Anemia of chronic disease

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Anemia of chronic disease
Other namesAnemia of chronic inflammation
Anemia of inflammation
Anemia of inflammatory response

Anemia of chronic disease (ACD) [1] [2] or anemia of chronic inflammation [3] is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin production and release from the liver. Hepcidin production and release shuts down ferroportin, a protein that controls export of iron from the gut and from iron storing cells (e.g. macrophages). As a consequence, circulating iron levels are reduced. Other mechanisms may also play a role, such as reduced erythropoiesis. It is also known as anemia of inflammation, [4] or anemia of inflammatory response. [5]

Contents

Classification

Anemia of chronic disease is usually mild but can be severe. It is usually normocytic, but can be microcytic. [6] The presence of both anemia of chronic disease and dietary iron deficiency results in a more severe anemia.

Pathophysiology

Anemia is defined by hemoglobin (Hb) concentration

In response to inflammatory cytokines, increasingly IL-6, [7] the liver produces increased amounts of hepcidin. Hepcidin in turn causes increased internalisation of ferroportin molecules on cell membranes which prevents release from 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 provides a unifying explanation for the condition, and more recent descriptions of human iron metabolism and hepcidin function reflect this view. [8]

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.; [9] (ii) inflammatory cytokines inhibit the release of erythropoietin (EPO) from the kidney; and (iii) the survival time of circulating red cells is shortened.[ citation needed ]

In the short term, the overall effect of these changes is likely positive: it allows the body to keep more iron away from bacterial pathogens in the body, while producing more immune cells to fight off infection. Almost all bacteria 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.[ citation needed ]

Because anemia of chronic disease can be the result of non-infective 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 neoplastic disorders and non-infectious inflammatory diseases. [6] Neoplastic disorders include Hodgkin disease and lung and breast carcinoma, while non-infectious inflammatory diseases include celiac disease, [10] rheumatoid arthritis, systemic lupus erythematosus, scleroderma and dermatomyositis.

Anemia of chronic disease, as it is now understood, is to at least some degree separate from the anemia seen in kidney failure in which anemia results from reduced 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 kidney failure can lead to inflammatory changes that also can produce anemia of chronic disease.

Diagnosis

While no single test is reliable to distinguish iron deficiency anemia from the anemia of chronic inflammation, there are sometimes some suggestive data:

Treatment

The ideal treatment for anemia of chronic disease is to treat the chronic disease successfully, but this is rarely possible.

Parenteral iron is increasingly used for anemia in chronic renal disease [11] and inflammatory bowel disease (IBD). [12] [13] There is low-certainty evidence that people receiving treatment for IBD-related anemia with Intravenous (IV) iron infusion may be 17% more likely to benefit than those given oral iron therapy, and could be 61% less likely to stop treatment early due to adverse effects. [14] However, the type of IV iron preparation may influence the degree of both benefit and harm: Moderate-certainty evidence suggests that IV ferric carboxymaltose treatment may be 25% more likely to improve anemia than IV iron sucrose preparation. [14] The risk of serious side effects such as bleeding, electrolyte depletion and cardiac arrest could be greater with ferric carboxymaltose therapy, however the certainty of this evidence is low. [14]

Erythropoietin treatment, which stimulates the production of red blood cell production, is sometimes used to treat severe or persistent anemia, both as a monotherapy and a combination therapy alongside IV iron, but is costly and the benefit is unclear. [12] [13] [15] [16] Very low-certainty evidence suggests that erythropoietin as a monotherapy may improve anemia more than a placebo. [14] Any additional benefit of treating someone with erythropoietin in combination with IV iron sucrose treatment is not clear. [14]

Limiting some microbes' access to iron can reduce their virulence, thereby potentially reducing the severity of infection.[ citation needed ] Blood transfusion to patients with anemia of chronic disease is associated with a higher mortality, supporting the concept. [16]

See also

Related Research Articles

<span class="mw-page-title-main">Anemia</span> Reduced ability of blood to carry oxygen

Anemia or anaemia is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin available for oxygen transport, or abnormalities in hemoglobin that impair its function.

<span class="mw-page-title-main">Iron deficiency</span> State in which a body lacks enough iron to supply its needs

Iron deficiency, or sideropenia, is the state in which a body lacks enough iron to supply its needs. Iron is present in all cells in the human body and has several vital functions, such as carrying oxygen to the tissues from the lungs as a key component of the hemoglobin protein, acting as a transport medium for electrons within the cells in the form of cytochromes, and facilitating oxygen enzyme reactions in various tissues. Too little iron can interfere with these vital functions and lead to morbidity and death.

<span class="mw-page-title-main">Ferritin</span> Iron-carrying protein

Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary intracellular iron-storage protein in both prokaryotes and eukaryotes, keeping iron in a soluble and non-toxic form. In humans, it acts as a buffer against iron deficiency and iron overload.

Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (thrombocytes). Bone marrow suppression is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine. The risk is especially high in cytotoxic chemotherapy for leukemia. In the case of non-small-cell lung cancer, myelosuppression predisposition was shown to be modulated by enhancer mutations.

<span class="mw-page-title-main">Iron overload</span> Human disease

Iron overload is the abnormal and increased accumulation of total iron in the body, leading to organ damage. The primary mechanism of organ damage is oxidative stress, as elevated intracellular iron levels increase free radical formation via the Fenton reaction. Iron overload is often primary but may also be secondary to repeated blood transfusions. Iron deposition most commonly occurs in the liver, pancreas, skin, heart, and joints. People with iron overload classically present with the triad of liver cirrhosis, secondary diabetes mellitus, and bronze skin. However, due to earlier detection nowadays, symptoms are often limited to general chronic malaise, arthralgia, and hepatomegaly.

<span class="mw-page-title-main">Acute-phase protein</span> Class of proteins involved in inflammation

Acute-phase proteins (APPs) are a class of proteins whose concentrations in blood plasma either increase or decrease in response to inflammation. This response is called the acute-phase reaction. The acute-phase reaction characteristically involves fever, acceleration of peripheral leukocytes, circulating neutrophils and their precursors. The terms acute-phase protein and acute-phase reactant (APR) are often used synonymously, although some APRs are polypeptides rather than proteins.

<span class="mw-page-title-main">Iron-deficiency anemia</span> Reduced ability of the blood to carry oxygen due to a lack of iron

Iron-deficiency anemia is anemia caused by a lack of iron. Anemia is defined as a decrease in the number of red blood cells or the amount of hemoglobin in the blood. When onset is slow, symptoms are often vague such as feeling tired, weak, short of breath, or having decreased ability to exercise. Anemia that comes on quickly often has more severe symptoms, including confusion, feeling like one is going to pass out or increased thirst. Anemia is typically significant before a person becomes noticeably pale. Children with iron deficiency anemia may have problems with growth and development. There may be additional symptoms depending on the underlying cause.

<span class="mw-page-title-main">Erythropoiesis</span> Process which produces red blood cells

Erythropoiesis is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell.

<span class="mw-page-title-main">Microcytic anemia</span> Medical condition

Microcytic anaemia is any of several types of anemia characterized by smaller than normal red blood cells. The normal mean corpuscular volume is approximately 80–100 fL. When the MCV is <80 fL, the red cells are described as microcytic and when >100 fL, macrocytic. The MCV is the average red blood cell size.

<span class="mw-page-title-main">Human iron metabolism</span> Iron metabolism in the body

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism, because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron-deficiency anemia.

<span class="mw-page-title-main">Hepcidin</span> Protein-coding gene in the species Homo sapiens

Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals.

<span class="mw-page-title-main">African iron overload</span> Iron overload disorder caused by consumption of home-brewed beer

African iron overload is an iron overload disorder first observed among people of African descent in Southern Africa and Central Africa. It is now recognized to actually be two disorders with different causes, possibly compounding each other:

<span class="mw-page-title-main">Iron supplement</span> Iron formulation used to prevent or treat iron deficiency anemia

Iron supplements, also known as iron salts and iron pills, are a number of iron formulations used to treat and prevent iron deficiency including iron deficiency anemia. For prevention they are only recommended in those with poor absorption, heavy menstrual periods, pregnancy, hemodialysis, or a diet low in iron. Prevention may also be used in low birth weight babies. They are taken by mouth, injection into a vein, or injection into a muscle. While benefits may be seen in days, up to two months may be required until iron levels return to normal.

Reticulocytopenia is the medical term for an abnormal decrease in circulating red blood cell precursors (reticulocytes) that can lead to anemia due to resulting low red blood cell (erythrocyte) production. Reticulocytopenia may be an isolated finding or it may not be associated with abnormalities in other hematopoietic cell lineages such as those that produce white blood cells (leukocytes) or platelets (thrombocytes), a decrease in all three of these lineages is referred to as pancytopenia.

Epoetin alfa, sold under the brand name Epogen among others, is a human erythropoietin produced in cell culture using recombinant DNA technology. Epoetin alfa is an erythropoiesis-stimulating agent. It stimulates erythropoiesis and is used to treat anemia, commonly associated with chronic kidney failure and cancer chemotherapy. Epoetin alfa is developed by Amgen.

Latent iron deficiency (LID), also called iron-deficient erythropoiesis, is a medical condition in which there is evidence of iron deficiency without anemia. It is important to assess this condition because individuals with latent iron deficiency may develop iron-deficiency anemia. Additionally, there is some evidence of a decrease in vitality and an increase in fatigue among individuals with LID.

<span class="mw-page-title-main">Erythroferrone</span> Mammalian protein found in Homo sapiens

Erythroferrone is a protein hormone encoded in humans by the ERFE gene. Erythroferrone is produced by erythroblasts, inhibits the production of hepcidin in the liver, and so increases the amount of iron available for hemoglobin synthesis. Skeletal muscle secreted ERFE has been shown to maintain systemic metabolic homeostasis.

Hemochromatosis type 4 is a hereditary iron overload disorder that affects ferroportin, an iron transport protein needed to export iron from cells into circulation. Although the disease is rare, it is found throughout the world and affects people from various ethnic groups. While the majority of individuals with type 4 hemochromatosis have a relatively mild form of the disease, some affected individuals have a more severe form. As the disease progresses, iron may accumulate in the tissues of affected individuals over time, potentially resulting in organ damage.

<span class="mw-page-title-main">Desidustat</span> Chemical compound

Desidustat is a drug for the treatment of anemia of chronic kidney disease. This drug with the brand name Oxemia is discovered and developed by Zydus Life Sciences. Desidustat reduces the requirement of recombinant erythropoietin (EPO) in anemia, and decreases EPO-resistance, by reducing IL-6, IL-1β, and anti-EPO antibodies. The subject expert committee of CDSCO has recommended the grant of permission for manufacturing and marketing of Desidustat 25 mg and 50 mg tablets in India, based on some conditions related to package insert, phase 4 protocols, prescription details, and GCP. Clinical trials on desidustat have been done in India and Australia. In a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study, a mean hemoglobin increase of 1.57, 2.22, and 2.92 g/dL in desidustat 100, 150, and 200 mg arms, respectively, was observed. The Phase 3 clinical trials were conducted in chronic kidney disease patients which were not on dialysis as well as on dialysis. Desidustat is developed for the treatment of anemia as an oral tablet, where currently injections of erythropoietin and its analogues are drugs of choice. Desidustat is a HIF prolyl-hydroxylase inhibitor. In preclinical studies, effects of desidustat was assessed in normal and nephrectomized rats, and in chemotherapy-induced anemia. Desidustat demonstrated hematinic potential by combined effects on endogenous erythropoietin release and efficient iron utilization. Desidustat can also be useful in treatment of anemia of inflammation since it causes efficient erythropoiesis and hepcidin downregulation. Desidustat has been shown to have significant effect in the treatment of complement-mediated diseases. Complement activation-induced membrane attack complex (MAC) formation and Factor B activity were also reduced by desidustat treatment. Owing to this mechanism, desidustat can be an effective therapy against membranous nephropathy and retinal degeneration, since it specifically inhibited alternative complement system, without affecting the lectin-, or classical complement pathway.In January 2020, Zydus entered into licensing agreement with China Medical System (CMS) Holdings for development and commercialization of desidustat in Greater China. Under the license agreement, CMS will pay Zydus an initial upfront payment, regulatory milestones, sales milestones and royalties on net sales of the product. CMS will be responsible for development, registration and commercialization of desidustat in Greater China. National Medical Products Administration of China (NMPA) accepted the new drug application for desidustat on 23 April 2024. It has been observed that desidustat protects against acute and chronic kidney injury by reducing inflammatory cytokines like IL-6 and oxidative stress. A clinical trial to evaluate the efficacy and safety of desidustat tablet for the management of COVID-19 patients is ongoing in Mexico, wherein desidustat has shown to prevent acute respiratory distress syndrome (ARDS) by inhibiting IL-6. Zydus has also received approval from the US FDA to initiate clinical trials of desidustat in chemotherapy Induced anemia (CIA). Desidustat was successfully introduced as an alternative treatment in patient of endogenous erythropoietin (EPO)-induced pure red cell aplasia (PRCA) due to anti-EPO antibodies. This led to a substantial and sustained improvement in hemoglobin levels, emphasizing the crucial role of desidustat intervention in EPO-induced PRCA cases. Zydus Lifesciences and Sun Pharmaceuticals have entered an agreement in October 2023 to co-market Desidustat. Sun Pharma will sell the drug as Rytstat, while Zydus will continue to sell it as Oxemia.

Iron preparation is the formulation for iron supplements indicated in prophylaxis and treatment of iron-deficiency anemia. Examples of iron preparation include ferrous sulfate, ferrous gluconate, and ferrous fumarate. It can be administered orally, and by intravenous injection, or intramuscular injection.

References

  1. ↑ "Anemia of chronic disease". MedlinePlus Medical Encyclopedia. National Library of Medicine. Retrieved 22 February 2022.
  2. ↑ "ICD-11 for Mortality and Morbidity Statistics". icd.who.int. Retrieved 6 February 2022.
  3. ↑ Madu AJ, Ughasoro MD (2017). "Anaemia of Chronic Disease: An In-Depth Review". Medical Principles and Practice. 26 (1): 1–9. doi:10.1159/000452104. PMC   5588399 . PMID   27756061. Anaemia of chronic disease (ACD) or anaemia of chronic inflammation
  4. ↑ Weiss G, Ganz T, Goodnough LT (January 2019). "Anemia of inflammation". Blood. 133 (1): 40–50. doi:10.1182/blood-2018-06-856500. PMC   6536698 . PMID   30401705.
  5. ↑ Bernstein M, Munoz N (2 January 2019). Nutrition for the Older Adult. Jones & Bartlett Learning. p. 473. ISBN   978-1-284-14900-5.
  6. 1 2 3 Weng CH, Chen JB, Wang J, Wu CC, Yu Y, Lin TH (2011). "Surgically curable non-iron deficiency microcytic anemia: Castleman's disease". Onkologie. 34 (8–9): 456–458. doi:10.1159/000331283. PMID   21934347. S2CID   23953242.
  7. ↑ Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T (May 2004). "IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin". The Journal of Clinical Investigation. 113 (9): 1271–1276. doi:10.1172/JCI20945. PMC   398432 . PMID   15124018.
  8. ↑ Nemeth E, Ganz T (2006). "Regulation of iron metabolism by hepcidin". Annual Review of Nutrition. 26 (1): 323–342. doi:10.1146/annurev.nutr.26.061505.111303. PMID   16848710.
  9. ↑ Maury CP, Andersson LC, Teppo AM, Partanen S, Juvonen E (December 1988). "Mechanism of anaemia in rheumatoid arthritis: demonstration of raised interleukin 1 beta concentrations in anaemic patients and of interleukin 1 mediated suppression of normal erythropoiesis and proliferation of human erythroleukaemia (HEL) cells in vitro". Annals of the Rheumatic Diseases. 47 (12): 972–8. doi:10.1136/ard.47.12.972. PMC   1003648 . PMID   3264697.
  10. ↑ Leffler DA, Green PH, Fasano A (October 2015). "Extraintestinal manifestations of coeliac disease". Nature Reviews. Gastroenterology & Hepatology (Review). 12 (10): 561–571. doi:10.1038/nrgastro.2015.131. PMID   26260366. S2CID   15561525. 'Anaemia of chronic disease' (a form of anaemia associated with inflammation) is seen in ~25% of patients with coeliac disease.2
  11. ↑ Zager RA (September 2006). "Parenteral iron compounds: potent oxidants but mainstays of anemia management in chronic renal disease". Clinical Journal of the American Society of Nephrology. 1 (Suppl 1): S24–S31. doi: 10.2215/CJN.01410406 . PMID   17699373.
  12. 1 2 Mowat C, Cole A, Windsor A, Ahmad T, Arnott I, Driscoll R, Mitton S, Orchard T, Rutter M, Younge L, Lees C, Ho GT, Satsangi J, Bloom S (May 2011). "Guidelines for the management of inflammatory bowel disease in adults". Gut. 60 (5): 571–607. doi:10.1136/gut.2010.224154. PMID   21464096. S2CID   8269837.
  13. 1 2 "Anaemia management in people with chronic kidney disease" (PDF). NICE clinical guideline 114. February 2011. Archived from the original (PDF) on 2013-11-02. Retrieved 2012-08-08.
  14. 1 2 3 4 5 Gordon M, Sinopoulou V, Iheozor-Ejiofor Z, Iqbal T, Allen P, Hoque S, et al. (January 2021). "Interventions for treating iron deficiency anaemia in inflammatory bowel disease". The Cochrane Database of Systematic Reviews. 1 (1): CD013529. doi:10.1002/14651858.CD013529.pub2. PMC   8092475 . PMID   33471939.
  15. ↑ Anemia of chronic disease at Mount Sinai Hospital
  16. 1 2 Zarychanski R, Houston DS (August 2008). "Anemia of chronic disease: a harmful disorder or an adaptive, beneficial response?". CMAJ. 179 (4): 333–337. doi:10.1503/cmaj.071131. PMC   2492976 . PMID   18695181.
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