Iron deficiency anaemia and iron therapy

Iron deficiency anaemia (IDA)

Anaemia is defined by the World Health Organization as a Hb level below 120 g/L in non-pregnant females and 130 g/L in males, which is consistent with the definition of anaemia in the National Blood Authority Patient Blood Management Guidelines.

Iron deficiency is the most common nutrient deficiency worldwide. If left untreated it can result in anaemia. The signs and symptoms of iron deficiency can include fatigue, inability to tolerate exercise and shortness of breath on exercise, craving substances that are non-nutritive (pica), restless legs syndrome, headache and weakness.

Patients with conditions such as heart failure (Grote Beverborg, et al. 2019) and ischaemic heart disease (Perera, et al. 2019) may have a worse prognosis and exacerbation of symptoms due to iron deficiency and anaemia.

Iron deficiency can occur at any stage in life and is often multifactorial. It results from physiological (such as periods of rapid growth and development, inadequate dietary intake, heavy menstrual loss and pregnancy) or pathological causes, (such as occult blood loss or malabsorption (Clark & Dodds, 2014).

Common causes of anaemia in older patients include iron deficiency (for example, due to chronic blood loss), Vitamin B12 or folate deficiency, anaemia of chronic disease/inflammation and chronic kidney disease.

The aetiology of anaemia should be identified and, if necessary, patients referred for further investigation and treatment.

Prior to surgery where there is a risk of blood loss of 500mL or greater, the assessment and optimisation of a patient is essential to identify and manage iron deficiency (ID) and iron deficiency anaemia (IDA) in a timely manner, as identified in PBM Module 2. The purpose is to improve patient outcomes and potentially reduce the risk of a blood transfusion. This should be discussed with patients as it may impact on the timing of surgery.

When assessing patients pre-operatively a thorough history and examination should be performed, along with a full blood count, (considering red cell indices/blood film examination/reticulocyte count), iron studies including ferritin, CRP and renal function. The current FBE should be compared with any previous full blood examination results available.

In patients without a clear physiological explanation for iron deficiency (especially men and post-menopausal women), referral to an appropriate specialist for further investigation/management (for evaluation by colonoscopy/gastroscopy to exclude a source of GI bleeding, particularly from a malignant lesion) should be made. Patients with iron deficiency should be assessed for undiagnosed coeliac disease.

Diagnosing iron deficiency (ID) or iron deficiency anaemia (IDA)

Iron deficiency anaemia may be effectively diagnosed in most cases by full blood examination and serum ferritin levels. Serum iron should NOT be used to diagnose iron deficiency. It is markedly labile, has diurnal variation and is also low in the presence of inflammation.

In the elderly or among patients with inflammation, iron deficiency may still be present with ferritin levels up to 60 -100 ug/L.

Measurement of C-reactive protein (CRP) may help identify co-existing inflammation. If uncertain, consult a haematologist. Clinicians need to be aware that numerous factors, can inhibit or block iron absorption or iron availability for erythropoiesis.

The effect of suboptimal iron stores in surgical patients

Surgical patients with suboptimal iron stores (as defined by a ferritin level < 100 mcg/L) in whom substantial blood loss (blood loss of a volume great enough to induce anaemia that would require therapy) is anticipated, should be treated with preoperative iron therapy (NBA 2012). Such patients may not have sufficient iron stores to recover their Hb post-operatively.

If preoperative ferritin is less than 100 mcg/L, blood loss resulting in a postoperative haemoglobin drop of more than 30 g/L would deplete iron stores (NBA, 2012). Further information regarding iron deficiency can be found in the Iron Deficiency Clinical Update 2022 on the Gastroenterological Society of Australia website.

General information for patients, families and carers can be found at BloodSafe South Australia Health.

Iron replacement

Choosing the type of iron replacement therapy is dependent on factors such as the severity of the anaemia, cost and availability of products, the ability of patients to tolerate oral preparations and the urgency of the iron replacement therapy.

Oral iron supplements

Most patients with uncomplicated iron deficiency anaemia may receive a trial of oral replacement therapy, as these products tend to be relatively inexpensive and easy to administer.

Oral iron preparations are available in both ferrous and ferric states. Ferrous salts are preferred as they are absorbed more readily.

Therapeutic doses of iron will slowly raise haemoglobin concentrations and should increase haemoglobin levels by 10 g/L in 2 - 3 weeks. Up to date Treatment of iron deficiency anaemia in adults reports that haemoglobin levels should return to normal by six to eight weeks. Further information is available at Treatment of iron deficiency anemia in adults - UpToDate.

A guide to taking oral iron tablets by Blood Safe SA Health outlines general information for patients, families and carers about oral iron therapy.

Comparative charts on oral iron preparations covering several different brand names and formulas, including the amount of elemental iron in each tablet, available in Australia can be found at:

• BloodSafe SA - The oral preparations for treatment of iron deficiency in Australia chart
• Australian Red Cross Lifeblood - Oral Iron Choices for Adults

Failure of oral iron therapy

Gastrointestinal side effects are extremely common. Up to date (2021) gastrointestinal side effects include nausea, vomiting, constipation, diarrhoea, dark-coloured stools and/or abdominal distress.

Poor adherence to oral therapy or gastrointestinal side effects remains a common reason for using IV iron.

Some strategies for minimising the adverse effects of oral iron:

• starting with half the recommended dose and gradually increasing to full dose
• taking the supplement in divided doses
• changing to a different iron preparation
• concomitantly using a stool softener to help alleviate constipation
• alternate day dosing.

Intravenous iron therapy

While oral iron remains the cornerstone of iron deficiency anaemia (IDA) therapy, some patients require intravenous (IV) iron therapy. IV iron is becoming a more common treatment as the newer preparations have improved safety profiles.

Iron polymaltose (Ferrum H® [Aspen Pharmacare], Ferrosig® [Sigma Pharmaceuticals]) Ferric carboxymaltose (Ferinject® [Vifor Phama]), iron sucrose (Venofer® [Aspen Pharmacare]) and Ferric derisomaltose (Monofer®) are the parenteral iron formulations currently available in Australia.

A ‘total-dose’ infusion (where iron stores can be replenished in a single treatment episode) can be administered with iron polymaltose. Ferric derisomaltose may be given at a dose of 20mg/kg in a single dose, to a maximum of 1,500mg, which may be sufficient to replenish iron stores in a single dose.

To ensure consistent iron therapy practice, it is important to seek pharmacy and health service policy committee approval regarding policy introduction into your own health service. These resources and guiding principles may assist you in developing policies and procedures.

Comparison of intravenous iron preparations, use and dosing is available at BloodSafe SA.

Iron product choice and dose calculation for adults: Guidance for Australian health providers - Developed by the Transfusion Policy and Education Unit of Australian Red Cross Lifeblood and published by the National Blood Authority. This document provides a comprehensive guide to iron therapy.

Contact the manufacturer for information on cost of iron preparations.

Precautions

• Iron may increase the pathogenicity of certain micro-organisms.
• Intravenous iron should not be administered concomitantly with oral iron preparations. Oral iron should not commence until at least one week after the last iron injection.
• There is a risk of hypersensitivity reaction with each IV iron administration, therefore the number of single IV iron administration should be kept to a minimum.
• Patients should be monitored for signs and symptoms of hypersensitivity reactions.
• Patients receiving IV iron therapy should be monitored for extravasation. Leakage of iron preparations can result in skin irritations and permanent brown discolouration (skin staining) at the injection site. Distant skin staining has been reported.
• Always read the product information before administering IV iron preparations.

Acute adverse reactions

• Acute severe hypersensitivity reactions usually occur in the first few minutes of administration; characterised by a sudden onset of respiratory difficulty and/or cardiovascular collapse.
• There have been reports of hypersensitivity reactions progressing to Kounis syndrome, an acute allergic coronary arteriospasm that can result in myocardial infarction.
• Oher signs and symptoms of adverse reactions include:
  • Facial flushing
  • Acute chest and or back pain
  • Chest tightness, with or without dyspnoea
• Management of adverse reactions
  • Stop the infusion
  • Provide supportive care/ emergency treatment if necessary
  • Assess vital signs
• IV iron (particularly Ferric carboxymaltose) can cause hypophosphataemia which in most cases is transient and without clinical symptoms. Cases of hypophosphataemia requiring medical attention have been reported, mainly in patients with existing risk factors and after prolonged exposure to high-dose IV iron. Cases of hypophosphataemia leading to hypophosphataemic osteomalacia and fractures have been reported. Patients should be asked to seek medical advice if they experience arthralgia or bone pain. Refer to product information for more information.
• If symptoms are mild and disappear shortly after the infusion is stopped, the infusion may be restarted at a slower rate (after medical review and on medical advice).
• Adverse reactions should be reported to the manufacturer.

Considerations for developing policies

When developing or reviewing policies for iron infusion, consideration must be given to the following points:

• patient information and consent, including risks of potentially permanent skin staining
• preparation and storage of infusion once reconstituted per product information
• patient monitoring and adverse reaction/anaphylaxis protocols and reporting (recognise, respond, report)
• approval for use from relevant committees within your health service
• awareness and education of staff prescribing and administering IV iron products.

Guidance for individual iron products

Iron polymaltose (Ferrosig) product information (tga.gov.au)

Ferric derisomaltose (MONOFER®) (tga.gov.au) - A proposed infusion guide provided by the manufacturer of Monofer®. It is intended as a guide only and relates to the specific product.

Ferric carboxymaltose (Ferinject) product information

Iron sucrose (Venofer)

National Blood Authority 2012, Patient Blood Management Guidelines: Module 2 – Perioperative, Australian Capitol Territory, Canberra.
Pasricha, SR, Tye-Din, J, Muckenthaler, M U, Swinkels, D W 2021, “Seminar: Iron Deficiency”, The Lancet vol 397, pp233-48

Perera, C A, Biggers, R P, Robertson A 2019, “Deceitful red-flag: angina secondary to iron deficiency anaemia as a presenting complaint for underlying malignancy”, BMJ Case Report