Anemia of chronic disease

Anemia of chronic disease (ACD) is principally caused by inflammation.[5] Various processes (e.g., infection, neoplasm, autoimmune reactions, and injury to tissue from trauma and major surgery) trigger the release of proinflammatory cytokines. Systemic changes in iron metabolism, regulated by the inflammatory cytokine cascade and hepcidin (an iron-regulatory peptide hormone produced by the liver), decrease red blood cell (RBC) production and reduce RBC survival.[1][2][17][18][19]

A range of underlying conditions can result in the release of proinflammatory cytokines, often with activation of the reticuloendothelial system.[5] These cytokines trigger changes in intracellular iron metabolism (notably upregulation of hepcidin synthesis and ferritin transcription).[1][20] Interleukin (IL)-6 and IL-1 play a role in some inflammatory states, and they have been shown to directly upregulate hepcidin synthesis.[21]

Hepcidin and erythroferrone are the major regulators of iron metabolism. Hepcidin negatively regulates free iron by increased expression of divalent metal transporter 1 and downregulation of ferroportin.[22][23][24] Hepcidin causes iron-trapping in macrophages, decreased iron absorption in the gastrointestinal tract, splenic sequestration of iron, and impaired bone marrow responsiveness to erythropoietin.[19] Erythroferrone, a protein hormone produced by erythroid progenitor cells in response to erythropoietin, makes iron available for erythropoiesis by inhibiting the production of hepcidin.[25][26]

Elevated levels of inflammatory cytokines, such as tumor necrosis factor-alpha, have been associated with apoptosis of erythroid precursor cells in the bone marrow, which might account for ACD seen in rheumatological conditions.[2]

In ACD, serum iron levels fall (as a result of elevated hepcidin), impairing erythropoiesis and causing anemia. This drop in iron can be beneficial in certain circumstances (e.g., rendering iron less available for microorganism growth).[27] However, red blood cells (RBCs) that are produced in this low serum iron milieu are individually microcytic and hypochromic. If inflammation is prolonged, the entire RBC population also gradually shifts into the microcytic hypochromic range.

Low levels of serum erythropoietin in patients with systemic infection compared with those in patients who have a similar degree of iron deficiency anemia, and downregulation of erythropoietin receptors on erythroid progenitor cells, indicate that reduced effects of serum erythropoietin may partially contribute to anemia in ACD.[17][28][29] Erythropoiesis is additionally impaired when infection involves the marrow (as in HIV, hepatitis C, and malaria) or tumor cells infiltrate the marrow.[5][17]

Finally, survival of circulating RBCs (especially those near the end of their lifespan) may be shortened by increased erythrophagocytosis by macrophages and damage by cytokine-generated free radicals.[5][18][30]

Underlying cause of inflammation

Collagen vascular and autoimmune disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, polymyalgia rheumatica, scleroderma, inflammatory bowel disease)[3][4]
Chronic infection, including occult illness (e.g., tuberculosis, chronic fungal infections, hepatitis, osteomyelitis, HIV)[5]
Acute infection (e.g., pneumonia, pyelonephritis, endocarditis, cellulitis, abscess)[5]
Chronic disease (e.g., chronic kidney disease, congestive heart failure, chronic pulmonary disease)[6][7]
Malignancy (e.g., lymphomas, carcinomas, sarcomas)[5][8]
Critical illness and major trauma.

Pathophysiology

Classification

Underlying cause of inflammation