Anemia of Chronic Disease

Anaemia of Chronic Disease (ACD)

• Anaemia of chronic disease (ACD), also known as anaemia of inflammation (AI), is a common type of anaemia, particularly in hospital populations. It occurs in the setting of chronic infection, chronic inflammation or neoplasia.

Inflammatory Diseases Associated with the Development of ACD

• I. Infections (acute and chronic)
• Viral infections including HIV
• Bacterial
• Parasitic
• Fungal
• Helminth
• II. Malignancies
• Haematologic
• Solid tumor
• III. Autoimmune
• Rheumatoid arthritis
• Systemic lupus erythematosus and connective tissue diseases
• Vasculitis
• Inflammatory bowel disease
• IV. Chronic kidney disease and inflammation
•

Pathophysiology—Cornerstones

The anaemia is not related to bleeding, haemolysis or marrow infiltration, is mild, with haemoglobin in the range of 85–115 g/L, and is usually associated with a normal MCV (normocytic, normochromic),

Hepcidin Master Regulator of Iron Homeostasis

Pathogenesis It has recently become clear that the key regulatory protein that accounts for the findings characteristic of ACD is hepcidin, which is produced by the liver.

Pathophysiology—Cornerstones

Hepcidin production is induced by pro-inflammatory cytokines, especially IL-6. Hepcidin binds to ferroportin on the membrane of iron-exporting cells, such as small intestinal enterocytes and macrophages, internalising the ferroportin and thereby inhibiting the export of iron from these cells into the blood.

Pathophysiology—Cornerstones

The iron remains trapped inside the cells in the form of ferritin, levels of which are therefore normal or high in the face of significant anaemia.






ACD Diagnosis

Parameter ACD IDA

Serum iron concentration Reduced to normal Reduced
Transferrin levels Reduced to normal Increased
Transferrin saturation Reduced to normal Reduced
Ferritin Normal to increased Reduced
Serum transferrin receptor Normal Increased

Percentage hypochromic RBC Normal High
Cytokines (TNF, IL-1, IL-6) Increased Normal

ACD Best Therapy

Treatment or Cure of the Underlying Disease!

Current Therapeutic Options in ACD

Blood transfusions
Recombinant human erythropoietin
Iron
Therapeutic measures are aimed to increase haemoglobin levels in ACD patients

ACD TherapyBlood Transfusions

Can be readily used for rapid correction of severe anaemia
Immediate increase of haemoglobin
1 unit contains ~200 mg of iron

ACD TherapyIron

NO, if infections or cancer underlie ACD; ferritin >100 ng/mL
May favor proliferation of pathogens
By countering iron-withholding strategy
By impairing immune function
May not reach erythroid cells due to diversion into reticulo-endothelial system
May cause tissue damage via formation of toxic radicals by the Fenton reaction (triggered by TNF-1a)
However, in autoimmune diseases, iron may inhibit pro-inflammatory immune effector pathways, thus reducing disease activity

ACD TherapyIron

What to do in ACD with true iron deficiency (ACD and bleeding)?
Iron is needed for basic metabolic functions

How to substitute iron?

Iron is very poorly absorbed in ACD (down-regulation of ferroportin in the duodenum by hepcidin)
IV iron administration is very effective in ACD ex: inflamatory bowel disease.

Iron Therapy in Dialysis Patients

Prospective study investigating the incidence of infectious complications in ESRD patients receiving IV iron therapy
Group 1: ferritin <100 ng/mL and TfS <20%
Group 2: ferritin >100 ng/mL and TfS >20%
Observation period: 1 year
Frequency of septicaemia in Group 2 was 2.5-fold higher than in Group 1

Why Is the Differential Diagnosis Between ACD and ACD + IDA Important?

Because these patients need contrasting therapies!!!
No iron in ACD
Iron needed in ACD/IDA

Therapy—Erythropoietin-Stimulating Agents (ESA)

Effective in increasing haemoglobin levels in ACD: patients with cancer, infections, and autoimmune disorders
Response rate to treatment depends on underlying disease, stage, immune activation, and iron availability
Increase of haemoglobin with ESA treatment is associated with a decreased need for blood transfusions

Therapeutic End Points

Avoid over-correction of anaemia (Hgb >12 g/dL)
Currently recommended therapeutic end point: Hgb 11–12 g/dL