1. Briefly describe the pathophysiology of ACD. 2.

Outline the investigations that help differentiate ACD from iron deficiency anaemia. 3. Briefly discuss the rationale for treatment of this condition. The anemia of chronic disease (ACD) is simply the deficiency of red blood cells (RBC) that accompanies chronic inflammatory, infectious, or neoplastic disorders, such as endocarditis, rheumatoid arthritis and breast carcinomas respectively. Similar to, and only second in incidence compared to and Iron-deficiency anemia (IDA), it is primarily due to the unproduction low production of RBC, with low reticulocyte production and is most often normochromic, normocytic. In this disease, there is primarily a decreased availability of iron, relatively decreased levels of erythropoietin, and a mild decrease in the lifespan of RBCs to 70-80 days (normally 120 days). The exact pathogenesis of the disease is unknown and many theories have been proposed to explain this phenomenon. One widely accepted theory elucidates that in the course of inflammatory disease, due to the release of IL-6, there is an increase in levels of Hepcidin, an endogenous antimicrobial peptide secreted by the liver. Hepcidin inhibits ferriportin function in macrophages and reduced the transfer of iron from the storage pool to developing erythoid precursors in the bone marrow, thus starving the erythroid precursors from iron despite abundant stores of iron in the tissue. When tThe body therefore senses a threat, due to the mentioned mechanisms, iron gets immediately shuttled to ferritin to be contained to prevent harmful pathogens utilizing it, leaving only enough erythropoeisis. Additionally the erythropoietin levels are also low, further disrupts adequate erythropoiesis. Although tThe exact mechanism of this phenomenon is not unknown, it may also be directly or indirectly due to the hepcidin release. Another proposed mechanism involves macrophage-derived cytokines such as IL-1 and IL-6, TNF which is released in the mentioned scenarios, cause or contribute to the destruction of RBC precursors and decrease the erythropoietin receptors on progenitor cells. IDA and ACD are similar, in that they result in decreased levels of serum Fe, % of transferring saturation, usually normochromic and normocytic. Thus, appropriate iron studies must be conducted in order to diagnose the patient, especially when treatment for IDA, such as oral iron replacement could be harmful or even fatal for ACD patients. Though there is a decrease of ferrin levels and bone marrow Fe stores in IDA, in ACD, serum ferritin levels are high and there are increased levels of iron stores in the bone marrow macrophages. Additionally, unlike IDA, transferrin levels may be normal or decrease in ACD as ferritin is an acute phase reactant which may be elevated in inflammation. Additionally, tTesting the soluble transferring receptor (sTfR) can differentiate IDA and ACD. In general there is an increase in IDA, and unlike ferritin, it is not affected by inflammation or infection. In most cases, in order to treat ACD, the underlying cause of the disease must be treated. As the anemia is generally mild, blood transfusions are generally not required. Recombinant erythropoietin may be offered with a high dosage as both reduced production and marrow resistance to EPO may occur. Iron supplements are required to ensure an adequate response to EPO. However, careful monitoring of Hb response is needed because if it rises to > 12 g/dL adverse effects may occur, (eg, venous thromboembolism, MI, death).

The anemia of chronic disease (ACD) is the second most common anaemia and is simply the deficiency of erythrocytes (RBC) that accompanies chronic inflammatory, infectious, or neoplastic disorders. Examples include, endocarditis, rheumatoid arthritis and breast carcinomas respectively. ACD is similar to Iron deficiency anemia (IDA), in that they result in decreased levels of serum Fe and % of transferrin saturation. Histologically ACD can be normochromic and normocytic or hypochromic and microcytic. Appropriate iron studies must be conducted in order to diagnose the patient, because treatment for IDA, such as oral iron replacement could be harmful or even fatal for ACD patients. Though there is a decrease of ferrin levels and bone marrow Fe stores in IDA, in ACD, serum ferritin levels are high and there are increased levels of iron stores in the bone marrow macrophages. Transferrin levels may be normal or decrease in ACD as ferritin is an acute phase reactant which may be elevated in inflammation. Additionally, in ACD, the soluble transferrin receptor (sTfR) levels are normal, but is increased in IDA. The exact pathogenesis of the disease is unknown and many theories have been proposed to explain this phenomenon. One widely accepted theory elucidates that in the course of inflammatory disease, the release of IL-6, induces the liver to increase the secretion of Hepcidin, an endogenous antimicrobial peptide. Hepcidin inhibits ferriportin function in macrophages and reduced the transfer of iron from the storage pool to developing erythoid precursors in the bone marrow. Therefore, the erythroid precursors are starved from iron despite abundant stores in the tissue. Additionally the erythropoietin levels are also low which further disrupts adequate erythropoiesis, though exact mechanism of this phenomenon is unknown, it may be directly or indirectly due to the hepcidin release. The rationale for the treatment of ACD is twofold, firstly the anemia can be detrimental by itself as it requires the compensatory increase in cardiac ouput in order to adequately maintain the systemic oxygen delivery. Additionally, anemia is associated with a poorer prognosis in various conditions, especially in patients older than 65 years old and those with additional risk factors such as coronary artery disease, pulmonary disease or chronic kidney disease. As iron supplements can be worsen some conditions recombinant erythropoietin may be offered with a high dosage as both reduced production and marrow resistance to EPO may occur. However, if the condition permits, iron supplements are given to ensure an adequate response to the EPO. However, careful monitoring of Hb response is needed because if it rises to > 12 g/dL adverse effects such as MI, venous thromboembolism or death may occur. If the anemia is severe, blood transfusions may be required but thankfully this is not usually the case. In conclusion, the diagnosis and treatment of ACD is fundamental in order to improve the quality of life for the chronically ill patient. Though the anemia may not be able to be treated unless the underlying cause is treated, the management of these patients may influence the prognosis of their condition.