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Last updated: 9/18/2023
Years published: 2009, 2012, 2015, 2018, 2023
NORD gratefully acknowledges Robert T. Means, Jr., MD, Professor of Internal Medicine and Clinical Professor of Pathology, James H. Quillen College of Medicine, East Tennessee State University, for assistance in the preparation of this report.
Anemia of chronic disease, also called the anemia of inflammation, is a condition that can be associated with many different underlying disorders including chronic illnesses such as cancer, certain infections and autoimmune and inflammatory diseases such as rheumatoid arthritis or lupus. Anemia is defined by low levels of circulating red blood cells or hemoglobin, the part of red blood cells that carries oxygen. Anemia of chronic disease is usually a mild or moderate condition. In mild cases, anemia may not be associated with any symptoms or may cause fatigue, paleness of the skin (pallor) and lightheadedness. The underlying mechanisms that cause anemia of chronic disease are complex and not fully understood.
Anemia of chronic disease varies in severity from one person to another. In most people, anemia is usually mild or moderate. Affected individuals may develop a variety of symptoms such as fatigue, paleness of the skin (pallor), lightheadedness, shortness of breath, a fast heartbeat, irritability, chest pain and additional findings. These symptoms may occur in any individual who has a comparable degree of anemia. In most cases, the symptoms associated with the underlying disease usually take precedent over the mild or moderate anemia symptoms. In rare cases, anemia of chronic disease can be severe and cause more serious complications.
The exact cause of anemia of chronic disease may vary. Usually, several processes occur at the same time. Anemia can be caused by a slight shortening of normal red blood cell survival. In addition, the production of red blood cells (erythropoiesis) or of erythropoietin (a hormone that stimulates red blood cell production) may be impaired. Red blood cells carry oxygen to the body. The exact cause of anemia of chronic disease may depend upon the underlying condition. For example, cancer cells or inflammatory diseases like rheumatoid arthritis can cause the secretion of certain substances (cytokines) that may suppress production of erythropoietin or limit the ability of immature red blood cell progenitors to respond to erythropoietin. These cytokines may also have effects on iron metabolism, as discussed below. In some cases, cancer cells or disease-causing microorganisms may infiltrate the bone marrow, the soft spongy material found in long bones where blood cells are formed.
Researchers have also learned that individuals with anemia of chronic disease have an imbalance in the distribution of iron in the body and as a result cannot effectively use iron to create new blood cells despite having sufficient or elevated levels of iron stored in the tissues. Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found in many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low functional iron levels) or damage to affected organs (due to abnormally high iron levels in certain tissues).
Iron is needed to produce hemoglobin, a protein contained in red blood cells that carries oxygen. A key finding in anemia of chronic disease is increased uptake and retention of iron within certain cells that store and release iron, which leads to reduced amounts of functional iron that is available to produce hemoglobin. The lack of functional iron hinders the development of hemoglobin, which, in turn, reduces the amount of oxygen delivered throughout the body (anemia).
Researchers believe that the immune system, which remains constantly active in individuals with chronic diseases, produces substances that influence the development, storage and transport of iron within the body. Cells in the immune system produce cytokines, specialized proteins that stimulate or inhibit the function of other immune system cells.
Hepcidin, a hormone produced in the liver that helps regulate the metabolism and transport of iron within the body, plays a significant role in the development of anemia of chronic disease. Researchers believe a specific cytokine known as interleukin-6 (IL-6) stimulates the production of hepcidin in most cases, although hepcidin can also be produced in response to inflammation by pathways that do not involve IL-6. Excess hepcidin causes too much iron to be trapped within storage cells, lowering the amount of iron available to produce hemoglobin, thereby resulting in anemia. Most researchers think that hepcidin is a key factor influencing the development of anemia of chronic disease.
Anemia of chronic disease affects males and females in equal proportion. Individuals of any age who have a chronic, inflammatory condition can potentially develop the condition. The exact incidence of anemia of chronic disease is unknown and some researchers believe that it is underreported or often goes unrecognized. Anemia of chronic disease is believed to be the second most common cause of anemia in the United States after iron-deficiency anemia.
A diagnosis of anemia of chronic disease is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Such tests can measure the levels of certain substances in the body including hemoglobin levels, levels of iron in the serum, total iron binding capacity, overall red blood cell count, or normal or increased levels of ferritin in the blood. Ferritin is a protein that binds to iron and is used as an indicator of the bodyโs iron stores in the blood plasma. Another test that may be performed measures transferrin saturation. Transferrin is a protein that is involved in the transport of iron from the intestines into the bloodstream. Methods to allow the reliable measurement of hepcidin in plasma have been developed but are not available or approved for use in the diagnosis of anemia of chronic disease at present.
Treatment
The treatment of anemia of chronic disease is geared toward the underlying disease. If the treatment of the underlying disease is successful, anemia usually improves or resolves completely without direct treatment of its own.
Efforts to treat the anemia by correcting the iron imbalance in the body with therapies such as oral iron supplements or vitamins have generally proven ineffective. In some circumstances where transferrin saturation is very low, intravenous iron may partially correct anemia of chronic disease. On the other hand, increased iron stores may increase susceptibility to infections by iron-dependent organisms. More research is necessary to understand the complex mechanisms that ultimately result in anemia of chronic disease and what role, if any, that traditional therapies for anemia and iron imbalance have in the treatment of affected individuals.
In rare cases associated with severe anemia, blood transfusions or treatment with drugs that stimulate the production of erythropoietin (a hormone that stimulates red blood cell production) may be necessary. However, in some studies, individuals taking these therapies have done worse than individuals who do not take them. More research is necessary to determine the long-term safety and effectiveness of such therapies for the treatment of individuals with anemia of chronic disease.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Ganz T. Anemia of inflammation. N Engl J Med 2019; 381:1148-1157
Camaschella C, Nai A, Silvestri L. Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica. 2020 Jan 31;105(2):260-272.
Lasocki S, Longrois D, Montravera P, Beaumont C. Hepcidin and anemia in the critically ill patient: bench to bedside. Anesthesiology 2011;114:688-694.
Baribeault D, Auerbach M. Iron replacement therapy in cancer-related anemia. Am J Health Syst Pharm. 2011 May 15;68(10 Suppl 1):S4-14
INTERNET
The Merck Manual Home Health Handbook. Anemia of Chronic Disease. June 2023. Available at: https://www.merckmanuals.com/professional/hematology-and-oncology/anemias-caused-by-deficient-erythropoiesis/anemia-of-chronic-disease Accessed Sept 13, 2023.
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