PATHOPHYSIOLOGY – DETAILED STUDY NOTES
Topics 99 and 165 | Aetiology, mechanisms, pathological changes and clinical manifestations
TOPIC 99. ANAEMIAS IN CHRONIC DISEASES
Definition. Anaemia of chronic disease (ACD), also called anaemia of inflammation, is an acquired anaemia occurring in persistent infection, chronic inflammatory disorders, malignancy and some chronic organ diseases. It is characterised by restricted availability of iron for erythropoiesis despite adequate or increased iron stores, together with an impaired bone-marrow response to anaemia.
1. Aetiology and associated conditions
Chronic infections: tuberculosis, osteomyelitis, infective endocarditis, chronic fungal infections and persistent bacterial infections.
Autoimmune and inflammatory disorders: rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and vasculitides.
Malignancy: solid tumours and haematological malignancies, particularly when associated with sustained cytokine release.
Chronic organ disease: chronic kidney disease (with reduced erythropoietin production and inflammation), chronic liver disease and chronic heart failure. These may produce mixed mechanisms rather than isolated ACD.
2. Core pathogenesis
The central mechanism is a cytokine-driven change in iron handling and red-cell production. Inflammation causes iron to be retained within macrophages and hepatocytes, reduces intestinal iron absorption, suppresses erythropoietin activity and shortens red-cell survival. The result is inadequate haemoglobin synthesis and an insufficient reticulocyte response.
A. Inflammatory cytokines and hepcidin
- Activated macrophages, T cells and other inflammatory cells release cytokines, especially IL-6, as well as IL-1, TNF-α and interferons.
- IL-6 stimulates hepatocytes to increase synthesis of hepcidin, the principal systemic regulator of iron homeostasis.
- Hepcidin binds to ferroportin, the iron-export channel on intestinal enterocytes, macrophages and hepatocytes. Binding causes ferroportin internalisation and degradation.
- With less ferroportin, dietary iron absorption from the duodenum falls, and iron recycled from senescent red cells remains trapped in macrophages. Stored iron is also less readily released from hepatocytes.
- Consequently, plasma iron and transferrin saturation decrease even though total-body iron stores are normal or increased. The marrow is functionally iron-deficient.
Key distinction: In ACD, iron is present in the body but is not adequately available to developing erythroblasts. This is called functional iron deficiency.
B. Suppression of erythropoiesis
- TNF-α, IL-1 and interferons inhibit proliferation and differentiation of erythroid progenitor cells in the bone marrow.
- Inflammatory cytokines reduce renal erythropoietin (EPO) production in some settings and blunt the marrow response to EPO. There is therefore an inappropriately low EPO response for the degree of anaemia.
- Inflammation may reduce the expression or availability of transferrin receptors and interfere with iron utilisation by erythroblasts.
- The combined effect is reduced red-cell production and a low or inappropriately normal reticulocyte count.