of overall bioavailable folate, thus limiting its accuracy. There are no evidence‐based guidelines regarding screening for folate deficiency, and routine screening is not recommended. However, screening should be considered in high‐risk individuals who are anaemic and also in the workup of anaemia of unknown aetiology.
In people with confirmed folate deficiency anaemia, supplementation must be initiated. Most commonly, folate deficiency is treated with oral replacement, although IV preparations are available for those unable to consume oral repletion. No evidence‐based guidelines exist regarding dose or duration of treatment; however, folic acid 1 mg daily is a typical supplementation dose. If the folate deficiency is secondary to malabsorption, supplementation will likely be needed indefinitely. If medication‐induced, supplementation should occur for as long as the individual is receiving the offending medication.
In summary, folate deficiency anaemia is not as common in the US as it once was because of government‐mandated grain‐fortification policies. However, it is still seen in countries that lack these policies and can occur globally in those with malnutrition or restrictive diets, impaired absorption, or high RBC turnover states. There are also several medications that induce folate deficiency. The diagnosis of folate deficiency anaemia typically relies on low haemoglobin and low serum folate levels and can be confirmed by low RBC folate, normal MMA, and elevated homocysteine levels. At the present time, there are no evidence‐based guidelines for screening or treatment, but generally, oral folic acid supplementation daily is sufficient for correction of plasma levels and stores.
Inflammatory anaemias
Anaemia of chronic disease
Anaemia of chronic disease is also known as anaemia of chronic inflammation and is a difficult‐to‐treat anaemia with a multifactorial pathophysiology. The cornerstone of anaemia of chronic disease is underlying inflammation (acute or chronic) and excess production of cytokines. It is considered a functional iron deficiency, meaning total body iron stores are normal or elevated but an inadequate amount of usable free iron is available for the bone marrow production of RBCs. In addition to deranged iron homeostasis, inflammation leads to diminished responses to renally produced erythropoietin and its effects on bone marrow stimulation, decreased proliferation of bone marrow progenitor stem cells, and decreased RBC lifespan (Figure 22.5). Anaemia of chronic disease is the most common type of anaemia seen at older age and is seen in up to 70% of hospitalized elderly patients.48 It is also quite common in morbidly obese patients because of circulating inflammatory factors released by excess adipose tissue.49 Treatment is challenging; the hallmark of treatment is eliminating the chronic inflammation, which is often not possible due to the underlying chronic disease processes that are present in so many older adults.
Figure 22.5 Key mechanisms for anaemia of chronic disease.
Anaemia of chronic disease is termed a functional iron deficiency because of the altered iron haemostasis that occurs as a result of circulating inflammatory cytokines (i.e. interleukins and tumour necrosis factor). Hepcidin, a peptide produced by the liver, is the driver of iron homeostasis and regulates iron uptake by the ferroportin transporter in the duodenal enterocytes.50 Additionally, hepcidin regulates the release of iron from macrophages into the circulation and release of iron bound to ferritin, its storage site in the liver. During inflammatory states, hepcidin, an acute‐phase reactant, is over‐produced and in turn prohibits iron uptake from dietary sources and its release into the blood from gut enterocytes. It also leads to increased iron uptake and retention by macrophages.51 The over‐expression of hepcidin in essence blocks the body’s natural iron‐recycling program occurring in the reticuloendothelial system and locks up iron in its storage form in ferritin, leaving little usable iron substrate for the bone marrow production of RBCs.
Another mechanism responsible for the pathogenesis of anaemia of chronic disease is diminished production and response to renally produced erythropoietin – a bone‐marrow stimulating hormone. Erythropoietin production is inversely regulated by haemoglobin and tissue oxygenation levels. Inflammatory cytokines have been shown to damage erythropoietin‐producing renal cells and also down‐regulate erythropoietin‐binding receptors on other cells, leading to decreased bone marrow production of RBCs.52 Pro‐inflammatory cytokines also directly damage erythroid precursor cells in the bone marrow and RBCs in the blood, shortening the lifespan of these cells through cytokine‐mediated apoptosis and free radical damage. These prohibitory mechanisms ultimately decrease the number of circulating RBCs.53,54
Anaemia of chronic disease is diagnosed by laboratory studies. Typically, it manifests as a normocytic anaemia with low haemoglobin, low to normal serum iron, low to normal transferrin, low transferrin saturation, and normal to elevated ferritin (Figure 22.3). Cytokine levels, which are not usually measured in the clinical setting, are elevated. Surrogate markers of inflammation, however, such as C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR), are more readily obtainable than cytokine levels and are also elevated.13 Ferritin, despite being categorized as an acute‐phase reactant, is the most useful test in differentiating anaemia of chronic disease from other anaemias and particularly from IDA. As discussed previously, a ferritin level of less than 30 ng/mL has a high positive predictive value for IDA, whereas a ferritin level of greater than 100 ng/mL indicates probable anaemia of chronic disease.20 Elevated ferritin reflects the increased storage and diminished usability of iron, which is the hallmark of anaemia of chronic disease. For equivocal levels of ferritin (30–100 ng/mL), the soluble transferrin receptor may be helpful in distinguishing anaemia of chronic disease from IDA and identifying concomitant IDA and anaemia of chronic disease.55 Soluble transferrin receptor levels are increased in IDA but are normal in anaemia of chronic disease because of the prohibitive effects of cytokines on its expression.56
The definitive treatment of anaemia of chronic disease relies heavily on the eradication of the inflammatory or chronic disease process. This is often difficult or impossible to achieve, particularly in debilitated, frail, or ill elderly individuals. Supplemental iron is not recommended for the treatment of anaemia of chronic disease unless concomitant iron deficiency is present. It should not be given in those with ferritin levels greater than 100 ng/mL because of a high risk of adverse effects.57 The pathophysiology of anaemia of chronic disease is such that iron is poorly absorbed and bound up in its storage form. Any supplemental iron given will be retained in the reticuloendothelial system or ferritin and not released into the bone marrow to be used as a substrate for RBC production.
Erythropoietic‐stimulating agents are currently approved by the US Food and Drug Administration (FDA) for individuals with anaemia of chronic disease who have cancer and are receiving chemotherapy or for those who have human immunodeficiency virus (HIV) and are receiving myelosuppressive treatment.58 Because of the rapid increase in bone marrow RBC production, absolute iron deficiency is frequently common when using erythropoietin‐stimulating agents, and concomitant iron therapy is often necessary.59 Iron studies should be checked prior to treatment initiation and during treatment with bone‐marrow stimulating agents. To monitor treatment response to erythropoietic‐stimulating agents, haemoglobin levels should be checked every two to four weeks, with a target haemoglobin level of 11–12 g/dL.60 It is important to note that while these agents improve haemoglobin levels and potentially quality of life, their effects are limited. Erythropoietic‐stimulating agents do not treat the underlying disease processes resulting in the anaemia.
In summary, anaemia of chronic disease is considered a functional iron deficiency that is caused by an underlying inflammatory or chronic disease process. It is diagnosed by a low haemoglobin, low to normal serum iron levels, and normal to elevated ferritin levels. Typically, CRP and ESR will also be