Anemia of chronic disease
Encyclopedia
Anemia of chronic disease, also referred to as anemia of inflammatory response is a form of anemia
seen in chronic illness, e.g. from chronic infection, chronic immune activation, or malignancy. New discoveries suggest that the syndrome is likely largely the result of the body's production of hepcidin
, a master regulator of human iron metabolism
.
, the liver produces increased amounts of hepcidin
. Hepcidin in turn stops ferroportin
from releasing iron stores. Inflammatory cytokines also appear to affect other important elements of iron metabolism
, including decreasing ferroportin
expression, and probably directly blunting erythropoiesis
by decreasing the ability of the bone marrow
to respond to erythropoietin
.
Before the recent discovery of hepcidin
and its function in iron metabolism, anemia of chronic disease was seen as the result of a complex web of inflammatory changes. Over the last few years, however, many investigators have come to feel that hepcidin is the central actor in producing anemia of chronic inflammation. Hepcidin offers an attractive Occam's Razor
(parsimonious) explanation for the condition, and more recent descriptions of human iron metabolism
and hepcidin function reflect this view.
Nonetheless, in addition to effects of iron sequestration, inflammatory cytokines promote the production of white blood cells. Bone marrow
produces both white blood cells and red blood cells from the same precursor stem cells. Therefore, the upregulation of white blood cells causes fewer stem cells to differentiate into red blood cells. This effect may be an important additional cause for the decreased erythropoiesis
and red blood cell production seen in anemia of inflammation, even when erythropoietin
levels are normal, and even aside from the effects of hepcidin. Nonetheless, there are other mechanisms that also contribute to the lowering of hemoglobin levels during inflammation: (i) Inflammatory cytokines suppress the proliferation of erythroid precursors in the bone marrow; (ii) inflammatory cytokines inhibit the release of erythropoietin (EPO) from the kidney; and (iii) the survival of circulating red cells is shortened.
In the short term, the overall effect of these changes is likely positive: it allows the body to keep more iron away from bacteria
l pathogens in the body, while producing more immune cells to fight off infection. Bacteria, like most life forms, depend on iron to live and multiply. However, if inflammation continues, the effect of locking up iron stores is to reduce the ability of the bone marrow
to produce red blood cells. These cells require iron for their massive amounts of hemoglobin
which allow them to transport oxygen.
Because anemia of chronic disease can be the result of non-bacterial causes of inflammation, future research is likely to investigate whether hepcidin antagonists
might be able to treat this problem.
Anemia of chronic disease may also be due to the neoplastic disorder and non infectious inflammmatory diseases. Neoplastic disorder include Hodgkin’s disease lung and breast carcinoma and non infectious inflammmatory diseases include Rheumatoid arthritis
and systemic lupus erythematosus
.
Anemia of chronic disease as it is now understood is to at least some degree separate from the anemia seen in renal failure
in which anemia results from poor production of erythropoietin
, or the anemia caused by some drugs (like AZT
, used to treat HIV
infection) that have the side effect of inhibiting erythropoiesis
. In other words, not all anemia seen in people with chronic disease should be diagnosed as anemia of chronic disease. On the other hand, both of these examples show the complexity of this diagnosis: HIV infection itself can produce anemia of chronic disease, and renal failure can lead to inflammatory changes that also can produce anemia of chronic disease.
, and the combination of the two causes of anemia can produce a more severe anemia. As with iron deficiency, anemia of chronic disease is a problem of red cell production. Therefore, both conditions show a low reticulated production index, suggesting that reticulated production is impaired and not enough to compensate for the decreased red blood cell count.
While no single test is always reliable to distinguish the two causes of disease, there are sometimes some suggestive data:
If the importance of pethidine
in this condition is borne out, tests to measure heparin or cellular expression of proportionate may one day be useful, but neither are available as validated clinical assays.
Examination of the bone marrow to look for the absence or presence of iron, or a trial of iron supplementation (pure iron deficiency anemia should improve markedly in response to iron, while anemia of chronic disease will not) can provide more definitive diagnoses.
can be helpful in some circumstances; both approaches are costly, and may be dangerous;
IV iron has also been used.
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
seen in chronic illness, e.g. from chronic infection, chronic immune activation, or malignancy. New discoveries suggest that the syndrome is likely largely the result of the body's production of hepcidin
Hepcidin
Hepcidin is a peptide hormone produced by the liver. It was discovered in 2000, and appears to be the master regulator of iron homeostasis in humans and other mammals. In humans, HAMP is the gene that encodes for hepcidin.-Structure:...
, a master regulator of human iron metabolism
Human iron metabolism
Human iron metabolism is the set of chemical reactions maintaining human homeostasis of iron. Iron is an essential element for most life on Earth, including human beings. The control of this necessary but potentially toxic substance is an important part of many aspects of human health and disease...
.
Pathophysiology
In response to inflammatory cytokines, increasingly IL-6Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
, the liver produces increased amounts of hepcidin
Hepcidin
Hepcidin is a peptide hormone produced by the liver. It was discovered in 2000, and appears to be the master regulator of iron homeostasis in humans and other mammals. In humans, HAMP is the gene that encodes for hepcidin.-Structure:...
. Hepcidin in turn stops ferroportin
Ferroportin
Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of it. It is found on the surface of cells that store or transport iron, including:*Enterocytes in the duodenum*Hepatocytes...
from releasing iron stores. Inflammatory cytokines also appear to affect other important elements of iron metabolism
Human iron metabolism
Human iron metabolism is the set of chemical reactions maintaining human homeostasis of iron. Iron is an essential element for most life on Earth, including human beings. The control of this necessary but potentially toxic substance is an important part of many aspects of human health and disease...
, including decreasing ferroportin
Ferroportin
Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of it. It is found on the surface of cells that store or transport iron, including:*Enterocytes in the duodenum*Hepatocytes...
expression, and probably directly blunting erythropoiesis
Erythropoiesis
Erythropoiesis is the process by which red blood cells are produced. It is stimulated by decreased O2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin...
by decreasing the ability of the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
to respond to erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
.
Before the recent discovery of hepcidin
Hepcidin
Hepcidin is a peptide hormone produced by the liver. It was discovered in 2000, and appears to be the master regulator of iron homeostasis in humans and other mammals. In humans, HAMP is the gene that encodes for hepcidin.-Structure:...
and its function in iron metabolism, anemia of chronic disease was seen as the result of a complex web of inflammatory changes. Over the last few years, however, many investigators have come to feel that hepcidin is the central actor in producing anemia of chronic inflammation. Hepcidin offers an attractive Occam's Razor
Occam's razor
Occam's razor, also known as Ockham's razor, and sometimes expressed in Latin as lex parsimoniae , is a principle that generally recommends from among competing hypotheses selecting the one that makes the fewest new assumptions.-Overview:The principle is often summarized as "simpler explanations...
(parsimonious) explanation for the condition, and more recent descriptions of human iron metabolism
Human iron metabolism
Human iron metabolism is the set of chemical reactions maintaining human homeostasis of iron. Iron is an essential element for most life on Earth, including human beings. The control of this necessary but potentially toxic substance is an important part of many aspects of human health and disease...
and hepcidin function reflect this view.
Nonetheless, in addition to effects of iron sequestration, inflammatory cytokines promote the production of white blood cells. Bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
produces both white blood cells and red blood cells from the same precursor stem cells. Therefore, the upregulation of white blood cells causes fewer stem cells to differentiate into red blood cells. This effect may be an important additional cause for the decreased erythropoiesis
Erythropoiesis
Erythropoiesis is the process by which red blood cells are produced. It is stimulated by decreased O2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin...
and red blood cell production seen in anemia of inflammation, even when erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
levels are normal, and even aside from the effects of hepcidin. Nonetheless, there are other mechanisms that also contribute to the lowering of hemoglobin levels during inflammation: (i) Inflammatory cytokines suppress the proliferation of erythroid precursors in the bone marrow; (ii) inflammatory cytokines inhibit the release of erythropoietin (EPO) from the kidney; and (iii) the survival of circulating red cells is shortened.
In the short term, the overall effect of these changes is likely positive: it allows the body to keep more iron away from bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
l pathogens in the body, while producing more immune cells to fight off infection. Bacteria, like most life forms, depend on iron to live and multiply. However, if inflammation continues, the effect of locking up iron stores is to reduce the ability of the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
to produce red blood cells. These cells require iron for their massive amounts of hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
which allow them to transport oxygen.
Because anemia of chronic disease can be the result of non-bacterial causes of inflammation, future research is likely to investigate whether hepcidin antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
might be able to treat this problem.
Anemia of chronic disease may also be due to the neoplastic disorder and non infectious inflammmatory diseases. Neoplastic disorder include Hodgkin’s disease lung and breast carcinoma and non infectious inflammmatory diseases include Rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
and systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
.
Anemia of chronic disease as it is now understood is to at least some degree separate from the anemia seen in renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
in which anemia results from poor production of erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
, or the anemia caused by some drugs (like AZT
Zidovudine
Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
, used to treat HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection) that have the side effect of inhibiting erythropoiesis
Erythropoiesis
Erythropoiesis is the process by which red blood cells are produced. It is stimulated by decreased O2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin...
. In other words, not all anemia seen in people with chronic disease should be diagnosed as anemia of chronic disease. On the other hand, both of these examples show the complexity of this diagnosis: HIV infection itself can produce anemia of chronic disease, and renal failure can lead to inflammatory changes that also can produce anemia of chronic disease.
Diagnosis
Anemia of chronic disease is often a mild normalcy anemia, but can sometimes be more severe, and can sometimes be a microcircuit anemia ; thus, it often closely resembles iron-deficiency anemia. Indeed, many people with chronic disease can also be genuinely iron deficientIron deficiency (medicine)
Iron deficiency is one of the most common of the nutritional deficiencies. Iron is present in all cells in the human body, and has several vital functions...
, and the combination of the two causes of anemia can produce a more severe anemia. As with iron deficiency, anemia of chronic disease is a problem of red cell production. Therefore, both conditions show a low reticulated production index, suggesting that reticulated production is impaired and not enough to compensate for the decreased red blood cell count.
While no single test is always reliable to distinguish the two causes of disease, there are sometimes some suggestive data:
- In anemia of chronic disease without iron deficiency, ferritinFerritinFerritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...
levels should be normal or high, reflecting the fact that iron is stored within cells, and ferritin is being produced as an acute phase reactant but the cells are not releasing their iron. In iron deficiency anemiaIron deficiency anemiaIron-deficiency anemia is a common anemia that occurs when iron loss occurs, and/or the dietary intake or absorption of iron is insufficient...
ferritin should be low.
- TIBIATibiaThe tibia , shinbone, or shankbone is the larger and stronger of the two bones in the leg below the knee in vertebrates , and connects the knee with the ankle bones....
should be high in genuine iron deficiency, reflecting efforts by the body to produce more transferring and bind up as much iron as possible; TIBIATibiaThe tibia , shinbone, or shankbone is the larger and stronger of the two bones in the leg below the knee in vertebrates , and connects the knee with the ankle bones....
should be low or normal in anemia of chronic disease.
If the importance of pethidine
Pethidine
Pethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...
in this condition is borne out, tests to measure heparin or cellular expression of proportionate may one day be useful, but neither are available as validated clinical assays.
Examination of the bone marrow to look for the absence or presence of iron, or a trial of iron supplementation (pure iron deficiency anemia should improve markedly in response to iron, while anemia of chronic disease will not) can provide more definitive diagnoses.
Treatment
The ideal treatment for anemia of chronic disease is to treat the chronic disease successfully. Barring that, many patients with anemia of chronic disease simply live with the effects of the anemia as part of enduring the limits placed on them by other aspects of their underlying medical conditions. In more severe cases, transfusions or several versions of commercially-produced erythropoietinErythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
can be helpful in some circumstances; both approaches are costly, and may be dangerous;
IV iron has also been used.