Anemia of Chronic Disease

Anemia of chronic disease (ACD) or anemia of inflammation refers to the mild or moderately severe form of anemia, usually associated with chronic inflammatory disorders, infections and cancers. The amount of circulating iron in the serum is low, but body stores remains more or less normal.

Overview

Anemia of chronic disease (ACD) or anemia of inflammation is the hypoproliferative anemia associated with chronic or acute immune activation [1]. After iron deficiency anemia, this is the second most common form of anemia. This condition was earlier thought to be associated with inflammation, infections and malignancies. Studies show that the clinical scope of anemia of chronic disease can now be expanded to include many other syndromes in which cytokines launch an inflammatory or immune response [2]. As the number of patients with chronic inflammatory conditions increase, the prevalence of this condition is expected to increase. ACD presents itself as a mild or moderately severe condition, and is characterized by slightly increased levels of erythropoietin and reduced amount of reticulocytes. Levels of leukocytes and platelets depend on the underlying disease that causes anemia. The most characteristic feature is the increase of non-heme iron storage [3].

Etiology

Etiology of ACD is multifactorial and is marked by low levels of iron in the serum. Iron stores are found to be normal or slightly elevated. ACD is a normocytic, normochromic anemia and falls under the category of anemia due to decreased red blood cell (RBC) production. Reduced response to erythropoietin and diversion of iron from serum to storage also are suspected to be responsible for anemia. Shortening of half-life of RBC’s may add to be another etiologic factor for the development of this condition. Diseases like rheumatoid arthritis, diabetes mellitus, heart disease and trauma are all conditions associated with decreased iron availability, erythropoietin levels and decreased life span of RBCs and hence may lead to ACD [4].

One of the recent studies report that hepcidin, an antimicrobial peptide secreted by liver, is one of the important factors in regulating serum iron levels. This endogenous peptide is considered to be involved in controlling absorption of iron in the intestine, release of iron from macrophages and transfer of iron from the stores. Inflammatory diseases increase the levels of hepcidin, which in turn brings alteration in iron metabolism through reduced absorption and storing of the element in macrophages, leading to hypoferremia [5].
Some another causative factors of ACD are interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF-alpha) [6]. These cytokines are known to destroy precursors of RBCs and decrease the levels of erythropoietin receptors [7]. IL-6 induces the production of hepcidin.

Epidemiology

Males have a 30% increased risk of developing ACD when compared to females. Prevalence of the condition ranges from 8% to 44% in elderly patients. Prevalence of ACD is greater in people above the age group of 85 years. About one third of patients with anemia has ACD. Among the general population, it is found in 11% of men while 10.2% of women are affected by this condition, particularly in the age group of 66 to 85 years. About 52% of the patients with anemia, but without iron deficiency, filled the criteria of ACD.

The most common risk factors for developing ACD include chronic inflammatory conditions like auto immune disorders, neoplasia, chronic kidney disease, acute or chronic infections, and chronic rejection after organ transplantation. Alcoholic liver disease, congestive heart failure, thrombosis, chronic pulmonary disease, diabetes mellitus, and other medical conditions also may precipitate ACD.

Pathophysiology

Alteration in the homeostasis of iron, proliferation of erythropoietin precursors, and reduction in life span of RBCs all play an important role in the development of ACD. As the infection or inflammation sets in, concentration of iron in the serum falls as a defensive mechanism to prevent proliferation of microbes. This reduction is brought about by the action of interleukins through production of the micropeptide hepcidin. The peptide binds to the iron efflux channel causing a considerable reduction in the efflux of iron. Increased use of iron from the serum reduces the extracellular pool of the element. This indirectly reduces the amount of iron reaching the site of heme synthesis.

Increased production of hepcidin by the cytokines affects absorption of dietary iron in the intestine. The demand of iron is high during infection and inflammation and this remains a long-lasting situation. Hepcidin affects the release of iron from the storage affecting the homeostasis of iron in the serum. Cytokines are also known to affect erythroid progenitors, reducing erythropoiesis. Inflammation increases removal of senescent RBCs through activation of macrophages. This causes a slight change in the life span of RBCs, adding to iron deficiency.

Prognosis

Prognosis of ACD often depends on underlying cause of the disease. Severity of symptoms and the sudden onset of the condition may also play an important role in the outcome. Some other factors that my influence the prognosis of ACD are age of the patient and presence of comorbid conditions.

Presentation

Clinical manifestations of ACD depend on the underlying disease that causes the condition. Many patients remain asymptomatic as anemia in itself may not present with any specific symptoms. When present, some of the common symptoms of the disease include pallor, fatigue, lethargy, irritability and loss of stamina. Increased tiredness, tachycardia, and breathlessness are also seen. Some less common symptoms of ACD include decreased tolerance for physical stress, palpitations, disturbed sleep, loss of appetite, myalgia, lightheadedness, and chest discomfort. Decreased cognitive ability, pallor of conjunctiva, orthostatic hypotension and ascites may be noted as physical findings.

Workup

Before confirming on ACD, other diseases that present with normochromic and normocytic anemia should be excluded. Conditions of liver and endocrine system also should be evaluated. Differential diagnosis would include aplastic anemia, myeloid metaplasia, liver cirrhosis, hyperthyroidism, hypoadrenalism, hypothyroidism and, primary and secondary hyperparathyroidism.

Laboratory tests are important in the evaluation of ACD. Tests that are of confirmatory value include RBC count, peripheral blood smear, reticulocyte count, and bone marrow biopsy. For differential diagnosis, serum levels of vitamin B12 and folic acid, serum bilirubin, heavy metals, iron panel and TSH would be of help. Patients with ACD may have adequate levels of reticulocyte in the serum, but with serum iron, total iron-binding capacity and transferrin may remain low. Measuring serum levels of ferritin helps in diagnosis as it is directly related to stores of iron. About 1µg/L of ferritin in serum corresponds to approximately 8 mg of stored iron. ACD is often characterized by increased levels of ferritin associated with immune activation seen in inflammatory diseases. ESR is elevated in most of the cases of ACD.

RBCs may be normochromic and normocytic, but in some cases hypochromic and microcytic. This is particularly noticed in case of Crohn disease and rheumatoid arthritis. Soluble transferrin receptor levels are also indicative of ACD as this is a mark of iron stores in the bone marrow. This helps to differentiate ACD from iron deficiency anemia [8].

Treatment

Treating the underlying disease or disorder is the initial therapy step to improve the symptoms. Care should be taken to treat confounding factors like concomitant blood loss, deficiencies of iron, vitamin B12, and folic acid. In most of the cases, degree of anemia is mild and may not require any specific treatment. In case of iron deficiency, steps should be taken to replenish the element.

In some rare cases, ACD may be severe and exacerbate the underlying cardiac and pulmonary disease. In cases of manifestations of cardiac ischemia, erythrocyte transfusion helps to resolve hypoxia and improve symptoms of ischemia. If symptoms cannot be resolved without complete treatment of the underlying disease, erythropoietin with or without iron is recommended.

In chronic cases of ACD, agents that stimulate erythropoiesis including epoetin alpha and darbepoetin alpha are suggested. As these proteins have a greater serum half-life, Hb levels can be maintained effectively for a longer duration [9]. Erythropoiesis-stimulating agents are given in case of rheumatoid arthritis, heart failure and malignancy [10]. Patients with chronic kidney failure, cancer patients undergoing chemotherapy, and those with HIV infections should be treated to improve the Hb level to more than 12 g/dl. In acute cases of ACD with severe form of anemia with Hb level lesser than 8.0 g/dl, blood transfusion is the recommended modality. This is particularly important if bleeding is continuous. Transfusion also helps to improve condition in patients with myocardial infarction.

Prevention

Patients with chronic diseases and cancer should monitor Hb levels to ensure that anemia does not set in.

Patient Information

Anemia of chronic disease (ACD) or anemia of inflammation refers to the mild or moderately severe form of anemia usually associated with chronic inflammatory disorders, infections and cancers. The amount of circulating iron in the serum is low but body stores remain more or less normal. This condition is more prevalent among men above the age of 85 years. ACD forms the second most common form of anemia, next only to iron deficiency anemia. About one third of the patients with anemia fall in this category. A number of risk factors increase the chance of developing ACD. This includes autoimmune disorders like rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus. Cancer, kidney disease and infections also are associated with increased risk of ACD.

Patients may not present any specific symptoms of ACD. In general, fatigue, pale skin, muscle pain and breathlessness are the most common symptoms of this form of anemia. A number of factors result in ACD. This includes:

  • Increased uptake of iron into the cells
  • Inadequate transfer of iron from the body stores
  • Reduced life span of red blood cells
  • Reduced production of red blood cells

A detailed history and physical examination are needed to check for the presence of this condition. Lab tests including RBC count, blood smear, level of iron and sometimes bone marrow biopsy are suggested for diagnosis of ACD. Hemoglobin levels of these patients normally fall in the range of 8 to 9 g/dl. Levels of iron in the serum will be lower than normal.

Treatment of the underlying condition is the first step in any modality. For those with very mild symptoms of anemia may not require any specific treatment. In chronic cases of ACD, agents that help to improve production of red blood cells are used in the treatment. Treatment aims to increase hemoglobin levels to more than 12 g/dl, particularly in patients who are undergoing chemotherapy, patients with chronic kidney disease and those infected with HIV. If symptoms of anemia are severe with Hb level falling lower than 8 g/dl, blood transfusion is suggested. If the condition is complicated with ongoing bleeding, blood transfusion helps to maintain the Hb level in normal range. Although ACD is a part of many other diseases, monitoring the Hb levels, particularly in patients with chronic kidney disease, cancer and inflammatory disorders, help to prevent anemia.

References

  1. Cash JM, Sears DA. The anemia of chronic disease: spectrum of associated diseases in a series of unselected hospitalized patients. Am J Med. 1989;87(6):638.
  2. Means RT Jr. Recent developments in the anemia of chronic disease. Curr Hematol Rep. 2003;2(2):116.
  3. Baynes RD, Flax H, Bothwell TH, et al. Haematological and iron-related measurements in active pulmonary tuberculosis. Scand J Haematol. 1986;36:280-287. 
  4. Besarab A, Levin A. Defining a renal anemia management period. Am J Kidney Dis. 2000;36(6 suppl 3):S13-23.
  5. Roy CN, Mak HH, Akpan I, et al. Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood. 1 2007;109(9):4038-44.
  6. Raj DS; Role of Interleukin-6 in the Anemia of Chronic Disease. Semin Arthritis Rheum. 2009;38(5):382-388.
  7. Taniguchi S, Dai CH, Price JO, Krantz SB. Interferon gamma downregulates stem cell factor and erythropoietin receptors but not insulin-like growth factor-I receptors in human erythroid colony-forming cells. Blood. 15 1997;90(6):2244-52.
  8. Koulaouzidis A, Said E, Cottier R, et al. Soluble transferrin receptors and iron deficiency, a step beyond ferritin. A systematic review. J Gastrointestin Liver Dis. 2009;18(3):345-52.
  9. Macdougall IC; Novel erythropoiesis-stimulating agents: a new era in anemia management. Clin J Am Soc Nephrol. 2008;3(1):200-7.
  10. Scrijvers D, Roila F. Erythropoiesis-stimulating agents in cancer patients: ESMO recommendations for Ann Oncol. 2009;20 Suppl 4:159-61.

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