From the Guidelines
Anemia of chronic disease is caused by a complex interplay of mechanisms involving inflammation, iron metabolism, and erythropoiesis, with the primary driver being the body's inflammatory response to chronic conditions. The inflammation triggers increased production of cytokines, such as interleukin-6, which stimulates the liver to produce hepcidin 1. Hepcidin is the key hormone that blocks iron absorption from the gut and prevents iron release from storage sites in macrophages, effectively trapping iron and making it unavailable for red blood cell production. Additionally, inflammatory cytokines directly suppress erythropoiesis (red blood cell production) in the bone marrow and reduce the body's production of erythropoietin, the hormone that stimulates red blood cell formation 1. Some inflammatory cytokines also shorten red blood cell survival time. These mechanisms collectively result in a mild to moderate anemia characterized by low serum iron levels despite adequate iron stores in the body, a condition fundamentally different from iron deficiency anemia. The anemia typically resolves when the underlying chronic condition is successfully treated. Key factors involved in the pathogenesis of anemia of chronic disease include:
- Increased hepcidin production
- Decreased iron availability
- Suppressed erythropoiesis
- Reduced erythropoietin production
- Shortened red blood cell survival time Understanding these mechanisms is crucial for the diagnosis and management of anemia of chronic disease, as highlighted in recent clinical practice guidelines 1.
From the Research
Mechanism of Anemia of Chronic Disease
The mechanism of anemia of chronic disease (ACD) is complex and involves multiple pathways. Some of the key factors include:
- Diversion of iron traffic, leading to iron retention in reticuloendothelial cells and making it unavailable for erythropoiesis 2, 3, 4
- Diminished erythropoiesis, resulting from a blunted response to erythropoietin and inhibition of erythroid cell differentiation by inflammatory mediators 2, 3, 5
- Shortened erythrocyte half-life, contributing to the development of anemia 3, 5
- Increased levels of hepcidin, the master regulator of iron homeostasis, which blocks intestinal iron absorption and causes iron retention in reticuloendothelial cells 3, 6
- Inflammatory cytokines, such as tumor necrosis factor, interleukins 1 and 6, and interferon, which mediate the inflammatory and immune response and contribute to the development of ACD 4, 5
Role of Iron Homeostasis
Iron homeostasis plays a crucial role in the development of ACD. The condition is characterized by:
- Low serum iron (hypoferremia) and increased reticuloendothelial stores of iron 3, 5
- Elevated levels of ferritin, the storage protein for iron, and hepcidin, the iron hormone 3, 6
- Dysregulation of iron metabolism, leading to iron restriction and impaired erythropoiesis 3, 4, 5
Pathogenesis
The pathogenesis of ACD is closely linked to the underlying chronic inflammatory or autoimmune disease. The condition is often superimposed by malnutrition, bleeding, and renal failure, which can further contribute to the development of anemia 5. The systemic inflammatory state of chronic obstructive pulmonary disease (COPD) is also an important pathogenic factor, and anemia in COPD patients is strongly associated with increased functional dyspnea, decreased exercise capacity, and mortality 5.