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Supplements Issues in Improving the Treatment of Anemia: Negotiating the Shifting Regulatory and Clinical Landsc

The Clinical and Economic Burden of Anemia

Robert E. Smith Jr, MD


Anemia is a prevalent condition that goes underrecognized and undertreated, yet still carries substantial costs for payers and is a burden on the health and quality of life of those diagnosed. Clinicians should recognize anemia of chronic diseases, such as cancer, chronic kidney disease, and human immunodeficiency virus infection, as a surrogate for more severe illness. Because of its prevalence and the health consequences associated with anemia, better detection and response is needed in vulnerable patient populations. Clinicians need to be more cognizant of the symptoms of anemia and more vigilant in its treatment to ensure better outcomes both clinically and financially.

(Am J Manag Care. 2010;16:S59-S66)


Anemia is a prevalent yet underrecognized and undertreated condition that imposes substantial costs to payers1,2 and negative consequences on the health and quality of life (QOL) of affected individuals.1,3-8 When anemia is associated with another disease, such as a cancer or kidney disease, it has adverse effects on the underlying disease, including worsening of symptoms,1,4,7,9 more rapid disease progression,7,10 and a poorer prognosis.1,7,10-21 Anemia is usually correctable, with resulting improvement in the health of the patient. Yet, clinicians concentrating on other aspects of a disease will often fail to recognize the need to treat the anemia associated with it, if the anemia is not alleviated by treating the primary disorder. For improved patient care, clinicians need to better understand that anemia is a predictor of a worse prognosis and higher treatment costs1,2-independent of the cost of anemia treatment-across a diverse group of disease processes.

Definition of Anemia

Anemia is a condition in which the number of circulating red blood cells, the concentration of hemoglobin (Hb), or the percentage volume of packed red blood cells in a centrifuged blood specimen (hematocrit [Hct]) is lower than normal.12 The World Health Organization criteria for anemia are Hb less than 12 g/dL in premenopausal women and less than 13 g/dL in men and postmenopausal women.12,22,23 Anemia can be an isolated condition, such as that caused by a nutritional deficiency (eg, iron, folate, vitamin B12),23,24 or it may develop secondary to another disease or its treatment.23,25-27

Anemia of chronic disease is the term used to describe anemia occurring in the setting of another illness that resolves if the underlying illness can be successfully treated. It is thought that this type of anemia is the consequence of a cytokine storm related to immune activation associated with the underlying disease, be it an infection, an inflammatory process, or a cancer.3,28 Acute or chronic immune activation causes inflammatory cytokine production, which reduces iron availability, impairs erythroid progenitor cell proliferation and erythropoietin production, and shortens red blood cell life span.3,29 When the comorbidity is kidney disease, accumulation of uremic toxins can also contribute to decreased erythropoiesis in addition to the decreased erythropoietin production.33,29 All of these changes result in anemia.


According to the Centers for Disease Control and Prevention (CDC), 5.5 million annual ambulatory care visits have anemia as their primary cause30; most often the anemia is due to a nutritional deficiency. A chronic disease is the second most prevalent cause of anemia,3 but the estimates of the particular disease responsible varies widely (Table).

Although anemia of chronic disease is common, it is underrecognized and undertreated.3 A claims database study examined approximately 2.3 million Medicare and commercial health plan members with solid tumors, chronic kidney disease (CKD), human immunodeficiency virus (HIV) infection, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), or congestive heart failure.22 Anemia was diagnosed in 3.5% of the patients, and of those, only 15% received an identified treatment for it.

Anemia Prevalence and Causes


Anemia occurs in up to 77% of patients with cancer,3 and is often overlooked, in part because many patients will not report fatigue (suggesting anemia) unless they are asked.4 Indeed, up to 60% of anemic cancer patients may receive no treatment for anemia.31 Anemia associated with a cancer can be due to many causes, such as blood loss, iatrogenic or otherwise, hemolysis, nutritional deficiency, marrow tumor, chemotherapy drugs, or hematophagic histiocytosis, but is most often caused by inflammatory cytokine production, which suppresses erythropoietin production and erythroid progenitor cell proliferation,3,32 and impairs iron metabolism due to upregulation of the iron-distributing regulator hepcidin.3,29

Chronic Kidney Disease

Anemia is also undertreated in CKD patients,13 especially those not undergoing dialysis. Of the approximately 20 million people in the United States with CKD, it is estimated that 2 million to 4 million have anemia.13 A large health maintenance study found 23% of patients with CKD had an Hct value less than 30%, and of those, only 30% were being treated for anemia.3 Other estimates of anemia prevalence in large CKD cohorts have ranged from 47% to 78%.10,33 Anemia has been found to increase as the glomerular filtration rate (GFR) declines, with anemia prevalences of 27% at GFR >60 mL/min/1.73 m2 and 76% at GFR <15 mL/min/1.73 m2.5 Even after renal transplantation, anemia was reported in 38.6% of recipients.34 The causes of anemia in CKD include insufficient erythropoietin production, iron or other nutritional deficiency, inflammation, and shortened red blood cell survival.13


Estimates of anemia prevalence in HIV-positive patients in the early 1990s reached 90%, then decreased to about 46% with the widespread adoption of highly active antiretroviral therapy (HAART).7 Anemia still occurs at high rates when HIV therapy regimens include zidovudine (AZT).7 The incidence of anemia increases with disease progression from HIV infection to autoimmune immunodeficiency syndrome (AIDS), with a correlation between CD4 T-lymphocyte counts and Hb levels.7,16 The causes of anemia in HIV/AIDS may include inflammatory cytokine production and suppression of hematopoiesis, decreased erythropoietin production and nutritional deficiency states in addition to renal disease,7 as well as the myelotoxic effects of AZT and other drugs.7,16 The use of HAART without AZT has been found to prevent or ameliorate anemia in some patients.7

Cardiovascular Disease

Anemia occurs frequently in cardiovascular disease, especially congestive heart failure.35,36 Estimates of anemia prevalence range from less than 10% in mild heart failure to greater than 40% in advanced heart failure.29 Anemia in congestive heart failure may be caused by excessive cytokine production, among other factors such as renal insufficiency.36

Hepatitis C

Anemia is common in hepatitis C infection,26,37 occurring in up to 67% of patients.26 In this condition, anemia is also associated with certain treatments used to combat the virus.26,37 Hemolytic anemia is a known adverse effect of ribavirin,26,37 and interferon may also induce anemia by a variety of mechanisms.26

Inflammatory Bowel Disease

Approximately one third of IBD patients have recurrent anemia,28 making it the most common IBD complication.37 In studies of Crohn's disease, the prevalence of anemia ranged from 10% to 73%, 9% to 74% in ulcerative colitis studies, and 17% to 41% in studies with IBD type unspecified.38 Anemia in IBD is caused by blood loss, iron malabsorption, and inflammation,37 and the inflammatory etiology is a classic example of the anemia of chronic disease.

Rheumatoid Arthritis

Anemia occurs in 30% to 60% of RA patients, with approximately one quarter of cases caused by iron deficiency, and three quarters attributed to chronic disease.39 The 2 types can be distinguished by the serum ferritin level; a ferritin level greater than 50 mcg/mL suggests anemia of chronic disease, whereas a lower level suggests iron deficiency anemia.39 In RA, iron deficiency anemia is usually caused by blood loss resulting from menstruation or gastrointestinal bleeding induced by nonsteroidal anti-inflammatory drugs.39 The anemia of chronic disease in RA is usually caused by inflammatory cytokines, which inhibit normal red blood cell formation and erythropoietin production.39

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