Anemia of Chronic Disease (ACD Overview)

Overview of Anemia of Chronic Disease (ACD)

• ACD is a common anemia, typically normochromic or mildly hypochromic.
• It occurs in individuals with systemic diseases.
• Reduced serum iron and iron binding capacity, with normal to raised serum ferritin levels, characterize it.
• Adequate iron stores are present in ACD.
• ACD is not caused by tumor infiltration of marrow, hemolysis, or hematic deficiency; it's a diagnosis of exclusion.

Conditions Associated with ACD

• Chronic infections, chronic inflammatory disorders, malignant diseases, and other conditions can be associated with ACD.
• Chronic infections include osteomyelitis, bacterial endocarditis, tuberculosis, abscesses, bronchiectasis, and chronic UTI.
• Chronic inflammatory disorders include rheumatoid arthritis, juvenile rheumatoid arthritis, polymyalgia rheumatica, and systemic lupus erythematosus.
• Scleroderma, inflammatory bowel disease, and thrombophlebitis are considered in ACD.
• Malignant diseases include carcinoma, lymphoma, and myeloma.
• Congestive heart failure, ischemic heart disease, and AIDS are also linked to ACD.

Pathogenesis of ACD

• ACD is primarily due to disturbances in erythropoiesis.
• There is reduced sensitivity to physiological erythropoietic stimuli and reduced iron utilization.
• Cytokines (Interleukin 1 (IL-1), IL-6, tumour necrosis factor (TNF), and transforming growth factor beta (TGFβ)) interact with marrow stromal cells and erythroid progenitors.
• Mildly decreased red cell lifespan can be compensated by normal bone marrow.

Relative Lack of Erythropoietin

• Plasma erythropoietin (Epo) levels in ACD are inversely correlated with hemoglobin levels.
• Epo levels are inappropriately low compared to other types of anemia and normal renal function.
• Elevated plasma levels of TNF-α, IL-1 (IL-1α and IL-1β), and IL-6 are found.
• These factors reduce Epo production by cultured hepatoma cells.
• IL-1α inhibits Epo production by isolated serum-free perfused kidneys.

Inhibition of Erythropoiesis

• TNF and IL-1 inhibit erythropoiesis in vitro, with TNF potentially increasing apoptosis of bone marrow erythroid cells.
• Interferon-γ (IFN-γ) secreted by T lymphocytes mediates IL-1 effects, while TNF action may be mediated by IFN-γ produced by marrow stromal cells.
• IL-6 and TGF-β can act as mediators of ACD by inhibiting erythropoiesis.

Iron Metabolism

• A low serum iron level and adequate reticuloendothelial iron stores are characteristic of ACD.
• Reduction of iron granules in marrow erythroblasts is seen.
• Serum transferrin decreases, and serum ferritin increases as part of the acute-phase response.
• A fall in serum iron may occur as early as 24 hours after the onset of a systemic illness and persist during a prolonged illness.
• The fall in serum iron results from impaired iron flow from cells to plasma, increased secretion of hepcidin by hepatocytes in response to inflammation.
• Hepcidin inhibits iron release from macrophages and iron absorption.
• Microbial products activate Kupffer cells to secrete IL-6, stimulating hepcidin secretion from hepatocytes.
• Low serum iron inhibits proliferation of microorganisms.

Hepcidin and Cytokine Influence

• A positive correlation exists between serum and urinary hepcidin and serum ferritin levels in clinical specimens.
• Cytokines such as TNF, IL-1, and IFN-γ reduce serum iron and increase serum ferritin concentrations.
• Hepcidin is the primary cause of reduced serum iron.
• Anemia usually reduces hepcidin secretion.

Lactoferrin and Apoferritin Role

• Increased lactoferrin, resulting from inflammation, competes with transferrin for iron.
• This forms a complex that is removed by macrophages in the liver and spleen.
• Increased intracellular apoferritin synthesis occurs in response to inflammation and malignancy.
• The amount of iron available for binding to transferrin and erythropoiesis decreases.

Hematological Features

• Hemoglobin levels are 9 g/dL and above.
• MCV is normal or mildly reduced (77-82fL).
• MCH is usually normal but occasionally reduced.
• Serum iron and TIBC are reduced.
• Transferrin saturation is mildly reduced.
• Serum ferritin is normal or increased.
• Serum and urine hepcidin, C-reactive protein, and ESR are raised.

ACD Treatment

• The severity of the anemia correlates with the activity and severity of the underlying chronic disease.
• Successful therapy reduces mediator cytokine levels, increases Epo production, and reduces inhibition of erythropoiesis.
• Anemia correction may require weeks or months.
• Pharmacological doses of recombinant Epo are used to improve anemia in rheumatoid arthritis, cancer, and myeloma patients.
• Inadequate Epo production and action is more important than disturbed iron metabolism.
• Responses to erythropoietin will be beneficial.
• Iron therapy should be reserved for those with genuine iron deficiency.