*3.4. Adverse Effects of Oral Iron Therapy*

While oral iron therapy as the first-line treatment for IDA is indisputable, considerable side effects are reported. A systematic review and meta-analysis of 43 RCTs by Tolkien et al. [9] confirmed that ferrous sulphate was 2.32 times (95% CI: 1.74–3.08, *p* < 0.0001) and 3.05 times (95% CI: 2.07–4.48, *p* < 0.0001) more likely to cause gastrointestinal side effects than placebo and intravenous iron therapy, respectively. Notably, meta-regression from this study did not find a significant relationship between the odds ratios of gastrointestinal side effects and dose. The common gastrointestinal side effects reported in the RCTs are constipation, nausea, diarrhoea, abdominal pain, vomiting, heartburn, dark stools, and flatulence [9].

There are also other negative impacts of oral iron therapy on the gastrointestinal tract besides symptoms of discomfort. Free iron, Fe2, is a divalent metal cation that can react with hydrogen peroxide in cells to produce hydroxyl radicals, which induce oxidative stress responses in cells. These radicals are cytotoxic to endothelial and smooth muscle cells and have deleterious impacts on health [110,125,126]. Hence, excess iron from oral iron supplements can lead to lipid peroxidation, which causes ferroptosis, mitochondrial damage, and endoplasmic reticulum dysfunction, leading to the destruction of the intestinal epithelial cells, affecting the intestinal mechanical barrier's integrity [126]. Such are the possible underlying mechanisms of frequent gastrointestinal side effects of oral iron therapy. Moreover, anaemic patients taking oral iron supplements also demonstrated increased systemic oxidative stress as measured by lipid peroxide, protein carbonyl, conjugated dienes, lipid hydroperoxide and oxidised glutathione levels accompanied by a reduced total antioxidant level [127]. Hence, it is advisable to increase dietary antioxidant intake while taking oral iron supplements.

Excessive unabsorbed iron may cause gut dysbiosis, as it can modify gut microbiota composition, promoting the growth of pathogenic bacteria at the expense of the healthy ones [128–130]. Specifically, increased luminal iron concentration appeared to favour the growth of *Escherichia coli*, *Salmonella*, and *Bacteroides* species of pathogenic bacteria while lowering the abundance of probiotics such as *Lactobacillus* and *Bifidobacterium* species [128]. The disruption of gut microbiota equilibrium can also lead to inflammation and chronic conditions such as inflammatory bowel disease and metabolic dysfunction [128,131], which, in turn, can also hamper iron absorption and reduce the effectiveness of iron supplementation [132,133].

Overuse of iron supplements also carries considerable risks. Intake of iron above 60 mg/kg body weight can result in severe toxicity leading to gastrointestinal tract injury and impaired cellular metabolism in the heart, liver, and central nervous system, which can be fatal without immediate medical attention [134,135]. Moreover, prolonged ingestion of iron supplements for years has been reported to cause iron overload, where the body stores too much iron, a condition that can cause severe organ damage [136].
