild anemia that occurs in this setting is part of the body’s response that has developed to infection.

Selected patients may benefit from erythropoietin, sometimes in combination with parenteral iron. Especially if the serum ferritin is in the lower range of normal, rather than above 200. Again, usually even though the anemia of chronic inflammation does respond to EPO, usually we don’t need to treat it. Now if the underlying inflammatory process is very very severe, and therefore the anemia of chronic disease in this setting is severe enough that you would consider giving a blood transfusion, well that’s an indication that this is the unusual patient that may