Anemia of chronic disease, also known as anemia of chronic inflammation, is caused primarily by infections, autoimmune disorders, chronic renal insufficiency, and malignancies (both hematologic and solid tumors).
It is the most prevalent cause of anemia in hospitalized patients and the second most common cause after iron deficiency anemia.
The following table include diseases associated with ACD
Infection
Malignancy
Auto Immune Condition
Renal Condition
Cardiac Condition
Viral
Bacterial
Parasitic
Fungal
Solid Tumors
Hematological Malignancy
Rheumatoid Arthritis
SLE and related conditions
Vasculitis
Sarcoidosis
Inflammatory bowel disease
Chronic Renal Failure
Chronic Heart Failure
SLE = Systemic lupus erythematosus
Pathophysiology of Anemia of Chronic Disease
ACD-related conditions share features of acute or chronic immune activation, with immune mechanisms playing a significant role in the observed anemia.
The pathophysiology of ACD is complex, but it can be summarized as three major causes, which are rooted in:
Increase in pro-inflammatory cytokines.
Increase in hepcidin plays a key role.
Inappropriate erythropoietin levels or hypo-responsiveness to erythropoietin, as well as erythropoiesis suppression in the bone marrow and reduced red blood cell survival.
The low serum iron levels seen in ACD patients are now known to be mediated by a polypeptide called hepcidin.
Hepcidin, which is produced in the liver, is essential for iron balance and transport.
Hepcidin production is increased by inflammatory cytokines, specifically interleukin (IL) 6, as well as iron overload, whereas levels decrease in iron deficiency.
Pathophysiology of anemia of chronic disease.
Summarized as three main causations rooted in increase
in pro-inflammatory cytokines: (i) increase in hepcidin
levels, (ii) inappropriate erythropoietin levels or hypo-responsive to erythropoietin, (and iii) suppression of
erythropoiesis in the bone marrow coupled with reduced
red blood cell survival. Abbreviation: EPO; erythropoietin.
Laboratory Characteristics of Anemia of Chronic Disease
ACD is a mild to moderate normocytic normochromic anemia, with less than 25% of cases showing microcytic hypochromic anemia, in which the mean corpuscular volume is rarely less than 70.
In contrast, iron deficiency anemia is microcytic, hypochromic, and has anisocytosis and poikilocytosis on a peripheral blood smear.
ACD patients have low serum iron, total iron-binding capacity, and transferrin saturation, which is accompanied by an increase in serum ferritin and bone marrow iron stores.
Serum iron, transferrin saturation, and ferritin are all low in iron deficiency anemia, while total iron-binding capacity is increased.
It can be difficult to distinguish between ACD and iron deficiency anemia based on available laboratory tests, and it’s even more difficult when the two conditions coexist.
How to distinguish between Anemia of Chronic Disease and Iron Deficiency Anemia
This can be done by measuring soluble transferrin receptors, which are truncated forms of the membrane receptors.
Soluble transferrin receptor levels are high in iron deficiency because iron availability is low, but soluble transferrin receptor levels are normal in ACD.
The difference between the two entities can also be determined by measuring serum hepcidin levels, but the problem remains the lack of a standard hepcidin assay.
Hepcidin levels are reduced in iron deficiency, and measuring hepcidin levels in blood or urine may be indicative of true iron deficiency.
Mass spectrometry and, more recently, enzyme-linked immunoassays (ELISA) have been developed for quantifying hepcidin in serum, plasma, and urine.
The Following table illustrates the laboratory investigations in the differential diagnosis of ACD
Laboratory Marker
ID without anemia
IDA
ACD
ACD/IDA
Hb
Normal
Low
Low
Low
MCV/MCH
Low
Low
Normal/Low
Low
Inflammatory Markers
Negative
Negative
High
High
Ferritin
Low
Low
Normal/High
Normal
Transferrin Saturation
Low
Low
Low
Low
sTfR/Log ferritin ratio
High
High
Low
High
Serum Hepcidin
Low
Low
Raised
Normal
ACD = Anemic of chronic disease; Hb = Hemoglobin; ID = iron deficiency; IDA = iron deficiency anemia; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; sTfR = soluble transferrin receptor.
Treatment of Anemia of Chronic Disease
Treatment for ACD aims to improve the blood’s oxygen-carrying capacity.
In the case of infections, autoimmune disorders, and malignancy, treatment is primarily directed at the underlying disease; however, most of these conditions are chronic, and eradication of the underlying disease is difficult.
The improvement of anemia contributes to the improvement of these patients’ quality of life.
The following table illustrates the currently available treatments either as conventional therapy or novel agents
Therapy types
Description
Dosing
Conventional
Red blood cell transfusions.
Intravenous iron with
erythropoiesis-stimulating agents.
Erythropoiesis-stimulating
agents
1–2 U, at the physician’s discretion
Iron sucrose 100 mg/dose
Iron dextran 25 mg test dose followed by
500 mg to 2,000 mgEpoetin-alpha, -beta 20,000 to 60,000 U
weekly.Darbepoetin 300 μg every 3 weeks
if hemoglobin <11 g/dL. Hold dose if
hemoglobin >12 g/dL.
Novel
Monoclonal antibodies
siRNA
Anticalins
Spiegelmers
BMP-HJV-SMAD inhibitors
IL-6 antagonists
JAK-STAT inhibitors
Ferroportin agonists/stabilizers
Direct hepcidin antagonists
mAb2.7, Ab12B9m
ALN-HPN
PRS-080
NOX-H94
LDN-193189
Tocilizumab
Siltuximab
AG490
PpYLKTK
Anti-ferroportin monoclonal antibody
Summary
Anemia of chronic disease, also known as anemia of chronic inflammation, is caused primarily by infections, autoimmune disorders, chronic renal insufficiency, and malignancies (both hematologic and solid tumors).
The pathophysiology of ACD is complex, but it can be summarized as three major causes, which are rooted in increase in pro-inflammatory cytokines, increase in hepcidin plays a key role and inappropriate erythropoietin levels or hypo-responsiveness to erythropoietin, as well as erythropoiesis suppression in the bone marrow and reduced red blood cell survival.
Measuring soluble transferrin receptors and hepcidin levels can be used to distinguish between anemia of chronic disease and iron deficiency anemia.
Treatment for ACD aims to improve the blood’s oxygen-carrying capacity.
The improvement of anemia contributes to the improvement of these patients’ quality of life. The currently available treatments either as conventional therapy or novel agents.
AP;, G. N. W. (2013, July). Anemia of chronic disease. Seminars in hematology. PubMed
Cullis, J. (2013, April). Anaemia of chronic disease. Clinical medicine (London, England). PubMed
Madu, A. J., & Ughasoro, M. D. (2017). Anaemia of Chronic Disease: An In-Depth Review. Medical principles and practice : international journal of the Kuwait University, Health Science Centre. PubMed
