Iron deficiency and new insights into therapy

Iron deficiency (ID) is a deficit in total body iron which, when severe, can lead to iron deficiency anaemia (IDA). ID is considered the most prevalent nutritional deficiency in the world.1,2 Recent estimates suggest that about a third of non-pregnant women worldwide are anaemic,1 with IDA comprising about half of all cases.2

In Australia, the burden of ID is harder to define, as only a few large scale studies exist. The prevalence of ID and IDA depends on the groups studied, but estimates for IDA range from 1% to 14% in toddlers and 10% to 55% in women.3 The highest rates of ID and IDA are seen in pre-menopausal women, socially disadvantaged people and those of Indigenous background.3-5 A recent study by the Australian Red Cross Blood Service found that, among new blood donors, 12% of female donors and 1.3% of male donors were iron deficient.6 The combined rate of anaemia (ie, haemoglobin level below normal) from all causes in new donors of both sexes was 5.6%.6 Whether these estimates represent the overall burden across Australian society is unclear, due to the strict age- and health-related criteria for potential blood donors in Australia. The Australian Health Survey in 2012 suggested that about 3% of Australia’s population were anaemic, with 71% of this attributable to IDA.5 It is therefore estimated that over a quarter of a million Australians live with IDA, and many more have ID without anaemia. Regardless of the exact number, ID and IDA continue to be major public health problems in Australia.

Here, we discuss the causes, effects, diagnosis and management of ID. For this narrative review, we searched PubMed for original papers and review articles published between 2000 and 2016, as well as using specialist society publications and guidelines, to formulate an evidence-based overview of ID and IDA.

Causes and effects of iron deficiency

The causes of ID have been reviewed previously.3,7 In their most simplistic form, ID and IDA are a result of unbalanced loss of iron, most commonly from bleeding, without adequate replacement by intake of oral iron. Important causes of ID are shown in Box 1.

The effects of ID and IDA in children include impaired cognition and behavioural problems.5,8,9 In adults, they can lead to reduced productivity, tiredness and lethargy.10 In pregnant women, IDA has been associated with neonates of low birthweight, prematurity and maternal morbidity.11 Given these potentially severe consequences, timely diagnosis, investigation and treatment of ID and IDA are important for optimal patient care.

Diagnosis of iron deficiency

One of the major problems in diagnosing ID and IDA is difficulty in interpreting test results. Classically, patients with suspected IDA will have a full blood examination and iron studies, in addition to other pertinent tests. Iron studies include measurement of serum or plasma iron levels, transferrin levels, transferrin saturations (calculated from total iron binding capacity) and ferritin levels. Serum iron levels, when assessed alone, are usually unhelpful for investigating ID, but they are used to calculate other measures within the iron studies. Transferrin is the transport molecule for iron in blood, and transferrin saturation is a measure of how much iron is bound to transferrin. Ferritin is a measure of iron reserve and is the most reliable parameter in the iron studies for the diagnosis of ID.12

The World Health Organization defines ID as a serum or plasma ferritin level of < 12 µg/L in children under 5 years of age or < 15 µg/L in adults and children over 5 years of age.13 However, these cut-offs are not universally adopted, with the Royal College of Pathologists of Australasia recommending that a ferritin level < 30 µg/L be considered abnormal for adults.14 Even more confusingly, laboratories may use different cut-offs depending on the method of ferritin analysis and the population in which the assay was validated.14,15 These differing definitions for abnormally low ferritin levels make interpretation of results difficult. Furthermore, ferritin is an acute phase reactant and its levels can be raised in inflammatory states such as infection, autoimmune disease or alcoholic and non-alcoholic fatty liver disease. It is often taught that patients with ferritin levels greater than 100 µg/L are unlikely to be iron deficient, although there are exceptions.3

A summary of how to interpret the results of a full blood examination and iron studies, adapted from the Australian Iron Deficiency Expert Group, is shown in Box 2.3 We recommend that the results of iron studies be interpreted as a whole. For example, a borderline low ferritin level may still represent ID in an unwell patient, and suspicion should be raised if the transferrin and transferrin saturation levels indicate IDA, regardless of the ferritin level.

The two main differential diagnoses for IDA (which is typically a microcytic, hyopchromic anaemia) are thalassaemia and anaemia of chronic disease. Thalassaemia can usually be differentiated from IDA by the presence of a family history, a disproportionately low mean corpuscular volume compared with haemoglobin level, a red cell distribution width within reference intervals or only slightly raised16 and an adequate ferritin level. A haemoglobin electrophoresis test or high performance liquid chromatography to determine the presence of haemoglobinopathy can often be diagnostic, although a-thalassaemia is more difficult to detect and may require genetic testing for diagnosis.17 On the other hand, anaemia of chronic disease can be particularly difficult to distinguish from IDA. In situations where iron studies are compromised by the presence of inflammation, we use soluble transferrin receptor assays to differentiate between the two conditions, as soluble transferrin receptor levels are raised only in the setting of ID. Although raised soluble transferrin receptor levels have high sensitivity and specificity for ID,18 this method has limited use in clinical practice because of confusion about the best method of reporting (total level or as a ratio to ferritin), unfamiliarity among clinicians and lack of a standardised cut-off.18 Nevertheless, we feel that soluble transferrin receptor assays are useful to differentiate IDA from anaemia of chronic disease in difficult cases.

The gold standard for diagnosing IDA remains bone marrow biopsy, with analysis of particulate iron using a Perls’ Prussian blue stain (Box 3).12 Due to the invasiveness of this procedure and the ability to diagnose most patients with serum testing, we do not recommend this investigation even in difficult cases. In our clinical practice, if ID cannot be clearly differentiated from other conditions, a trial of iron replacement is often attempted, with close clinical monitoring. Nevertheless, bone marrow biopsies are sometimes performed in the diagnostic investigation of anaemia or other cytopenias to exclude primary bone marrow disease. When it is performed, the information available from a bone marrow biopsy should not be ignored. We recommend that a Perls’ stain be performed to analyse body iron stores in all patients who have a bone marrow biopsy for the investigation of anaemia.

Management of iron deficiency

The management of ID consists of investigation and treatment of the cause, iron replacement by either the enteral (oral) or parenteral (injectable) route, follow-up and further investigations when required.

Investigation of the cause of iron deficiency

Investigation of ID should include a detailed history, physical examination and appropriate biochemical and interventional investigations. Importantly, consideration should be given to a patient’s family history, age, sex and risk factors for causes.

An algorithm of how we investigate ID, adapted from the guidelines of the Gastroenterological Society of Australia and the Australian Iron Deficiency Expert Group, is shown in Box 4.3,7 Our algorithm is a general guideline and does not replace a clinician’s need to consider the patient’s unique situation and investigate when appropriate.

Iron replacement therapies

Oral iron

Daily oral iron is commonly prescribed as an initial intervention by clinicians treating ID and IDA and is recommended by the World Health Organization.19 However, oral iron replacement is not without its risks. While some risks, such as a reported increased rate of malaria,20-22 are less relevant in Australia, clinicians should be aware of the adverse effects and risks of treatment with oral iron.

The relative benefits of daily oral iron replacement in different at-risk populations have been analysed in a series of recent systematic reviews and meta-analyses.10,23-26 Evidence-based benefits and risks according to these studies are summarised in Box 5, which illustrates the quality of the evidence that daily oral iron replacement has an effect on the stated outcome, not the magnitude of its effect. In some age groups, insufficient numbers were studied for the stated outcomes, so although no effect could be demonstrated in the meta-analysis, it is possible there is an effect that has not been detected. For example, as very few studies reported cognitive outcomes in females older than 12 years, no benefit could be observed.10 It remains unclear if daily oral iron therapy has a benefit for cognitive outcomes in this population. Further, only females were included in the meta-analysis for people aged over 12 years, as ID is rare in males above this age and should be investigated as shown in Box 4. Nevertheless, it is likely that males will have similar benefit and risk profiles as females for oral iron replacement. Although these studies give a general overview of the effects of daily oral iron therapy in different age groups, the included studies encompassed areas with different endemic infections and socio-economic status than Australia. These differences should be considered when weighing up the risks and benefits of iron replacement in Australia. We feel that the data strongly support the use of daily oral iron replacement to treat ID and IDA for all ages, but clinicians should be aware of, and monitor for, possible adverse effects during therapy.

The type of iron, dose and duration of daily oral iron therapy were also analysed in these studies. Commonly available forms of oral iron in Australia are shown in Box 6. Our recommendations for choice of iron replacement therapy, based on these studies and previous recommendations, are shown in Box 7. Some evidence suggests that ferrous sulfate (compared with other forms of iron) and the addition of vitamin C may help further reduce rates of anaemia; however, we do not feel this evidence is sufficiently robust to specifically recommend these interventions.10 A reticulocyte response is expected after about 72 hours of treatment with daily oral iron, with improvements in haemoglobin levels of about 20 g/L every 3 weeks.3 If daily oral iron is not feasible because of adverse effects or problems with patient adherence, intermittent oral iron (once, twice or three times a week) has been shown to be effective.28 Studies have suggested that second-daily oral iron dosing may maximise iron absorption and reduce intestinal exposure to non-absorbed iron, which may reduce adverse effects;29 however, longer term studies to confirm these findings are required. A Cochrane review of intermittent oral iron replacement showed it improved haemoglobin levels and iron status, but not as effectively as daily dosing. Hence, our preference is for daily oral iron where possible.28

Parenteral iron

Parenteral iron is an alternative for patients who have major adverse effects from oral iron, are unwilling to take regular oral medication or are unable to absorb oral iron. In these cases, we recommend intravenous (IV) iron replacement (Box 7). We also recommend IV iron for adults with severe IDA (haemoglobin level < 80 g/L), as evidence suggests that IV iron corrects haemoglobin levels faster than oral iron.30-32 Intramuscular iron has previously been used, but we strongly discourage its use due to the safety of new IV iron formulations, pain associated with intramuscular injection and the possibility of permanent skin discolouration.3

Three IV iron formulations are available on the Pharmaceutical Benefits Scheme in Australia: iron sucrose, iron polymatose and ferric carboxymaltose. Several others are available overseas (eg, iron dextran, ferumoxytol and iron gluconate). Iron sucrose and iron polymatose are second-generation iron agents that have largely been superseded by the newer formulation, ferric carboxymaltose, as they cannot be given in high doses because of possible instability in the iron–carbohydrate complex and toxicity from non-transferrin-bound iron.33 Ferric carboxymaltose has an excellent safety profile, is easily administered and can be given at high doses.34 It is administered at a dose of up to 1000 mg, either undiluted via a slow IV push or diluted in 250 mL of 0.9% sodium chloride over at least 15 minutes.33,34 For most patients, one dose of ferric carboxymaltose is sufficient to return haemoglobin and ferritin levels to within normal reference intervals. However, when required, a repeat dose can be administered 7 days after the first dose. In trials and post-marketing experience of ferric carboxymaltose, anaphylactic or anaphylactoid reactions have been reported in only about 0.1% of patients.31,34,35 More common adverse reactions include headache, nausea, injection site reactions, hypertension, hypophosphataemia (usually asymptomatic) and flushing. Importantly, rates of hypotension appeared to be lower with ferric carboxymaltose than with other iron formulations.34

Blood transfusions

Although red cell transfusion is an effective treatment for IDA, we recommend it only in life-threatening circumstances. As a single unit of fractionated red blood cells (resuspended) is estimated to contain about 200 mg of elemental iron,36 it is an inefficient method of replacing iron. Additionally, transfusion of red blood cells is expensive and exposes patients to rare but potentially life-threatening complications, including fluid overload and immunological and infectious hazards.3,37 We therefore only recommend it for use in patients who have severe anaemia that is compromising organ function (eg, angina pectoris or cardiac failure).3 When blood transfusion is required, each transfused unit of red blood cells is expected to increase the haemoglobin level by 10 g/L, in the absence of bleeding. We recommend transfusing the minimal number of units of red blood cells to control symptoms. Transfusion should always be followed by appropriate iron replacement (usually with IV iron, to facilitate the most rapid correction of haemoglobin level30).

Follow-up and further investigations

All patients should be routinely followed up after investigation and treatment of an underlying cause. Optimal timing of follow-up is not clear, as no firm guidelines exist. In our clinic, we routinely review patients with severe IDA (haemoglobin level < 80 g/L) within 2 weeks to ensure an appropriate reticulocytosis (indicated by a raised reticulocyte count and/or percentage) and response in haemoglobin level. We generally review patients with mild to moderate IDA (haemoglobin level > 80 g/L) in 3–6 months to ensure they remain iron replete and that no new symptoms requiring further investigation have evolved. Other clinicians may feel that more regular monitoring is warranted; we feel shorter intervals for follow-up are reasonable.

Common reasons why patients fail to respond to iron replacement therapies include poor adherence, impaired iron absorption and ongoing blood loss.3 When investigating a non-responding patient, we recommend that clinicians consider non-adherence and all conditions shown in Box 2, as well as following the algorithm in Box 4. Where appropriate, further investigation should include endoscopy to exclude gastrointestinal bleeding sources, regardless of symptoms, age and demographic characteristics. Failure to adequately monitor patients and appropriately investigate can have devastating consequences.38

Special situations

Children

As ID and anaemia have been associated with reduced cognitive function and behavioural problems in children, it is important to ensure they maintain adequate iron levels.5,8,9 We recommend the use of oral iron replacement as the first-line intervention for children (Box 7).39 IV iron can be given to children and has been shown to be safe when administered under the supervision of those familiar with its use.40 We recommend that children under the age of 16 years who need IV iron replacement because oral iron replacement has failed should see a specialist paediatrician for further investigation and appropriate dosing before receiving an IV iron infusion. Dosing is particularly important in children, as 20 mg/kg of elemental iron can be enough to cause iron poisoning, which can be lethal.41 Clinicians prescribing iron replacement therapies to children should educate parents to ensure that overdosing (either accidental or intentional) does not occur.

Pregnancy

Iron requirements are increased during pregnancy because of increased maternal red cell mass, placental and fetal iron requirements and peripartum blood loss.11 Additionally, it is commonly believed that breastfeeding increases the burden of iron loss in the nursing mother, although robust evidence for this is lacking.42 Regardless, women are at particularly high risk of ID and IDA during the peripartum period. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists recommends all women be screened using a full blood examination at the first antenatal (booking) visit, with further testing including iron studies when suspicion of ID is raised by the presence of anaemia or reduced mean corpuscular volume.43 Given that ID in pregnancy has been associated with adverse outcomes for infants,11,44 close monitoring and correction of ID is crucial for optimal perinatal care.

A systematic review found that daily oral iron therapy is effective at improving maternal iron status and haemoglobin levels, with no evidence of increased rates of adverse effects.45 Daily oral iron showed a trend towards increased birthweight and lower rates of preterm labour, although these outcomes were not statistically significant. Another systematic review found that, similar to the findings for non-pregnant women, intermittent oral iron therapy was effective at reducing rates of anaemia and improving iron status in pregnant women and is therefore an alternative for those who cannot take daily oral iron.46 IV iron is safe to use in pregnancy, with trials showing superior correction of haemoglobin level and iron status compared with oral iron, with minimal adverse effects.11,47 Given the potential (if unproven) benefits of correcting iron status in pregnant women and their infants, in our practice we have a lower threshold for IV iron administration in pregnant women.

Peri-operative care

Anaemia in the peri-operative setting is associated with increased morbidity and mortality.48 Additionally, blood loss associated with surgery increases iron requirements in the peri-operative period. Evidence suggests that pre-operative iron replacement therapy (either parenteral or enteral) can help reduce red cell transfusions and hospital length of stay.48,49 Post-operative use of ferric carboxymaltose has also been shown to be effective in improving post-operative haemoglobin levels and reducing red cell transfusions.50 While the role of iron replacement in the peri-operative setting is currently being further examined through a meta-analysis,51 we feel that oral or IV iron should always be considered in appropriate patients to help reduce surgical complications and red cell transfusions.

Conclusions

ID and IDA remain prevalent in Australia. Diagnosing ID can be difficult, particularly in the setting of inflammation, and the results of iron studies should always be considered as an overall picture rather than focusing on single parameters. Adequate management of ID involves investigation and treatment of the cause, as well as appropriate iron replacement with enteral or parenteral iron. All patients with ID should be monitored clinically to ensure that iron stores remain replete and that further investigation is performed when warranted.

Box 1 – Important causes of iron deficiency

Box 2 – Interpretation of results of full blood examination and iron studies*

Box 3 – Perls’ Prussian blue stain for iron on bone marrow biopsy samples

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A: Bone marrow particle showing adequate particulate iron (iron reserves), indicated by the presence of blue iron deposits. B: Bone marrow particle of an iron-deficient patient with marked reduction in iron, indicated by the lack of blue deposits.

Box 4 – Algorithm for investigating iron deficiency*

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FBE = full blood examination. * Adapted from the guidelines of the Gastroenterological Society of Australia and the Australian Iron Deficiency Expert Group.3,7 Clinicians should consider referring patients with unexplained bleeding to a specialist haematologist for further investigation of possible bleeding disorders.

Box 5 – Benefits and adverse effects of daily oral iron replacement, by age group*

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* Quality of evidence for an effect of daily oral iron replacement, as defined by the Cochrane Handbook for Systematic Reviews of Interventions using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach.27 The colours represent the quality of the evidence that daily oral iron replacement has an effect on the stated outcome, not the magnitude of its effect. The GRADE system also includes a “very low” quality category; none of the outcomes shown were classified in this category during meta-analysis.