Clinical signs and presentation
Symptoms and signs of both iron deficiency and iron deficiency anaemia include lethargy, brittle nails, hair loss and restless leg syndrome.13-15 Pica (ingestion of non-food substances, such as soil) and pacophagia (excessive ice consumption) can occur and appear more common in women and children than in men.15 Clinical signs of iron deficiency include atrophy of the tongue papillae, angular cheilosis and nail abnormalities such as Mees lines and koilonychia (spoon nails). However, these classic signs are not commonly seen, and patients with iron deficiency may have few signs. Even those with mild to moderate anaemia, if otherwise healthy, may have few to no symptoms except tiredness.
Identification of the underlying cause of iron deficiency is vital, and thus the clinician should be mindful of states that predispose to a negative iron balance. In addition to life stages associated with increased physiological iron requirements, any scenario that reduces ingestion or absorption of iron or increases blood loss can lead to iron deficiency. Causes of iron deficiency are listed in Box 2.
Investigations to diagnose iron deficiency
No single test in isolation is able to identify all patients with iron deficiency. It is often necessary to consider many laboratory results and the clinical context to assess a patient’s iron stores.
Serum ferritin and other iron studies
The serum ferritin level reflects body iron stores, and a low level confirms iron deficiency. A serum ferritin level less than 15mcg/L (less than 12mcg/L in children) is highly specific for iron deficiency but lacks sensitivity. The Royal College of Pathologists of Australasia recommends adopting a cut-off of 30mcg/L, with lower levels seen as abnormal in adults.16 Using this cut-off improves sensitivity (to 92%) and maintains an adequate positive predictive value (83%).17 However, the serum ferritin level is difficult to interpret in patients with inflammation as it is an acute phase reactant and will therefore be elevated, making it an unreliable indicator of body iron stores in that setting. Other causes of an elevated serum ferritin level include liver disease, infection and malignancy, and assessment of iron deficiency can be challenging in patients with these conditions. A low serum ferritin level, including in patients with inflammation, confirms iron deficiency.
The remaining tests included in an iron studies panel are less robust diagnostic tools for iron deficiency. The serum iron level indicates iron bound to transferrin and is of limited diagnostic utility because of its considerable diurnal variation, day-to-day variability and susceptibility to the effects of iron supplements and food ingestion. Consequently, the serum iron level is not used to test for iron deficiency. The total iron binding capacity (TIBC), transferrin level and transferrin saturation are markers of iron delivery to the tissues. A transferrin saturation less than 16% is insufficient for red blood cell synthesis and thus is an accepted indicator of iron deficiency. However, the TIBC, transferrin level and transferrin saturation cannot distinguish reliably between anaemia caused by iron deficiency and by chronic inflammation.
Red blood cell parameters
A full blood count can facilitate diagnosis of iron deficiency and is required to evaluate potential anaemia. Over time, iron deficiency results in reduced mean corpuscular volume (MCV) and reduced mean corpuscular haemoglobin (MCH), manifesting as a microcytic, hypochromic blood film, with additional morphological findings of elliptocytes, including very narrow forms that may be reported as pencil cells.18 The normal lifespan of red blood cells is three months, and therefore erythrocyte changes take time to manifest; when seen, these changes indicate that iron deficiency has been present for some time. An elevated platelet count is a common finding in patients with iron deficiency anaemia and can be due to iron deficiency or an underlying condition such as malignancy. Leukopenia and thrombocytopenia are seen in 10% of patients with iron deficiency.18
Red cell indices are diagnostically useful. In a healthy adult, the MCV is quite stable across time, and thus new-onset microcytosis can alert to iron deficiency or anaemia of chronic disease, whereas lifelong microcytosis may prompt consideration of an underlying haemoglobinopathy.
More recently developed red cell indices, such as reticulocyte haemoglobin content and percentage of hypochromic red cells, have been found to be potentially useful, reliable, early indicators of iron deficiency but are not in widespread clinical use.
An assay of soluble transferrin receptor (sTfR) was thought to offer potential as a means of distinguishing iron deficiency anaemia from anaemia of chronic inflammation. Unfortunately, the sTfR assay has a specificity of 84% and a positive predictive value of just 58% when evaluated in populations for which it would be considered most useful.19 Furthermore, there is variability between the different sTfR assays and a lack of adequate standardisation between testing platforms. Consequently, the role of STfR in the evaluation of iron balance is more limited than expected.