*3.2. IDA and Its Aetiology*

Iron deficiency anaemia can result from insufficient intake from the diet, decreased absorption, or blood loss [113]. Age, sex, lifestyle, and socioeconomic status may influence the adequacy of dietary iron intake. For example, growth spurts in children and adolescents or pregnancy may increase iron demand and cause iron deficiency without increased consumption of iron-rich foods. Poverty and poor diet can lead to malnutrition with low iron intake [114]. Decreased absorption can be due to dietary factors (e.g., high phytate diet or improper vegetarian or vegan diet), surgery, or gastrointestinal conditions (e.g., coeliac disease, inflammatory bowel disease, or gastritis) [113]. Blood loss due to heavy menstrual bleeding commonly leads to IDA in premenopausal women. Other sources of blood loss, such as injury, surgery, or occult gastrointestinal tract bleeding, also deplete the available RBCs and cause IDA [115].

There is also a reciprocal relationship between iron deficiency and inflammation, as shown in a 3-year prospective longitudinal study of 2141 relatively healthy older adults aged 70+ [116]. Posthoc analysis of the high sensitivity C-reactive proteins (CRP) and interleukin (IL)-6 levels, measured at 12, 24, and 36 months of follow-up, found baseline iron deficiency was associated with a more significant increase in IL-6 levels (mean difference in change: 0.52 ng/L, 95% CI: 0.03–1.00, *p* = 0.04) over 3 years. Additionally, iron deficiency at any yearly time point was associated with higher increases in CRP (mean difference in change: 1.62 mg/L, 95% CI: 0.98–2.26, *p* < 0.001) and IL-6 levels (mean difference in change: 1.33 ng/L, 95% CI: 0.87–1.79, *p* < 0.001) over 3 years. The results were independent of anaemia status as there was no interaction between iron deficiency and anaemia. As such, the findings suggest that iron deficiency may be involved in low-grade inflammation even in relatively healthy older adults [116].

Consequently, chronic inflammatory conditions such as cancer, chronic infections, immune-mediated diseases, and obesity can also reduce RBCs. An estimated 40% of all anaemia cases worldwide are due to chronic disease or inflammation as a contributing cause [117]. Anaemia of inflammation (AI) or anaemia of chronic disease is the second most common type of anaemia after iron deficiency. Unlike absolute IDA, whereby the body's iron store is depleted, the iron store of a patient with AI can remain normal. Hence, AI is also sometimes referred to as functional iron deficiency, which is characterised by the body's inability to mobilise the available iron for erythropoiesis [118]. However, IDA and AI may co-exist in some patients, with anaemia due to inflammatory bowel disease being one example. As such, the diagnosis and management of IDA require a systematic evaluation of the case history and haematological profile, plus an investigation of the potential underlying causes of blood loss [115,119].

#### *3.3. Treatment of IDA*

Repleting iron stores is the primary strategy in IDA treatment, with prompt treatment needed to alleviate fatigue, improve quality of life, and reduce cognitive impairment [114]. Research evidence has shown that iron supplements are more effective than dietary iron for restoring iron status and Hb recovery [120,121]. A meta-regression analysis with data from 41 RCTs by Casgrain et al. [120] showed that iron supplementation affected serum ferritin (SF) concentration linearly related to duration (+0.51 μg/L per week, 95% CI: 0.02–1.00, *p* = 0.04) and dose (+0.10 μg/L per g Fe, 95% CI: 0.01–0.20, *p* = 0.036). Hb concentration is also expected to increase significantly by 0.8 g/L for every 10 μg/L increase in baseline SF level with iron supplementation (*p* = 0.02). It should be noted that these effects were observed in the healthy adult population as per the inclusion criteria of Casgrain et al. [120]. Another systematic review and meta-analysis by Houston et al. [122] further demonstrated that iron supplementation is more effective than placebo in reducing self-reported fatigue (standardised mean difference: −0.38, 95% CI: −0.52 to −0.23) among iron-deficient adults with no anaemia. Hence, for patients with iron deficiency or straightforward and uncomplicated IDA, oral iron supplement (ferrous sulphate, ferrous gluconate, or ferrous fumarate) is considered the standard care [123]. However, for IDA with complications such as intolerance, intestinal malabsorption, and ongoing blood losses that exceed iron absorption capacity, intravenous iron therapy may be needed to rapidly restore iron supply [124].
