Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease. It affects approximately two billion people worldwide, is a global health concern and a common comorbidity in multiple medical conditions. Iron deficiency in the absence of anaemia occurs more frequently.
Particularly affecting growing children, pre-menopausal and pregnant women, IDA is increasingly a clinical condition that can also affect older people and those with chronic conditions.
Several chronic diseases are frequently associated with IDA, notably chronic kidney disease, chronic heart failure, cancer, and inflammatory bowel disease.
Anaemia can be defined as a haemoglobin (Hb) concentration below the lower limit of normal for the relevant population and laboratory performing the test.
The World Health Organisation (WHO) defines anaemia as a haemoglobin concentration below 130g/L in men over 15 years of age, below 120g/L in non-pregnant women over 15 years of age, and below 110g/L in pregnant women in the second and third trimester. IDA, according to the Global Burden of Disease Study 2016, is one of the five leading causes of years lived with disability burden and is the first cause in women.
Globally, IDA has medical and social impacts, accounting for impairment of cognitive performance in young children, adverse outcomes of pregnancy for both mothers and newborns, decreased physical and working capacities in adults, and cognitive decline in older people.
The aetiology of IDA is variable and attributed to several risk factors; decreasing iron intake and absorption or increasing demand and loss, with multiple aetiologies often coexisting in an individual patient.
There are multiple physiological, environmental, pathologic and genetic causes of iron deficiency that lead to IDA. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal pathologies.
The multiple aetiologies and non-specificity of symptoms can challenge the diagnosis, and the availability of different formulations of iron supplementation can complicate treatment decisions.
Iron homeostasis involves a number of important processes, including the regulation of intestinal iron absorption, the transport of iron to the cells, the storage of iron, the incorporation of iron into proteins, and the recycling of iron after red blood cell degradation.
As there is no active iron excretion mechanism, under normal physiological conditions iron homeostasis is strictly controlled at the level of intestinal absorption.
Iron deficiency occurs in two main forms: Absolute, or functional. Absolute iron deficiency arises when total body iron stores are low or exhausted.
Absolute iron deficiency may occur in instances of increased demand, decreased intake, decreased or malabsorption, or chronic blood loss.
Functional iron deficiency is a disorder in which total body iron stores are normal or increased, but the iron supply to the bone marrow is inadequate. Absolute and functional deficiencies can coexist.
Pathophysiology
Iron, a micronutrient, is essential for life. It is an essential component of haemoglobin in red blood cells and of myoglobin in muscles, which contain around 60 per cent of total body iron. Iron is also necessary for the functioning of various cellular mechanisms, including respiration, enzymatic processes, DNA synthesis, and mitochondrial energy generation.
In adults, the body contains 3-to- 5g of iron and 20-to-25mg is needed daily for production of red blood cells and cellular metabolism. Because dietary intake is limited (1-to-2mg per day), other sources are needed for iron homoeostasis, including recycling of ageing erythrocytes in macrophages, exchange of iron in iron-containing enzymes, and iron stores.
About 1-to- 2mg of iron is lost daily as a result of menstrual bleeding, sweating, skin desquamation, and urinary excretion. Iron does not have an excretion regulation pathway, and dietary intake, intestinal absorption, and iron recycling have to be finely regulated.
Dietary iron is available in two forms; haem, and non-haem iron. Haem iron is estimated to contribute 10-to-15 per cent of total iron intake in meat-eating populations, but because it is generally better absorbed than non-haem iron, it can account for more than 40 per cent of total absorbed iron.
Foods which include haem iron are liver, beef, lamb, pork, chicken, and oily fish, such as salmon and sardines. Some components of diet directly affect iron bioavailability. Non-haem iron is found mainly in non-meat foods, such as fortified breakfast cereals, bread, broccoli, cabbage, peas, beans, lentils, eggs, and nuts.
Eating foods which contain vitamin C at the same time as eating non-haem iron helps with its absorption. Vitamin C can be found in berries, fruit juices, vegetables, and salads. Phytates, found in cereals and vegetables, polyphenols found in vegetables, fruits, some cereals and legumes, tea, coffee, wine, calcium, and proteins inhibit iron absorption. By contrast, ascorbic acid and muscle tissue enhance iron absorption.
Symptoms of IDA include lethargy, fatigue, dizziness, shortness of breath, palpitations, and pale skin
Hepcidin plays a crucial role in the control of iron availability to tissues. High expression of hepcidin decreases plasma iron concentrations, and low expression increases concentrations. Hepcidin is a naturally-occurring protein, secreted by the liver. It acts as a regulatory hormone, controlling the amount of iron in the body.
In inflammation, hepcidin levels rise, causing iron to be trapped within macrophages and liver cells; therefore, serum iron levels fall. This typically leads to anaemia due to an inadequate amount of serum iron being available for developing red cells. This leads to functional iron deficiency, which develops under conditions where the demand exceeds iron availability.
Risk factors
The maximum absorption of iron from the diet is less than the body’s requirements for iron, resulting in a risk of iron deficiency. In infants and young children aged 0-to-15 years, rapid growth consumes the iron stores that accumulated during gestation, which can lead to an absolute deficiency. Adolescent girls and women of childbearing age are particularly at risk of IDA because of menstrual iron losses.
During pregnancy, iron needs are tripled because of expansion of maternal red cell mass and growth of the foetus and placenta. Anaemia is the most common medical disorder in pregnancy. Pregnancy causes a two-to-three-fold increase in the requirement of iron, and a 10-to-20-fold increase in folate requirement. Daily iron supplementation is significantly associated with reduced risk of anaemia at term.
Both pregnancy and lactation place heavier demands on the body for the use of iron and iron stores, particularly as the baby develops and when the body responds to the demands to nurture the baby during feeding. In addition, there are greater physical demands on the body when caring for a newborn, with the change in sleep and dietary patterns of the mother.
There are, however, many other recognised causes of IDA, including blood loss, malabsorption, poor dietary intake, chronic disease, genetic alterations, and the use of non-steroidal anti-inflammatory drugs (NSAIDs). Regular blood donors are also at increased risk of iron deficiency.
Blood loss is the most common cause, especially from the digestive tract. The most common causes of iron malabsorption are coeliac disease, gastrectomy, bypass gastric surgery, and Helicobacter pylori colonisation. Anaemias caused by genetic defects are a large group of rare, heterogeneous disorders that include haemolytic anaemias, and anaemias arising from mutations in genes that control duodenal iron absorption. A ferritin deficiency can deplete iron stores quickly and lead to IDA.
Symptoms
Symptoms of IDA include lethargy, fatigue, dizziness, shortness of breath, palpitations, and pale skin. Less-common symptoms include headache, tinnitus, pruritus, sore tongue, hair loss, pica, dysphagia, angular stomatitis, spoon-shaped nails, and restless leg syndrome.
Investigations and diagnosis
Investigations for IDA are guided by a complete history of the presenting symptoms, physical examination and assessment for risk factors. IDA is diagnosed by blood tests that include a full blood count (FBC), and additional tests may be ordered to evaluate the levels of serum ferritin (SF), iron, total iron-binding capacity, and/ or transferrin.
Haemoglobin normal range values for males is 13.8-17.2g/dL and for females is 12.1-15.1g/dL. If the FBC result shows a low haemoglobin and mean cell volume (MCV — normal range 80-100fL), ferritin levels should be checked. Ferritin levels may be less reliable in pregnancy.
SF level is considered to be a reliable indicator of iron deficiency in the first trimester of pregnancy in the absence of infection or inflammation. However, in the second and third trimesters, it is of limited use, as SF levels fall independently of iron stores.
Serum markers of iron deficiency include low ferritin, low transferrin saturation, low iron, raised total iron-binding capacity, raised red cell zinc protoporphyrin, increased serum transferrin receptor (sTfR), low reticulocyte Hb (Retic-Hb), and raised percentage hypochromic red cells.
SF is the most specific test and useful marker of IDA, but other blood tests, such as transferrin saturation, can be helpful if a false-normal ferritin is suspected.
An SF less than 15μg/L is highly specific for iron deficiency (specificity 0.99). A cut-off of 45μg/L provides a respectable specificity of 0.92, and figures below this may warrant consideration of GI investigation, especially in the context of a chronic inflammatory process with anaemia.
Vitamin B12 and folate levels should be considered if the person is anaemic and the anaemia is normocytic with a low or normal ferritin level; vitamin B12 or folate deficiency is suspected; if there is inadequate response to iron supplements in proven IDA; and in elderly patients.
Initial investigation of confirmed IDA should include urinalysis or urine microscopy, screening for coeliac disease, and in appropriate cases, endoscopic examination of the GI tract.
Once a diagnosis of IDA has been established, every effort must be made to determine the pathogenesis of the disease. Coeliac disease should be considered in all patients, particularly those with a history of IDA refractory to oral iron.
Treatment and management
The treatment of IDA aims to restore normal circulating Hb levels, replenish body iron stores, and improve quality-of-life and physiological function.
Oral iron supplements
Oral iron supplements should be considered for all people diagnosed with iron deficiency to help correct anaemia and replenish iron stores. However, there are some instances when it is inappropriate to take oral iron, particularly if the person has inflammatory bowel disease that is active, has an oral iron intolerance, or is taking erythropoiesis-stimulating agents. There are several iron compounds available as tablets, including ferrous sulphate, ferrous fumarate, and ferrous gluconate. Oral iron preparations contain varying amounts of ferrous iron and the frequency of gastrointestinal side-effects related to each different preparation tends to be directly related to the content of ferrous iron. When people are able to take and tolerate iron supplements effectively, haemoglobin should rise by 2g/l every three weeks. British Society of Gastroenterology 2021 guidelines for the management of IDA in adults suggest that a good response to iron therapy (Hb rise ≥10g/L within a two-week time frame) in anaemic patients is highly suggestive of absolute iron deficiency, even if the results of iron studies are equivocal.
There are several limitations to taking iron supplements. Only a small amount is actually absorbed, particularly if there is inflammation. Between 10-to-40 per cent of people taking oral iron supplements experience gastrointestinal side-effects, including diarrhoea or constipation, and do not fully adhere to the prescribed course.
Regular Hb monitoring is recommended to ensure a satisfactory response and FBC and iron levels should be checked monthly until the Hb is in the normal range. Once Hb is normal, oral iron is continued for three months, but may need to be continued for longer. The patient should be advised of potential GI side-effects, including constipation and dark stools, and that taking ascorbic acid (vitamin C) can help with iron absorption. After the restoration of Hb and iron stores with iron replacement therapy (IRT), the blood count should be monitored periodically, every six months initially to detect recurrent IDA.
Traditional oral iron salts, ferrous sulfate, ferrous gluconate and ferrous fumarate are inexpensive, effective, safe, and readily available, and remain the standard therapies for IDA. Iron supplements should be taken either two hours before or four hours after administration of antacids. Iron as a ferrous salt is more easily absorbed. Iron salts should not be taken with food, because the phosphates, phytates, and tanates in food bind to the iron and affect absorption. Other factors that can affect absorption of iron salts include antacids, H2 receptor antagonists, proton pump inhibitors, antibiotics — for example, quinolones and tetracyclines — and food and drinks containing calcium. The most economic iron preparation is ferrous sulphate. Each tablet contains 325mg of iron salts, of which 65mg is elemental iron. Adverse effects occur in the digestive tract, and include abdominal discomfort, nausea/vomiting, diarrhoea and/or constipation, and are directly related to the amount of elemental iron ingested.
Intravenous iron
Intravenous iron is given when there is an oral iron intolerance/poor adherence, or if there is a poor response to oral iron. It needs to be given in a specialist environment. The intravenous route for iron replacement therapy (IRT) may be preferable from the outset in those with ongoing significant bleeding, malabsorption due to GI disease, the combination of iron deficiency and anaemia of inflammation, or issues with administration, such as severe dysphagia or compliance issues. However, there are a number of contraindications, including known hypersensitivity to intravenous iron, anaemias not caused by iron deficiency, iron overload, and first trimester of pregnancy. Precautions to take into account include asthma, eczema or other atopic allergy, liver dysfunction, acute or chronic infection, and hypotension.
Parenteral IRT preparations are more expensive than traditional oral iron preparations, and there are additional associated costs relating to the facilities, staffing, and equipment required for administering infusions. All IV iron preparations should be administered in a setting where resuscitation facilities are available and appropriately-trained staff are present. The patient should be observed for adverse effects for at least 30 minutes following each administration.
Although intravenous iron is more reliably and quickly distributed to the reticuloendothelial system than oral iron, it does not provide for a more rapid increase in haemoglobin levels. The most common adverse effect of intravenous iron is nausea. While rare, anaphylaxis may occur with intravenous iron infusions. Infusion-related reactions are uncommon with modern intravenous iron preparations, but hypersensitivity-type and infusion reactions (approximate incidence –0.5 per cent) are more common than with oral iron. Serious adverse reaction rates are low, however, and are similar for oral and parenteral iron preparations. Hypophosphataemia has been reported with all parenteral iron preparations. This relates to the molecules complexed to the iron, rather than the iron itself.
While most oral iron supplements are cheap, they are not always well tolerated, often due to GI side-effects. Intravenous IRT is often necessary for patients with comorbidities, which impair iron absorption. While there are several studies reporting the cost-effectiveness of intravenous iron preparations in comparison to oral IRT for specific conditions, such as chronic kidney disease, chronic heart failure, and inflammatory bowel disease, it is the associated comorbidity which accounts for the improved cost-effectiveness of intravenous iron in these circumstances.
Blood transfusion
Red blood cell transfusions may be given to patients with severe iron deficiency anaemia who are actively bleeding or who have significant symptoms, such as chest pain, shortness of breath, or weakness. Transfusions are given to replace deficient red blood cells and will not completely correct the iron deficiency. Red blood cell transfusions will only provide temporary improvement. It is important to find and treat the cause as well as the symptoms.
Dietary recommendations
In general, a broad range of foods should be incorporated in the diet to prevent iron deficiency. A normal balanced diet contains a total of 12-to-18mg of iron per day. However, only a small amount of iron ingested is absorbed (3-to-5mg per day). Iron in the diet comes in two forms: Haem iron, and non-haem iron. Haem iron is found in animal-derived foods, and non-haem iron in plant-derived foods. Non-haem iron is less easily absorbed, therefore a balanced diet with iron enhancers is recommended. Foods that enhance iron intake include lean red meat, oily fish, vitamin C in fresh fruit and juices, and fermented products, such as soy sauce and bread. Foods that inhibit iron absorption include calcium, particularly from milk and dairy products, phytates present in cereal brans, grains, nuts and seeds, and polyphenols and tannin in tea and coffee.
Iron deficiency anaemia in the elderly
Anaemia is common in older people, affecting more than 20 per cent over the age of 85 years, and more than 50 per cent of residential/nursing home residents. Aetiologies responsible for anaemia in this age group are complex and often multiple. Iron deficiency is a contributory factor in about half of cases, sometimes associated with deficiencies of vitamin B12 and/or folate. Anaemia in older patients has been shown to contribute to worsening of physical performance, cognitive function and frailty. Iron deficiency in the elderly has many potential contributory causes, including poor diet, reduced iron absorption, occult blood loss, medication, and chronic disease. Blood loss from mucosal lesions may be compounded by concurrent antiplatelet/anticoagulant therapy. Older patients are more likely than younger people to have more than one contributing cause. The diagnosis can be confirmed by measurement of ferritin and transferrin saturation, although the former may be difficult to interpret in the presence of coexisting inflammatory conditions. The potential risks and benefits of invasive investigation should be carefully weighed-up in older adults, particularly those who are frail, have significant comorbidities or reduced life expectancy.
Outlook
Although iron deficiency is one of the oldest and most common medical disorders, the condition has still not received adequate clinical attention and evaluation. IDA presents in primary care and across a range of specialties in secondary care, and because of the insidious nature of the condition, it has not always been optimally managed despite the considerable burden of disease, with investigation sometimes being inappropriate, incorrectly timed or incomplete. Many children, elderly patients, and pregnant women continue to have undiagnosed IDA or remain under-treated. IDA is a significant global public health concern that can cause debilitating clinical consequences across age groups, genders, geographies and clinical conditions. Early diagnosis and effective management is required to avoid associated sequelae. Although effective means for iron supplementation exist, making the right and timely choice of treatment is essential to avoid unnecessary delays in iron repletion and correction of anaemia. This can be achieved with increased awareness of the prevalence and causes of IDA, as well as the benefits of treatment, among all healthcare professionals in secondary and primary care settings. Primary care healthcare providers, especially GPs and general practice nurses (GPNs), play a pivotal role and are often the first to investigate and treat the presence of IDA in patients. Other practitioners involved in IDA include laboratory technologists, haematologists, and pharmacists.
Patient education, improving health literacy and health awareness is an important intervention in the prevention and treatment of IDA. The role of the clinician is to provide ongoing assessment, management, support and education. Key roles are to establish a therapeutic relationship with the patient, assess their understanding of the condition, establish goals and expectations for successful management of the condition, and evaluate the patient’s physical, emotional, and psychological wellbeing. By implementing person-centred care, monitoring and evaluating symptoms, outcomes, and responses to therapy, clinicians play a pivotal role in managing IDA and improving the patient’s quality-of-life.
The design and implementation of preventative and therapeutic interventions to combat disorders of iron metabolism, most commonly IDA, are greatly aided by a clearer understanding of the precise mechanisms regulating iron metabolism. Pharmaceutical companies are actively developing hepcidin agonists and antagonists to combat iron overload and anaemia. Ongoing research in science and medicine to better understand iron metabolism and the role of hepcidin as a diagnostic tool and treatment target could bring advances and more novel diagnostic and therapeutic interventions for IDA in the future.
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