Iron is an abundant element on Earth – it is a biologically essential component for living organisms.³ Although iron is present in geological abundance, it is often access-limited in the environment because, upon contact with oxygen, iron forms highly insoluble oxides. These oxides are thus not readily available for uptake.³ The human body stores iron mainly in complex forms bound to proteins (haemoprotein) as haem compounds (haemoglobin or myoglobin), haem enzymes or non-haem compounds (flavin-iron enzymes, transferrin, and ferritin).¹¹

The human body needs iron for the synthesis of haemoglobin and myoglobin, as well as the formation of haem enzymes along with other iron-containing enzymes.¹¹ Approximately 66% of the body’s iron is found in the haemoglobin present in circulating erythrocytes, 25% in a readily mobilisable iron store, and the last 15% is typically bound to myoglobin in the muscle tissue and in a variety of enzymes involved in the oxidative metabolism and many other cellular functions.¹¹

Iron is conserved in the body by means of recycling. Iron is delivered to tissues by circulating transferrin ‒ a transporter able to capture iron released into the plasma from the intestinal enterocytes or reticuloendothelial macrophages. The binding of iron-laden transferrin to the cell-surface transferrin receptor-1 (TfR) results in endocytosis, which allows for the uptake of the metal cargo. Internalised iron is transported to the mitochondria for the synthesis of haem, as well as iron-sulphur clusters. These clusters are important parts of several metalloproteins, and excess iron is stored and detoxified in cytosolic ferritin. Once iron is absorbed, there is no physiologic mechanism for excretion of excess iron from the body other than blood loss, such as that occurring during pregnancy, menstruation or other types of bleeding.¹²

Adults store around 1 g – 3 g of iron in the body, with about 1 mg of iron lost daily through the natural sloughing of dead skin cells and mucosal surfaces, and the lining of the gastrointestinal tract.¹³ Daily loss is increased to about 2 mg per day during menstruation. Iron requirements are also increased during the augmentation of body mass during neonatal and childhood growth spurts.^11,12

The clinical signs and symptoms of an iron deficiency with or without anaemia are limited and often neglected ‒ the most important being fatigue, which is very nonspecific. Alterations within the epithelial cells, such as dry mouth, cheilitis, atrophic glossitis Plummer-Vinson pharyngeal webs, along with severe hair loss, are typical symptoms observed in a longstanding deficiency. In elderly patients, IDA may cause heart failure or even angina.^{7,8,9,10,11,12}

It is thus crucial to confirm a diagnosis using laboratory testing. Low serum ferritin levels – which reflect exhausted stores – are the hallmark of absolute iron deficiency. Serum ferritin levels below 30 mg/L are the accepted threshold for identifying mild cases. In the presence of anaemia, ferritin levels are often lower (< 10 mg/L – 12 mg/L). In the absence of inflammation or infection, serum ferritin levels indicate the best correlation with bone marrow stainable iron (iron stored in bone marrow).^{7,8,9,10,11,12}

Measuring transferrin (TF) saturation (< 16%) is unnecessary for diagnosis, although it has diagnostic value in functional deficiency when serum ferritin is unreliable. Similarly, hepcidin levels, which are low or undetectable in absolute iron deficiency, are unnecessary. Exceptions are the rare iron-refractory iron deficiency anaemia (IRIDA) patients who show low TF saturation and normal/high hepcidin and serum ferritin levels, reflecting increased macrophage iron. Measuring serum hepcidin may be diagnostic of this atypical iron deficiency, if inflammation is excluded.^{7,8,9,10,11,12}

Anaemia is defined as a haemoglobin level two standard deviations below normal for age and sex.¹²

The fraction of iron absorbed from dietary uptake is typically low, ranging from 5% to 35%, depending on circumstances and the type of iron. Dietary iron occurs either as haem or non-haem. The primary sources of haem iron are haemoglobin and myoglobin from the consumption of meat, poultry and fish. Non-haem iron is obtained from cereals, pulses, legumes, fruits and vegetables. Haem iron is highly bioavailable (15% – 35%), and dietary factors have little effect on its absorption, whereas non-haem iron absorption is much lower (2% – 20%) and strongly influenced by the presence of other food components. Despite its lower bioavailability, non-haem presents in larger quantities in the diet and thus contributes more to iron nutrition than haem iron.^14,15

The major players in influencing iron absorption are inhibitors such a phytates and calcium, and competitors, manganese, zinc and other heavy metals, while ascorbic acid and citrate facilitate absorption.^14,15

Dietary modifications aim to correct micronutrient deficiencies by increasing the intake of iron-rich foods – especially flesh foods, increasing consumption of fruits and vegetables rich in ascorbic acid to enhance non-haem iron absorption, and reducing the intake of tea and coffee, which may inhibit non-haem iron absorption. Iron salts, with high bioavailability, are preferred when it comes to oral iron supplementation. Iron absorption is typically higher when iron supplementation is administered on an empty stomach; however, nausea and epigastric pain may present, reducing compliance. Lower doses between meals may thus be advised or salt forms adjusted in order to reduce these side effects.^14,15

Oral iron supplementation is the first-line treatment for iron deficiency. Conventional iron salts have typically been associated with a variety of side effects, which include nausea, vomiting, abdominal discomfort, constipation, diarrhoea and dyspepsia. The absorption of these salts is often reduced by ingredients in a meal, such as calcium and tannins, which oxidise the ferrous iron (Fe²⁺) to ferric iron (Fe³⁺), the latter being poorly absorbed. These limitations have resulted in the emergence of newer oral iron preparations like iron polymaltose. All iron must be reduced from the ferrous state to enter the mucosal cells.^16,17

Iron (III)-hydroxide polymaltose complex (IPC) is classified as a stable, orally administered non-ionic Fe (III) preparation which demonstrates efficacy to correct iron deficiency anaemia. Iron (III)-hydroxide polymaltose complex exhibits low toxicity and is generally well tolerated.^{16,17,18,19,20,21}

Iron (III)-hydroxide polymaltose complex is one of the few oral iron compounds that acts as a slow-release iron preparation. The polymaltose component forms a casing around the trivalent iron – this allows for slower release of the iron from the complex. Iron (III)-hydroxide polymaltose complex presents with unique advantages, including a favourable side-effect profile compared with iron (II) salts because of its slow release and its ability to be taken with meals. Iron (III)-hydroxide polymaltose complex exhibits a higher tolerability compared with iron sulphate salts. This is as a result of a reduced formation of oxygen radicals and thus decreased plasma lipid peroxidation.^{16,17,18,19,20,21}

Equal amounts of iron are available from iron polymaltose complex or ferrous sulphate (FS) in correcting haemoglobin levels over a 12-week observation period. This occurs with significantly fewer gastrointestinal side effects from the former. In another study performed on anaemic pregnant rats, it was clear that IPC, ferrous fumarate (FF) and FS were all efficient in correcting IDA during pregnancy. However, in contrast to FF and FS, treatment with IPC reduced IDA-mediated oxidative stress, that is, all the analysed oxidative stress markers returned to normal levels.^18,19,20,21

Oral iron supplementation and IV iron administration are theoretically able to effectively treat anaemia within the clinical context of South Africa. The degree of effectivity, however, largely depends on tolerance. Intravenous iron supplementation is evidently the best-tolerated option – but expensive and timely. This makes the IV iron supplement option unaffordable for most South Africans. Most patients would need to travel to a specific clinic and need to take time off work for IV iron administration, making it highly infeasible. Oral iron supplementation is thus preferred for convenience of use, availability and costs – despite adverse effects associated with consumption. The key is thus to minimise or eliminate side effects by selecting an iron salt best suited to the individual patient.

Available products in South Africa are summarised in Table 2.

Dosage and treatment duration for Iron deficiency are individualised according to the extent of deficiency (see Table 3).

Oral iron-replacement therapy is the mainstay of treatment for iron deficiency with or without anaemia; however, it is often poorly tolerated or ineffective. Haemoglobin response at day 14 of oral iron supplementation may be useful in assessing whether and when to transition patients from oral to intravenous (IV) iron supplementation.³⁹ Although IV iron supplementation is increasingly recognised as a crucial, effective intervention for managing IDA in South Africa, particularly when oral iron is poorly tolerated, ineffective, or when rapid correction is required – IV iron carries risks, including rare but severe hypersensitivity reactions as well as higher costs and the need for medical infrastructure. When comparing IV iron with oral agents – IV raises Hb levels significantly faster than oral iron and is preferred for patients who cannot tolerate oral iron, have severe deficiencies or suffer from conditions that hinder iron absorption (e.g. IBD). Intravenous iron can replete iron stores in one or a few visits, whereas oral iron often requires months of daily administration. Oral iron supplements are often accompanied by gastrointestinal side effects such as constipation, nausea and abdominal pain, where IV is generally well tolerated with fewer side effects. Although both are effective, IV is superior for speed and overcoming absorption issues, while oral iron is best for low-cost, long-term maintenance, with oral iron being less expensive and easier to obtain. Intravenous iron requires a clinical visit, medical scheme approval, and professional administration.^32,33,39