Iron Deficiency Anaemia. Causes, Symptoms and Treatment

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Iron deficiency anaemia Causes, symptoms and treatment

LISA CLARKE MB BS, BMedSc; ANTHONY J. DODDS MB BS(Hons), FRACP, FRCPA Key points Iron deficiency anaemia remains a significant problem in Australia and • Iron deficiency is a has impacts on development, health and wellbeing. This review focuses significant problem in on the causes, diagnosis and management of iron deficiency and Australia. • Iron deficiency can occur provides some useful advice regarding iron replacement. with or without anaemia. • Measurement of serum iron ron deficiency is the most common nutri- BODY IRON STORES in isolation is not a reliable tional deficiency worldwide, affecting more At birth, a full-term baby is born with about screening test for iron than two billion people, and it is the under- 250 mg of stored iron. These stores are used deficiency. The diagnosis lying cause of anaemia in 50% of cases.1 during breastfeeding because breast milk only I 2 relies on the interpretation Although the burden is greater in developing provides 0.15 mg of absorbed iron per day. of iron studies. countries, iron deficiency with or without When oral intake of iron is adequate throughout • Iron deficiency results from anaemia remains a significant problem in childhood and adolescence, a net positive a combination of an increased Australia. Iron deficiency results from a com- iron balance of about 0.5 mg per day results demand, decreased intake or bination of increased demand, decreased intake in the accumulation of 3 to 4 g of body iron by absorption, and/or increased or absorption, and/or increased loss. Chronic ­adulthood.3 Two-thirds of these stores circulate loss. iron deficiency subsequently results in iron as haemoglobin and a further quarter is stored • Identifying and treating the deficiency anaemia. Tissue effects of chronic as ferritin or haemosiderin. About 1 mg of iron underlying cause of iron iron deficiency such as glossitis and pharyngeal is lost per day with up to an additional 1 mg lost deficiency are the most webs are now rarely seen in developed countries. per day in menstruating women. important aspects of The management of patients with iron defi- management. ciency involves identification and treatment of IRON SOURCES • Iron replacement with oral the underlying cause in addition to iron There are two types of dietary iron: iron supplementation should replacement. • haem iron – found in animal sources such be commenced in all patients with iron deficiency Dr Clarke is an Advanced Trainee in Haematology at St Vincent’s Hospital, Sydney. Associate Professor Dodds is as first-line therapy. Senior Staff Specialist in Haematology and Bone Marrow Transplantation, Kinghorn Cancer Centre, St Vincent’s Copyright _LayoutHospital, 1 17/01/12 Sydney; 1:43 and PM Associate Page Professor4 (Conjoint), School of Medicine, University of New South Wales,

Sydney, NSW. © SCIENCE PHOTO LIBRARY RM/DAVID MACK/DIOMEDIA.COM

36 MedicineToday x NOVEMBER 2014, VOLUME 15, NUMBER 11 Downloaded for personal use only. No other uses permitted without permission. © MedicineToday 2014. TABLE 1. RECOMMENDED DAILY INTAKE (RDI) OF IRON ACCORDING TO AGE GROUP4

Age group RDI (mg/day)

7 to 12 months 11 as red meat and, to a lesser extent, in poultry and fish 1 to 3 years 9 • nonhaem iron – found in eggs and 4 to 8 years 10 plant-based sources such as nuts, cereals, 9 to 13 years 8 bread, beans and vegetables. About 50% of haem iron is absorbed into Boys 14 to 18 years 11 the body whereas only up to 10% of nonhaem Girls 14 to 18 years 15 iron is absorbed. Vitamin C enhances the absorption of nonhaem iron, whereas calcium Men >18 years and women >51 years 8 inhibits the absorption of both haem and non- Women 18 to 50 years 18 haem iron. Gastric pH also influences iron absorption and is affected by the use of proton Pregnant women 27 pump inhibitors, the presence of Helicobacter Lactating women 9 pylori and atrophic gastritis in the elderly. Table 1 highlights the recommended daily intake of iron in various age groups.4 In practical terms, ferritin is an acute-phase reactant so a normal adults need to consume red meat two to three level does not exclude iron deficiency. There- times per week to meet their weekly iron fore, the result should be interpreted in the requirements. context of additional inflammatory markers, primarily C-reactive protein (CRP) levels. IMPACT OF IRON DEFICIENCY In the context of chronic inflammation, Iron deficiency has important consequences on such as inflammatory bowel disease, iron defi- development and a patient’s general health and ciency is likely when serum ferritin levels are wellbeing. Iron deficiency in pregnancy is asso- less than 50 µg/L. Care should be taken when ciated with an increased risk of low birth weight interpreting serum iron levels because they and maternal anaemia with its associated com- exhibit significant diurnal variation, are altered plications.5 Children’s mental and physical by a fed or fasted state and are influenced by development can be delayed or impaired by iron inflammation as the transferrin concentration, deficiency and in adults it can result in fatigue and therefore the serum iron level, falls in with subsequent reduced productivity and inflammatory states. Therefore, serum iron in behavioural issues.2 Iron deficiency is also asso- isolation is not a reliable screening tool for iron ciated with impaired immune function at all deficiency. ages, resulting in an increased risk of infection Iron deficiency anaemia is the most likely particularly upper respiratory tract infections. cause of hypochromic microcytic anaemia Iron deficiency anaemia results in the well- (Table 2); however, iron deficiency can occur in known symptoms of lethargy and dyspnoea on the context of a normal full blood count. It is exertion. worth noting that iron studies should be performed when screening patients for a DIAGNOSIS OF IRON DEFICIENCY haemoglobinopathy because testing is best ANAEMIA interpreted in the context of current iron studies. The World Health Organization defines ­anaemia The Figure is an example of a blood smear from as a haemoglobin level of less than 130 g/L in a patient with iron deficiency anaemia. men, less than 120 g/L in women and less than 110 g/L in pregnant women and children.2 CAUSES OF IRON DEFICIENCY In general, the diagnosis of iron deficiency The underlying causes of iron deficiency can can be made on serum iron studies, which are be either physiological or pathological. Physi- quick, easily accessible and inexpensive. The ological iron deficiency occurs at times of most reliable marker is serum ferritin. A low increased iron requirements in response to serum ferritin level of less than 15 µg/L is diag- periods of growth and development including nostic of iron deficiencyCopyright and _Layoutlevels between 1 17/01/12 15 1:43infancy, PM Page adolescence 4 and pregnancy. Patholog- and 30 µg/L are highly suggestive. However, ical iron deficiency generally results from occult

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TABLE 2. DIFFERENTIAL DIAGNOSIS OF HYPOCHROMIC MICROCYTIC ANAEMIA

Iron deficiency Anaemia of chronic Haemoglobinopathy disease

Hb N or ↓ ↓ N or ↓

Serum iron ↓ ↓ N

Ferritin ↓ N or ↑­ N

MCV N or ↓ N or ↓ ↓

RCC N or ↓ N or ↓ ↑­ Figure. Light micrograph of a blood Transferrin ↑­ N or ↓ N smear showing iron deficiency

ABBREVIATIONS: Hb = haemoglobin; MCV = mean corpuscular volume; N = normal; RCC = red cell count. anaemia. blood loss or malabsorption. The box dis- increase the risk of iron deficiency. Stud- adolescent women are thought to be iron cusses two cases of iron deficiency anaemia ies have found that about 15% of breastfed deficient.6 Dietary changes often occur with different causes. infants and 20% of infants with only in this age group as adolescents search cow’s milk in their diet are iron deficient.3 for autonomy and their choices are influ- Physiological iron deficiency Adolescence marks the second period of enced by their peers. In infants, low birth weight, exclusive rapid growth and development. This is A woman’s total iron requirement breastfeeding and early consumption of exacerbated in women by the onset of increases by 1 g during pregnancy due to an cow’s milk (before the age of 1 year) menstruation and about 20% of young increase in red cell mass and the development

EXAMPLES OF PATIENTS WITH IRON DEFICIENCY ANAEMIA

Case study 1 Case study 2 Ms TG was a 22-year-old university student who presented to Mr AK was a 64-year-old retired plumber who presented to the the emergency department with a two-month history of emergency department with a two-week history of progressive progressive lethargy, light headedness and shortness of breath shortness of breath on exertion and lethargy. on exertion. His medical history was significant for osteoarthritis, for Ms TG denied any significant medical or family history, was a which he took a sustained-release paracetamol tablet and lifelong nonsmoker and did not consume any alcohol. She gave ibuprofen as needed. He was an ex-smoker with a 15 pack-year a history of menorrhagia with menstruation lasting seven days history and he consumed about 10 standard drinks per week. and being ‘very heavy’ for the first four days. She was not taking On specific questioning, he said his osteoarthritis had been the oral contraceptive pill and had not sought any medical troubling him lately so he had been taking six to eight ibuprofen advice previously. She was also a vegetarian. tablets per day. Ms TG was anaemic with a haemoglobin level of 64 g/L and Mr AK was anaemic with a haemoglobin level of 78 g/L and hypochromic microcytosis (mean corpuscular haemoglobin hypochromic microcytosis (MCH 18.2 pg, MCV 68.4 fL). His iron [MCH] 14.4 pg, mean corpuscular volume [MCV] 56.2 fL). Her studies confirmed iron deficiency with the following results: iron studies confirmed iron deficiency with the following results: • iron level 2.8 mmol/L • iron level 2.2 mmol/L • iron saturation 2.4% • iron saturation 2% • transferrin 4.1 g/L • transferrin 4.5 g/L • ferritin 12 µg/L. • ferritin 3 µg/L. Mr AK was commenced on a proton pump inhibitor, told to She received one unit of packed red blood cells and an iron avoid NSAIDs and received an iron infusion. He also underwent infusion without complications. She was discharged and an endoscopy. An ulcer on the lesser curve of the stomach advised to discuss optimisation with her GP including referral to was identified with evidence of active bleeding and treated a gynaecologist. Copyright _Layout 1 17/01/12 1:43 PM Page 4 accordingly. © SPL/DR E. WALKER

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of the fetal–placental circulation. Breastfeed- children and in adults with refractory iron patients with iron deficiency anaemia ing results in about 1 mg of iron loss per day; deficiency. However, IgA levels should be detected in the pr­ imary care setting were however, this is generally counterbalanced measured to eliminate false negatives due subsequently found to have a malignancy by lactation-induced amenorrhoea. Finally, to IgA deficiency. of the gastrointestinal tract.9 A capsule the incidence of iron deficiency increases in The main cause of iron deficiency in endoscopy may be considered in those the elderly due to impaired iron absorption premenopausal women is heavy men- with a normal endoscopy and colonoscopy. secondary to the pro-inflammatory state strual blood loss defined as more than Faecal occult blood testing is not sufficient associated with ageing.7 80 mL of blood loss or menstruation because it is unable to differentiate between ­lasting more than seven days. Coexisting the ­different causes of gastrointestinal Pathological iron deficiency malabsorption or gastrointestinal blood blood loss. Coeliac disease is the most common cause loss rarely occurs, but should be investi- In a small subset of patients, an under- of malabsorption-associated iron defi- gated in cases of persistent iron defi- lying cause of iron deficiency cannot be ciency. Although duodenal biopsy remains ciency despite optimisation of iron found or patients are refractory to iron the gold standard for the diagnosis of replacement. replacement defined by the failure of ­coeliac disease, screening for anti-tissue In men and postmenopausal women, ­haemoglobin to rise by 10 g/L over four transglutaminase (anti-tTG) IgA anti­ gastrointestinal blood loss is the most com- to six weeks of appropriate iron replace- bodies has an estimated specificity of 99% mon cause of iron deficiency and referral ment. Referral to a haematologist should and sensitivity of 90%.8 (These antibodies to a gastroenterologist for consideration be considered for investigation of more are directed towards the enzyme tissue of an endoscopy and/or colonoscopy is obscure causes of iron deficiency such as transglutaminase, which is normally pres- indicated in all patients. The cause of blood disorders of iron regulation and func- ent in the gastrointestinal tract). As such, loss can range from gastric erosions sec- tional iron deficiency. Functional iron coeliac serology should be considered in ondary to NSAID use to colon cancer. One deficiency can be seen in patients with the initial workup of iron deficiency in study has found that about 11% of all end-stage renal failure and occurs when

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MED119_Discover_4567_HPC_AW_OL.indd 2 Downloaded for personal use only. No other uses permitted without permission. © MedicineToday 2014. 23/09/11 2:22 PM PERIOPERATIVE ASSESSMENT OF IRON DEFICIENCY IN THE 10 adequate iron stores are available but are PRIMARY CARE SETTING unable to be mobilised for red cell Patient presents for perioperative assessment production.

TREATMENT Is the patient anaemic? Treatment of patients with iron deficiency Women Hb <120 g/L anaemia should be focused on addressing Men Hb <130 g/L the underlying cause of the iron deficiency and replenishing iron stores. Increasing dietary iron intake alone is insufficient to treat cases of established iron deficiency. Yes No First-line therapy involves oral iron replace- ment in doses of 100 to 200 mg of elemental iron in two to three divided doses in adults Ferritin Ferritin Ferritin Ferritin Ferritin and 3 to 6 mg/kg of e­ lemental iron in chil- <30 µg/L 30-100 µg/L >100 µg/L <30 µg/L 30-100 µg/L dren.10 Reticulocytosis should occur within 72 hours of t­herapeutic iron replacement and haemoglobin levels should rise by Iron deficiency Possible iron Not iron Iron deficiency Possible iron about 20 g/L every three weeks.10 deficiency deficient deficiency It is recommended that iron sup­ plementation continue for three to six months once the haemoglobin level Investigate Interpret in Consider Investigate Consider iron has normalised to improve iron stores. including referral to context of alternative including referral to replacement Gastrointestinal­ ­disturbances including gastroenterologist CRP level causes of gastroenterologist if significant nausea and constipation are responsible Commence iron and renal anaemia Commence iron blood loss for the major side effects and in patients replacement function replacement expected with mild iron deficiency the dosing interval can be increased to every second ABBREVIATIONS: CRP = C-reactive protein; Hb = haemoglobin. day to minimise these complications. There are a number of different oral In Australia, three intravenous iron advantage of this preparation is that a iron preparations available and all preparations are currently available – iron single total dose can be administered ­contain different amounts of elemental polymaltose, iron sucrose and ferric within 30 minutes. Adverse reactions are iron. It is important to ensure that ­carboxymaltose. The major concern with rare and appear similar among the three patients are taking the appropriate prepa- intravenous iron replacement arose with preparations. ration to achieve daily therapeutic doses the occurrence of anaphylactic reactions Adverse reactions include sensations of elemental iron. to iron dextran. This preparation is no of warmth or itching, rash, chest pain, Parenteral iron therapy should be longer available in Australia. To date, no dyspnoea, nausea or headache at the time reserved for patients: cases of anaphylaxis have been reported in of infusion. Occasionally minor self-lim- • who are intolerant or noncompliant Australia to the currently available prepa- iting delayed arthralgias, headaches and with oral preparations rations; however, the data are limited. fevers occur. It should be given in a hos- • diagnosed with intestinal Iron polymaltose can be administered pital or clinic setting where access to malabsorption as a total dose infusion, but infusion resuscitation equipment is available. • who require rapid increases in times range from four to six hours. Iron Intramuscular iron replacement is best haemoglobin sucrose use is limited to patients with avoided because it is painful and associated • with ongoing losses that exhaust the chronic ­kidney disease, who are taking with permanent skin scarring.2 absorptive capacity. erythropoietin-stimulating agents and In general, haemoglobin responds faster react to iron polymaltose. Ferric carboxy- Red cell transfusion to intravenous iron therapy than to oral maltose given as an intravenous infusion The transfusion of red cells should be iron therapy. However, both methods has recently been listed on the PBS for reserved for patients with significant anae- achieve the same haemoglobinCopyright _Layout concentra 1 17/01/12- patients 1:43 PMwith Page iron 4 deficiency who cannot mia affecting end-organ function or when tion in time. tolerate oral iron preparations. The major ongoing acute blood loss is expected.

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SPECIAL CONSIDERATIONS care setting and has been adapted review. Nutricion Hospitalaria 2014; 29: 1240-1249. Pregnancy from the National Blood Authority’s 7. Spahn DR, Goodnough LT. Alternatives to blood Although pregnancy represents a time of perioperative­ guidelines.10 transfusion. Lancet 2013; 381: 1855-1865. increased iron demand, the National Blood 8. Hershko C, Camaschella C. How I treat Authority’s obstetrics and maternity guide- CONCLUSION ­unexplained refractory iron deficiency. Blood 2014; lines do not recommend the routine In the appropriate clinical setting iron defi- 123: 326-333. administration of iron supplementation to ciency should be considered even in the 9. Short MW, Domagalski JE. Iron deficiency all pregnant women.12 Instead they recom- absence of anaemia. The diagnosis relies anaemia: evaluation and management. Am Fam mend the commencement of iron replace- on the correct interpretation of iron studies Physician 2013; 87: 98-104. ment once iron deficiency is diagnosed. To with ferritin as the most useful marker. In 10. National Blood Authority. Patient blood manage- limit the development of gastrointestinal addition to iron replacement, identification ment guidelines: module 2 – perioperative. Canberra: side effects, and therefore improve compli- and treatment of the underlying cause are National Blood Authority; 2012. Available online at: ance, the guidelines recommend consid- essential for appropriate management. Oral http://www.blood.gov.au/system/files/documents/ ering the use of lower iron doses (20 to and intravenous iron replacement achieve pbm-module-2.pdf (accessed October 2014). 80 mg/day) if deficiency is diagnosed before the same results; however, intravenous 11. Auerbach M, Ballard JG. Clinical update: intrave- the development of anaemia. preparations more rapidly replenish hae- nous iron for anaemia. Lancet 2007; 369: 1502-1504. Intravenous iron replacement in preg- moglobin and iron stores and therefore 12. National Blood Authority. Patient blood nancy should be considered when haemo- should be considered when timely replace- ­management guidelines: module 5 – obstetrics and globin and iron stores need to be restored ment is required. Special considerations maternity. Canberra: National Blood Authority; 2014. rapidly or when oral iron supplementation should be made in pregnancy and in the Available online at: http://www.blood.gov.au/ is not tolerated. The risks of an iron infusion preoperative period to prevent the compli- system/files/documents/pbm-mod5-draft- in pregnancy are the same as for the general cations of anaemia and avoid unnecessary obstetrics-maternity-for-consultation.pdf (accessed population with the greatest concern being red cell transfusion. MT October 2014). the rare but potentially dangerous anaphy- 13. European Medicines Agency. New recommen- lactic reaction. As this potentially affects REFERENCES dations to manage risk of allergic reactions with not only the mother but also the developing intravenous iron containing medicines. London: fetus, the benefits need to outweigh any 1. International Nutritional Anemia Consultative EMA; 2013. Available online at: http://www.ema. potential risks. A recent European review Group (INACG), World Health Organization (WHO), europa.eu/docs/en_GB/document_library/Referrals_ has recommended the use of oral iron United Nations Children's Fund (UNICEF). Guidelines document/IV_iron_31/WC500151308.pdf (accessed ­supplementation in the first trimester and for the use of iron supplements to prevent and treat October 2014). then careful consideration of intravenous iron deficiency anaemia. Washington: ILSI Press; 1998. replacement in the second and third tri- Available online at: http://www.who.int/nutrition/ COMPETING INTERESTS: None. mesters with the preference for intravenous publications/micronutrients/guidelines_for_Iron_ replacement closer to delivery. supplementation.pdf?ua=1 (accessed October 2014). 2. Pasricha SR, Flecknoe-Brown SC, Allen KJ, et al. Online CPD Journal Program Perioperative assessment Diagnosis and management of iron deficiency anae- Does iron For every 100 mL of blood lost, the hae- mia: a clinical update. Med J Aust 2010; 193: 525-532. deficiency moglobin level drops by 2.5 g/L, 50 mg of 3. Zimmermann MB, Hurrell RF. Nutritional iron occur in iron is lost and 5 µg of ferritin is required deficiency. Lancet 2007; 370: 511-520. breastfed to restore the loss. In elective surgeries 4. Australian National Health and Medical infants? where patients are at risk of significant Research Council (NHMRC) and the New Zealand blood loss the preoperative assessment of Ministry of Health (MoH). Nutrient reference values iron stores in the primary setting allows for Australia and New Zealand. Canberra: NHMRC; adequate time to optimise red cell mass 2006. Available online at: http://www.nrv.gov.au/ and therefore prevent the complications nutrients/iron (accessed October 2014). © ISTOCKPHOTO/DEAN MITCHELL of anaemia and avoid unnecessary red 5. Haider BA, Olofin I, Wang M, Spiegelman D, Review your knowledge of this topic cell transfusion. This includes cardiotho- Ezzati M, Fawzi WW. Anaemia, prenatal iron use, and earn CPD points by taking part in racic, major ortho­paedic, vascular and and risk of adverse pregnancy outcomes: systemic MedicineToday’s Online CPD Journal Program. major general ­surgery. The flowchart is review and meta-analysis. BMJ 2013; 346: f3443. Log in to a useful guide for theCopyright perioperative _Layout assess 1 17/01/12- 6. C1:43airo RC,PM Silva Page LR, 4 Bustani NC, Marques CDF. www.medicinetoday.com.au/cpd ment of iron deficiency in the p­ rimary Iron deficiency anaemia in adolescents; a literature

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