Iron Deficiency: Translating New Evidence into Practice

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1 EXPERT MONOGRAPH ISSUE 16 title sub title Iron Deficiency: Translating New Evidence into Practice DR SANDRA MINCK DR PRADEEP JAYASURIYA MBBS, FRACGP MBBS Sandy is a Medical Officer with the Transfusion Policy and Education (TPE) team at the Australian Red Cross Blood Service. She comes from a General Practice background and has a long history in medical education, both in Australia and overseas. Sandy is actively involved in the development of numerous educational materials, tools and resources. She is particularly interested in safe and appropriate transfusion practices, patient blood management and iron deficiency anaemia. Dr Pradeep Jayasuriya is the principal of a small independent general practice in the Perth metropolitan area for the last 25 years. He led the development of the first community based iron infusion facility in collaboration with a Medicare Local and related educational activities. He is a member of the advisory group for the National Patient Blood Management Collaborative Project by the ACSQHC. Co-authors: Dr Michael Leahy MBChB, FRACP, FRCP (London), FRCPath and Trudi Gallagher RN This article discusses the importance, particularly in high risk groups, of the identification and correct management of iron deficiency Introduction T here is renewed interest in iron deficiency and a growing recognition of its impact on health outcomes. In Australia from 2013 to 2014, there were 42,466 potentially preventable hospitalisations for iron deficiency anaemia1 and primary care is strategically placed for early intervention. Iron deficiency and iron deficiency anaemia are common and prevalence increases with age. They are both associated with significant consequences, but these are preventable in many cases. Diagnosis is complicated by differences between laboratory reference ranges, variation in defined cut-off levels and the role of ferritin as an acute phase reactant. As research progresses, the diagnostic criteria have been redefined to provide better guidelines for patient management. Take Home Messages Iron deficiency is common and treating it before anaemia develops improves outcomes. Low ferritin is diagnostic of absolute iron deficiency, but a raised ferritin does not exclude it. Fasting samples give an accurate measure of serum iron and is necessary to calculate transferrin saturation. High ferritin and a transferrin saturation of lower than 20% is suggestive of functional iron deficiency. First line therapy is oral iron for most patients; intramuscular iron is best avoided. When iron deficiency is identified a cause (or causes) must be determined. Page 1

2 Hormonal Contraception Iron Deficiency: Trouble-shooting Translating title sub New title Part Evidence One: The into Overweight Practice Woman Iron Deficiency and Iron Deficiency Anaemia Are Common In Australia from 2011 to 2012, the incidence of anaemia in people aged eighteen and over was 4.5%. 2 The incidence was higher in women and the elderly, rapidly increasing to 16% in those over seventy-five years of age (Figure 1). 2 There are many reasons for anaemia and iron deficiency is the most common cause worldwide. 3 The relationship between iron deficiency and iron deficiency anaemia is depicted in Figure 2 as stages in a spectrum of the condition. Iron deficiency occurs before anaemia develops and is three times more common than iron deficiency anaemia. 4 Accurate assessment of the prevalence of iron deficiency in Australia is not available, but in a study of women under fifty years of age was stated to be 20%. 5 This figure is likely to be an underestimate, as it is a measure of absolute iron deficiency using a serum ferritin lower than 20 µg/l (this is well below the cut-off level of less than 30 µg/l that is now recommended by the Royal College of Pathologists of Australasia). 6 Figure 1: Incidence of Anaemia* in Australians Aged Twelve Years and Over, % Age group (years) *The definition of anaemia is based on World Health Organisation Guidelines of Hb below 130 g/l for males, 120 g/l for non-pregnant females, and 110 g/l for pregnant females. Source: Australian Health Survey: Biomedical Results for Chronic Diseases 2 tissue hypoxia and increased erythropoiesis. Low hepcidin levels increase iron absorption and release of storage iron. 3 Iron Deficiency Can Occur Even When Iron Stores Are Present Absolute iron deficiency occurs when there is insufficient iron in body stores for red blood cell production. In contrast, functional iron deficiency occurs when the iron in body stores cannot be effectively used for this purpose. Functional iron deficiency can occur through two main mechanisms. In anaemia of chronic disease, the iron is not utilised due to the action of elevated hepcidin levels that block the release of iron from storage cells (iron sequestration). 7 This occurs in inflammatory states such as chronic kidney disease, autoimmune conditions and malignancy. The second mechanism is where iron is unable to be released rapidly enough to keep pace with the demand for erythropoiesis, even when storage iron is present. This is most commonly seen in patients with chronic renal failure treated with erythropoiesis stimulating agents. 7 Absolute Iron Deficiency Can Be Prevented Absolute iron deficiency results from ongoing negative iron balance. Iron depletion leads to iron deficient erythropoiesis and culminates in iron deficiency anaemia (Figure 2). The progression to iron deficiency anaemia can be prevented if it is detected and appropriately managed. Iron Deficiency is Not Obvious Awareness is the first step towards diagnosis and management of iron deficiency. Patients with iron deficiency and iron deficiency anaemia may be asymptomatic or attend with nonspecific symptoms, such as tiredness or fatigue. Symptoms may not relate to the degree of iron deficiency. Iron deficiency will be present before anaemia develops and so may not be identified if the haemoglobin is normal. Knowledge of the causes and patient risk factors (Table 3) will enable appropriate testing. Hepcidin is the New Key Player in Iron Metabolism Normal iron utilisation in the body is tightly regulated with efficient salvage of iron from senescent erythrocytes and gastrointestinal absorption to balance the 1mg to 2mg daily losses. The role of hepcidin in iron homeostasis is now established. Hepcidin is a peptide hormone produced primarily in the liver that acts as an acute phase reactant. 3 Hepcidin controls plasma iron concentration and tissue distribution by regulating intestinal iron absorption, its recycling by macrophages, and mobilisation from hepatic stores. 3 Hepcidin is affected by inflammation and iron levels. 3 High hepcidin levels stimulated by systemic inflammation, infection or liver disease supress iron absorption and retain iron in macrophages and other cells. 3 Hepcidin production is inhibited by iron deficiency, Iron Deficiency Has Significant Consequences Iron is essential to many biological functions, including oxygen storage and transport, energy metabolism, nucleotide synthesis and host defence. 3,8,9 Deficiency results in numerous clinical consequences (Table 1). 3,7-10 In congestive heart failure, iron deficiency affects approximately 50% of patients. It relates to disease severity and is associated with a 60% increased mortality at six months. 10 In patients with congestive heart failure, ferritin may be raised as an acute phase reactant, and so patients with levels under 100 µg/l, or 100 µg/l to 299 µg/l, and with transferrin saturations of less than 20%, would be considered to be iron deficient. 10 Identification and treatment of iron deficiency with intravenous iron results in improved quality of life, an easier six minute walk test and a 68% decrease in hospitalisation for heart failure. 11,12 Page 2

3 Iron Deficiency: Translating New Evidence into Practice A significant consequence of untreated iron deficiency is the potential need for red blood cell (RBC) transfusion if haemodynamic compromise occurs. Whilst this will help to correct the anaemia, it does not address the underlying iron deficiency and iron stores still need to be replenished. A red cell unit contains around 220mg of Red blood cell transfusion does not address the underlying iron deficiency and iron stores still need to be replenished. iron. Approximate iron storage levels are 300mg in premenopausal females, 600mg in post-menopausal females and 800mg in males, so a typical transfusion will not replace iron stores. RBC transfusion is not without risk and in addition to potential adverse events is associated with increased mortality, morbidity and intensive care and hospital length of stay. 13 Therefore it is important to intervene early to prevent unnecessary transfusion. 13 Examples of Potentially Preventable Transfusions for Iron Deficiency Anaemia Include: Preoperative anaemia is found in approximately 30% of elective surgery patients and up to 75% of colorectal cases. It results in a 66% increase in morbidity and an 83% increase in thirtyday mortality. 14 If adequately managed, it has been estimated to result in an approximately 50% reduction of allogeneic RBC transfusions and shorter hospital length of stays. 15 An Australian tertiary level Obstetrics Unit retrospective audit found untreated anaemia prior to delivery in 12.2% of cases of post-partum haemorrhage. These women were almost twice as likely to receive a transfusion as those who did not have anaemia prior to delivery, but who also had a post-partum haemorrhage (31.3% compared to 17.8%). 16 Figure 2: Stages of Absolute Iron Deficiency SPECTRUM OF IRON DEFICIENCY STORAGE IRON (eg. liver, RES bone marrow) TRANSPORT AND FUNCTIONAL IRON (eg. HB, myoglobin and cytochromes) Storage iron present Storage iron depleted NORMAL IRON DEPLETION IRON DEFICIENT ERYTHROPOIESIS IRON DEFICIENCY ANAEMIA Iron depletion Iron deficient erythropoiesis Iron deficiency anaemia Progressive iron depletion Modified with permission from Sarah Cusick PhD, Centers for Disease Control and Prevention, 2008 Ferritin levels decrease as body stores become depleted. Transferrin saturation (reflecting iron transport capacity), declines. Total iron binding capacity (the number of available sites for transferrin to bind iron) increases. Iron available for red cell production is limited. The haemoglobin (Hb) is within normal range but may be lower than the person s usual Hb. Red cells distribution width (RDW) increases as red cells will vary in size. Mean cell haemoglobin (MCH) and mean cell volume (MCV) are usually still in the normal range, but may have fallen from usual level for that individual. Red cell production is reduced resulting in low Hb, MCH and then MCV. As Hb progressively decreases, abnormal red cells such as elliptocytes and pencil cells may appear on the blood film. Page 3

4 Iron Deficiency: Translating New Evidence into Practice Table 1 Clinical Consequences of Iron Deficiency 3,7-10 (composed by Authors) Anaemia Decreased memory, learning and concentration Impaired immune function, leading to increased risk of infection Decreased aerobic sports performance Decreased work productivity Fatigue, sleep disturbance Restless legs syndrome Increased risk of mortality and hospitalisation Increased risk of transfusion and associated outcomes Adverse pregnancy outcomes increased risk of low birth weight increased risk of prematurity increased risk of maternal morbidity Impaired motor and cognitive development and behavioural problems in children Laboratory Results Require Clinical Interpretation Diagnosis of iron deficiency and iron deficiency anaemia requires a full blood examination (FBE), iron studies and a C-reactive protein (CRP). The World Health Organisation (WHO) definitions of anaemia (including a haemoglobin level less than 130 g/l in males and less than 120 g/l in females), are higher than the lower limit of many Australian laboratory reference ranges (Table 2). 17 Table 2: WHO definition of anaemia according to age and gender 17 Age or Gender Group Children 6 to 59 months Children 5 to 11 years Children 12 to 14 years Non-pregnant females ( 15 years) Pregnant females Males ( 15 years) Haemoglobin (g/l) <110 g/l <115 g/l <120 g/l <120 g/l <110 g/l <130 g/l Iron studies are reported as ferritin (iron stores), serum iron, transferrin (or total iron binding capacity) and transferrin saturation (iron transport capacity). Fasting samples are preferred because these give an accurate measure of serum iron, which is necessary to calculate transferrin saturation. After ferritin, transferrin saturation is the next most important measure to consider when assessing a patient s iron status. Serum iron levels should not be used alone to diagnose iron deficiency. 6,8 A low serum ferritin is the most sensitive and specific test for absolute iron deficiency. 4,8,9 However higher levels do not necessarily exclude iron deficiency, because ferritin is an acute phase reactant and will be elevated in the presence of inflammation. Relying on serum ferritin alone will result in under-diagnosis of iron deficiency. There are variations in the reported ferritin cut-off, but overall consensus in the literature and the recommendation of the Royal College of Pathologists of Australasia is that a serum ferritin level of less than 30 µg/l in an adult is diagnostic of absolute iron deficiency. 5 As for the haemoglobin level, this is higher than the lower level of many laboratory reference ranges. Ferritin levels are affected by haemodilution, for example in pregnancy, but a cut off of <30 µg/l is still considered gold standard for diagnosis of iron deficiency. 6,18 A low serum ferritin is the most sensitive and specific test for absolute iron deficiency, however higher levels do not necessarily exclude iron deficiency The diagnosis of iron deficiency anaemia in the presence of inflammation may mean that a higher ferritin level cut-off level of 60 to 100 µg/l is required. 6,8 The C- reactive protein (CRP) will help to identify cases where inflammation is not clinically obvious. 6 Ferritin levels up to 300 µg/l can be present when there is functional iron deficiency in conditions such as heart failure and chronic kidney disease. 6 The serum transferrin saturation can be useful in these cases, as levels less than 20% saturation indicate that iron supply to the developing red cells is insufficient to support normal erythropoiesis. 19 The diagnosis of iron deficiency in patients with chronic conditions can be challenging, so seeking specialist advice may be necessary. In the future, tests such as serum transferrin receptor (stfr) levels and serum hepcidin levels will enable a more accurate determination of iron status and hence guide treatment. Currently these are tests that are not recommended in the General Practice setting as there are issues with reliability, standardisation and interpretation. The Cause of Iron Deficiency Must Be Determined Iron deficiency is not a diagnosis, but an indicator of other pathological processes (see Table 3). It occurs when requirements or losses exceed absorption. Causes are often multifactorial and dual Page 4

5 Iron Deficiency: Translating title sub New title Evidence into Practice pathology in the upper and lower gastrointestinal tracts occurs in 1-10% of patients, particularly if they are elderly. 4,8 Approximately 15% of patients with iron deficiency anaemia will have malignancy, most commonly of the gastrointestinal tract. 4 A rare autosomal recessive disorder, iron-refractory, iron deficiency anaemia (IRIDA) is unresponsive to oral iron and has recently been recognised. 3 Age-specific differential diagnoses in children with iron deficiency are summarised in the Neonatal and Paediatric Patient Blood Management Guidelines. 20 Most Cases of Iron Deficiency Can Be Investigated and Managed in Primary Care The guiding principle of management is that any level of iron deficiency or iron deficiency anaemia should have the cause investigated. Lower levels of haemoglobin should prompt more urgent investigation, as this suggests more serious disease. 4 Investigation of iron deficiency and iron deficiency anaemia should not delay the commencement of iron therapy. There are numerous guidelines available to assist with the investigation of this condition in adults and the key considerations are outlined in Table 4. 4,8,9,13,18,21 History, examination, the presence or absence of anaemia, age and gender all guide investigations. Faecal occult blood testing is of no benefit in the investigation of iron deficiency anaemia as it is insensitive and non-specific. 4 Medication history should not be neglected. For example, nonsteroidal anti-inflammatories (via gastrointestinal bleeding) and proton pump inhibitors (via malabsorption) are both associated with iron deficiency. Dietary Interventions are Inadequate to Treat Iron Deficiency Anaemia but are Important for Prevention Increasing the intake of foods containing iron in adults is inadequate to treat iron deficiency anaemia, however it may be valuable for secondary prevention. 8 Iron deficiency in infants and toddlers is typically a nutritional disorder and measures to improve dietary intake of iron-rich foods are fundamental for primary prevention and to prevent recurrence. 20 The recommended dietary intake (RDI) of iron is listed in Table Iron absorption also depends on the type of dietary iron consumed. Food provides iron in two forms: haem and non-haem. Haem iron is present in foods of animal origin (especially red meats, but also poultry and fish) and is absorbed four to five times more easily than non-haem iron, which is found in plant foods such as rice, maize, black beans, soybeans and wheat. The absorption of non-haem iron foods is three times greater when taken with haem iron foods. Vitamin C and acidic foods (e.g. vinegar, which is acetic acid, and lemon juice, which is citric acid), also enhance absorption of both haem and non-haem iron. Natural compounds found in plants such as oxalic acid (spinach), phytates (cereals and legumes), phosphates (eggs), polyphenols (red wine), tannins (tea and coffee) and some Table 3: Causes of Iron Deficiency and Patients at Risk 3,4,8,9 (composed by Authors) Cause Increased Demand (Physiological) Decreased Iron Intake (Environmental) Increased Iron Loss (Pathological) Decreased Iron Absorption (Pathological) Example/Patients at Risk Growing infants, children and adolescents Menstruating women Pregnancy, childbirth, lactation Individuals with a lack of balanced diet or poor oral intake, e.g. elderly low socio-economic status vegetarian or vegan diets excessive alcohol intake Patients with gastrointestinal blood loss, e.g. oesophagitis, gastritis and ulceration gastric or colonic carcinoma inflammatory bowel disease infection, e.g, intestinal parasites angiodysplasia medication related, e.g. aspirin, antiinflammatories Patients with non-gastrointestinal blood loss, e.g. menorrhagia blood donation post-op patients with significant blood loss haematuria e.g. renal tract malignancy Genetic Iron refractory irondeficiency anaemia Medications that decrease gastric acidity or bind iron e.g. protonpump inhibitors Chronic renal failure Malabsorption resulting from gastrointestinal disease or surgery, e.g.: coeliac disease, inflammatory bowel disease (e.g. ulcerative colitis, Crohn s disease) proteins (such as those found in soybeans) can bind to iron and limit absorption. When iron intake is marginal, it is therefore recommended to drink tea and coffee between meals instead of with them. Calcium-rich foods and calcium supplements inhibit the absorption of both haem and non-haem iron in foods. 9 Page 5

6 Iron Deficiency: Translating New Evidence into Practice Table 4: Factors to Consider When Investigating the Underlying Cause of Iron Deficiency Anaemia 4,6,8,9,13,18,21 All Patients Screen for coeliac disease (Grade B). 4,8,9,13 small bowel biopsy is essential to confirm the diagnosis. 4 Perform urine testing (Grade B). 4 approximately 1% will have renal tract malignancy. 4 Faecal occult blood testing is of no benefit (Grade B). 4 GI investigations if suggestive of upper or lower GI symptoms, regardless of age. 9 Males and Postmenopausal Females The most common cause of iron deficiency anaemia in adult males and postmenopausal females is gastrointestinal (GI) blood loss 4, iron deficiency is associated with a thirty-fold increase in the incidence of colorectal cancer. 6 Upper and lower GI investigations should be considered unless there is significant overt non-gi blood loss (Grade A). 4 In young males it is reasonable to avoid investigations where there is an obvious cause of blood loss (e.g. blood donation) unless anaemia recurs despite correction of that cause (Grade C). 4 Premenopausal Females Menstrual blood loss is the most common cause of iron deficiency anaemia in premenopausal females; increased demands of pregnancy and breastfeeding, and dietary deficiency also contribute. 4,8,9 Consider other causes of blood loss (including blood donation) and/or inadequate iron intake. 4,8,9 GI investigation should be reserved for those with symptoms suggesting GI disease, a strong family history of colorectal cancer (two affected first-degree relatives or just one first-degree relative affected before the age of fifty), or persistent iron deficiency anaemia after iron supplementation and correction of potential causes (Grade B). 4 Pregnant Females A trial of oral iron should be considered as the first line diagnostic test for normocytic or microcytic anaemia. An increase in haemoglobin must be demonstrated at two weeks, otherwise further tests are needed (Grade 1B). 18 Serum ferritin should be checked prior to starting iron therapy in patients with known haemoglobinopathy (Grade 1B). 18 If response to oral iron replacement is poor, concomitant causes that may be contributing to the anaemia, such as folate deficiency or anaemia of chronic disease, need to be excluded. The patient may need to be referred. (Grade 1A). 18 Iron Deficiency Without Anaemia Iron deficiency without anaemia is three times as common as iron deficiency with anaemia. 4 There is no consensus on whether patients with iron deficiency without anaemia should be investigated, however the British Society of Gastroenterology tentatively recommends: Coeliac serology in all patients; Perform GI investigation only for postmenopausal women and men over fifty years and only after discussing the risks and benefits (Grade C); 4 prevalence of cancer is 0.9% in men and postmenopausal women, who have iron deficiency without anaemia, but approaches 0% in premenopausal women; 4 Treat all others empirically with oral iron replacement for three months and investigate if iron deficiency recurs within twelve months (Grade C). 4 Preoperative Patients Patients with unexplained iron deficiency anaemia or unexplained isolated hypoferritinaemia (serum ferritin under 15 µg/l) should be considered for further investigation and/or specialist referral (Grade 1B). 21 Consult with team and consider deferral of non-urgent surgery until anaemia is investigated and treated. 13,21 Page 6

7 A Little Red FAVOURITE of THE IRON DEFICIENT WOMAN # FERRO-GRAD C ORAL FIRST-LINE TREATMENT FOR IRON DEFICIENCY 1 Ferro-Grad C is Australia s No.1 GP-recommended iron supplement 2 the only one with added Vitamin C to aid absorption. *1,3 Recommend daily for 3-6 months. 1,4 # Based on IMS Sales Data, February Market research, October 2014, GP diagnosed iron deficient consumers. *Of the commercially available forms of iron therapy suitable for the treatment of iron deficiency anaemia. Ferro-Grad C contains dried ferrous sulphate 325 mg (equivalent to 105 mg elemental iron) and sodium ascorbate mg (equivalent to 500 mg Vitamin C). For the prevention and treatment of iron deficiency. References: 1. Iron Deficiency [revised March 2016]. In: etg complete [Internet]. Melbourne: Therapeutic Guidelines Limited; March Accessed April National Prescribing Service (NPS). Case study 66 report: Iron-deficiency anaemia. January Brise H & Hallberg L. Acta Med Scand 1962;171 (Suppl 376): Pasricha SS et al. Med J Aust 2010;193: Mylan Health Pty Ltd trading as Mylan Health (ABN ) of Level 1, 30 The Bond, Hickson Road, Millers Point, NSW 2000, Australia. Ph: Ferro-Grad C is a registered trademarks. FCG April 2017 ABB3325_A3.

8 Iron Deficiency: Translating New Evidence into Practice Table 5: NHMRC Recommended Dietary Intake (RDI) of Iron (mg/day) 22 Age Male Female Pregnancy 0-6 mths mths years years years years years > 51 years 8 8 The First Line Treatment is Oral Iron Oral iron is a suitable and effective first line therapy for most patients. The usual recommended adult dose is 100mg to 200mg of elemental iron in two to three divided doses per day. 8 Only a few of the vast array of iron containing preparations available from the supermarket and pharmacies have sufficient quantities of iron for therapeutic purposes. There are aids available to assist with iron product choice and prescription advice For example, Iron product choice and dose calculation guide for adults includes a chart of currently available oral iron preparations that contain sufficient iron for therapeutic purposes (Table 6) and considerations regarding dosage. 25 A handout specifically for maternity patients demonstrating common pregnancy vitamins and their iron content compared to recommended products is also available. 26 There is a lack of randomised controlled trials on the treatment of iron deficiency anaemia in the paediatric population. Trials that are focused on the iron formulation, dose, adverse effects, adherence and total length of therapy are needed to better inform treatment decisions. 20 However, oral iron therapy is considered safe and effective as first-line therapy in most paediatric patients with iron deficiency or iron deficiency anaemia. The recommended dosage for the treatment of iron deficiency anaemia in children is 3 to 6 mg/kg/ day of elemental iron, depending on the degree of anaemia. Dosing guidance for paediatric patients is now available in Patient Blood Management Guidelines Module 6: Neonatal and Paediatrics. 20 Iron salts (ferrous sulphate and fumarate) should ideally be taken on an empty stomach, however iron polymaltose is advised to be taken with food. Ascorbic acid (250mg to 500mg twice daily with the iron preparation) may enhance iron absorption, but there are no data for its effectiveness in the treatment of iron deficiency anaemia. 4 Other considerations include avoiding taking iron supplements with foods that may inhibit iron absorption (see section on Dietary Interventions above). 9 Common side-effects of oral iron therapy are gastrointestinal, including nausea and constipation. Lower dosing (e.g. 20mg to 80mg daily) or intermittent dosing (one 200mg tablet, two to three times per week) may be better tolerated than higher doses 8,27-28 and may be considered in pregnant patients who have iron deficiency without anaemia. 29 Recent studies suggest that intermittent dosing may reduce the raised hepcidin levels associated with daily oral iron dosing and allow improved iron absorption, however further studies are required before introducing to routine practice. 27,28 Haemoglobin levels should rise by approximately 20 g/l every three weeks following daily therapeutic doses of oral iron. 8 Timing of review and response to therapy will depend on the degree of anaemia and may be affected by adherence due to side-effects. An initial check at approximately three weeks will determine if the haemoglobin is rising as expected and will provide an opportunity to discuss the importance of ongoing therapy. Oral iron therapy should be continued for three months after normalisation of the haemoglobin in order to replenish stores. 4,8 Adequate replacement should be confirmed with iron studies to evaluate iron status a week or two after therapy has ceased. 9 Persisting normal iron stores should be confirmed again a few months after repletion to ensure iron deficiency has not recurred. 9 Multiple Factors May Contribute to an Inadequate Response to Oral Iron There are many reasons for an inadequate response to oral iron. Inadequate intake can occur if patients cease or decrease the dose due to side-effects. This can also occur if patients are using a supplement that does not contain a therapeutic dose of iron. 8 Inadequate absorption may be due to intestinal mucosal disorders such as coeliac disease (which must be excluded) or inflammatory bowel disease. 8 Concomitant consumption of iron inhibitors or medications which impair gastric acid secretion (such as proton pump inhibitors and H2-receptor antagonists) may also limit absorption. 8 Helicobacter pylori infection decreases iron absorption by a number of mechanisms. 3,8 Ongoing iron losses in excess of absorption can occur with gastrointestinal, genitourinary and haematological disorders. 8 Co-existing conditions interfering with the bone marrow response can impair effectiveness of oral iron, including primary bone marrow disease or suppression; superimposed infection; inflammation; malignancy or renal failure; and concomitant vitamin B12 or folate deficiency. 8 Incorrect diagnosis, multiple pathologies and/or alternative diagnoses such as haemoglobinopathy; anaemia of inflammation or chronic renal failure (functional iron deficiency); or other causes of anaemia such as haemolysis should also be considered. 8 Iron refractory irondeficiency anaemia is a genetic disorder which is unresponsive to treatment with oral iron. 3 Intravenous Iron is an Option When Oral Iron is Inadequate Intramuscular iron is discouraged when alternatives are available as it is painful, associated with permanent skin discolouration 8,29 and is variably effective. 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9 Iron Deficiency: Translating New Evidence into Practice Table 6: Oral Preparations for Treatment of Iron Deficiency Anaemia in Australia 25 Name Manufacturer Tablet Formulation Elemental Iron Content FERRO-GRAD C Mylan (formerly Abbott) Ferrous Sulphate 325mg Ascorbic acid 500mg Modified release tablet 105mg FERRO-GRADUMET Mylan (formerly Abbott) Ferrous Sulphate 325mg Modified release tablet 105mg FGF Mylan (formerly Abbott) 250mg Ferrous Sulphate Modified release tablet 80mg FERRO-LIQUID PBS listed AFT pharmaceuticals Ferrous Sulphate Oral solution 30mg/5 ml Ferro-f-tab AFT pharmaceuticals Ferrous Fumarate 310mg Folic acid 350 mcg 100mg Ferro-tab AFT pharmaceuticals Ferrous Fumarate 200mg 65.7mg Maltofer # Aspen Pharmacare Iron polymaltose 370mg 100mg Maltofer Syrup # Aspen Pharmacare Iron polymaltose 185mg Oral solution 50mg/5ml FEFOL Iron & folate supplement Pharm-a-care Ferrous Sulphate 270mg Folic acid 300 mcg Delayed release capsule 87.4mg # Response to oral iron polymaltose (Maltofer) may be slower than with ferrous iron. Maltofer is licensed in Australia for treatment of iron deficiency in adults and adolescents where the use of ferrous iron supplements is not tolerated, or otherwise inappropriate. Modified from: BloodSafe Oral Iron Table Version 1.7 October 2011, TP-L National Blood Authority, Iron Product Choice and Dose Calculation, Page 9

10 Iron Deficiency: Translating New Evidence into Practice ADVERTISEMENT IDA algorithm app Red blood cell transfusion should only be used in the rare instances where severe anaemia compromises end-organ function (e.g. angina or cardiac failure) or serious, acute ongoing blood loss is occurring. 8,13 If required, iron stores must also be replaced. 8,13 Intravenous iron is indicated in cases where oral iron is ineffective, cannot be used, or when rapid restoration of haemoglobin and iron stores is required (Table 7). 3,4,8,9 There are three intravenous iron preparations available in Australia: ferric carboxymaltose, iron sucrose and iron polymaltose. All have good evidence for safety and efficacy in a range of patient groups. 25 Rates of infusion and maximum dose per infusion are not interchangeable among the three preparations. 25 Intravenous iron increases haemoglobin levels more quickly than oral iron. An allergy to one agent does not necessarily preclude the use of another. In the past, intravenous iron was administered primarily in a hospital setting. However when intravenous iron is indicated, newer preparations allow for safe and effective iron replacement in primary care. Adequate staff training, protocols and procedures, and resuscitation equipment are essential requirements to administering IV iron in primary care. Summary Iron deficiency and iron deficiency anaemia are common. General practitioners play a primary and central role in identification, diagnosis and management of patients who have, or at risk of having iron deficiency and iron deficiency anaemia. 30 An improved knowledge of iron metabolism, understanding how to interpret laboratory investigations and knowing new management strategies will enable earlier and more effective intervention and management of this condition. Acknowledgement Australian governments fund the Australian Red Cross Blood Service for the provision of blood, blood products and services to the Australian community. Table 7: Indications for Intravenous Iron 3,4,8,9 (composed by Authors) Declaration Dr Sandra Minck, Dr Pradeep Jayasuriya, Trudi Gallagher and Dr Michael F Leahy were commissioned by Healthed for this article. The ideas, opinions and information presented are solely those of the authors. Intolerance of oral therapy after modification of dose, timing and frequency; Non-adherence with oral therapy; Lack of efficacy of oral therapy (including iron refractory iron deficiency anaemia) Ongoing blood loss in excess of iron absorption; Intestinal malabsorption (note that in inflammatory bowel disease, oral iron may also aggravate intestinal inflammation); Severe iron deficiency needing rapid iron repletion to prevent physical decompensation/red cell transfusion e.g. a short-time to non-deferrable surgery associated with blood loss; Pregnancy (beyond first trimester) and postpartum if lack of efficacy/tolerance/compliance, or to avoid imminent decompensation or need for red cell transfusion; Treatment of absolute or functional iron deficiency in chronic heart failure is a potential indication (with limited supporting data). Note: Confirmed iron deficiency by laboratory testing is first required The authors declare no significant competing financial, professional or personal interests that might influence this article. Page 10

11 Iron Deficiency: Translating New Evidence into Practice Video Resources Managing Iron Deficiency And Intravenous Iron Replacement by Dr Pradeep Jayasuriya Iron Infusions Practical Set Up by Dr Pradeep Jayasuriya Iron Deficiency Clinical Situations by Dr Pradeep Jayasuriya Iron Deficiency In Women Assessment & Management by Dr Pradeep Jayasuriya Watch full lectures on the Healthed website. Visit Further Reading Patient Blood Management Guidelines: Module 6 Neonatal and Paediatrics. National Blood Authority [cited 4 May 2016]. Available from: National Blood Authority. Iron product choice and dose calculation guide for adults. [Internet] [cited 26 November 2015]. Available from: Gastroenterological Society of Australia. Clinical update: Iron deficiency, 1st Edition. Sydney, Australia, Digestive Health Foundation, Updated October Available from: clinical-guidelines-and-updates/iron-deficiency/ Co-authors Medicine. He led the successful patient blood management program at Fremantle Hospital from 2008 to 2015 and was state director of the WA blood management program. He is Clinical Professor in Medicine at the University of Western Australia TRUDI GALLAGHER RN Ms. Gallagher is the Senior Comprehensive Patient Blood Management Specialist for ACCUMEN (USA based company). She is the former State Clinical Coordinator for Patient Blood Management for the Western Australia Department of Health (2011 through 2015) under the direction of the Chief Medical Officer of the DOH. During her time in Western Australia she sat on National PBM Steering Committee (established by the National Blood Authority). She has specialized in the field of patient blood management for over 20 years. Her sub specialty is iron deficiency with or without anaemia as well as implementing well rounded PBM programs. She has been an RN over 45 years. DR MICHAEL F LEAHY MBChB, FRACP, FRCP (London), FRCPath Dr Michael Leahy is currently a Consultant Haematologist, Head of Haematology at Royal Perth Hospital and the Deputy Director of the Fiona Stanley Hospital Network of PathWest Laboratory References A list of references is included in the website version of this article. Go to Page 11

12 HAY FEvEr relief ASAp *1 15 mins * 1 *Provides hayfever symptom relief within 15 minutes. ALWAYS READ THE LABEL. USE ONLY AS DIRECTED. IF SYMPTOMS PERSIST SEE YOUR HEALTHCARE PROFESSIONAL. References: 1. Azep Nasal Spray Product Information. Azep contains azelastine hydrochloride. Meda Pharmaceutical Pty Ltd (a Mylan Company), Hickson Road, Millers Point NSW Tel: /2017 AZE