**Background:** Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide, with increasing drug-resistant cases. Anaemia is a common complication in TB patients, with normocytic normochromic anaemia reported in up to 71.7% of patients and iron deficiency anaemia (IDA) in 1–53%, depending on the population. The relationship between iron availability, the TB bacterium (Mycobacterium tuberculosis, Mtb), and the host immune response is complex. Iron is essential for Mtb growth and virulence, and the host innate immune response actively restricts iron availability through multiple mechanisms. This review aimed to summarise the literature on iron deficiency and anaemia in TB and the possible role of iron supplementation.
**Methods:** This is a narrative review summarising preclinical and clinical studies on iron status, anaemia, and iron supplementation in TB. The authors synthesised findings from studies on iron acquisition and host immune response, iron status biomarkers, clinical outcomes associated with iron biomarkers, preclinical studies of iron supplementation, and clinical trials of iron supplementation in TB patients.
**Key Results:** The host response to TB involves iron sequestration through multiple mechanisms: (1) iron-sequestering proteins (lactoferrin, lipocalin-2, transferrin, haptoglobin, hemopexin) that gather in necrotic centres of caseous granulomas; (2) upregulation of hepcidin driven by proinflammatory cytokines (primarily IL-6, also IL-1, IL-22, IFN-α), causing ferroportin endocytosis and proteolysis, reduced gastrointestinal iron absorption, and intracellular iron sequestration in macrophages, hepatocytes, and enterocytes; (3) IFN-γ-mediated myeloid cell production at the expense of erythropoiesis; (4) TNF-α impeding erythroid proliferation and directly reducing iron absorption. Anaemia of infection and IDA co-exist in 30–94% of TB patients. Biomarker challenges include that ferritin acts as an acute-phase protein in TB and is not an accurate indicator of iron stores, while transferrin is a negative acute-phase protein. Hepcidin may help differentiate anaemia of infection (high hepcidin) from IDA (low hepcidin). Clinical outcomes associated with iron biomarkers include: anaemia with and without ID was related to a two- to threefold independent rise in mortality risk; anaemia without ID was also related to TB recurrence; plasma ferritin correlates positively with disease severity, sputum positivity, and higher mortality; hepcidin concentrations correlate with mycobacterial burden and predict mortality; low transferrin and haemoglobin and elevated ferritin are consistent with higher TB incidence and susceptibility. Preclinical studies showed mixed results: some found iron overload worsened TB (e.g., Lounis et al. found higher bacterial loads in iron-loaded mice; Schaible et al. found 10 times higher lung Mtb burden with iron overload), while more recent studies found no worsening of bacterial load and potential anti-inflammatory effects (e.g., Kolloli et al. found no effect on bacterial burden or pathology; Nienaber et al. found iron lowered IL-1α, IL-1β, TNF-α, and IL-6). Only two clinical trials on iron supplementation in TB were identified. Devi et al. (n=117 male pulmonary TB patients) found that 75 mg ferrous fumarate twice daily elevated haemoglobin, MCV, and erythrocyte count at 1 month, but this difference disappeared at 2 and 6 months, with no effect on radiological or clinical improvement. Cercamondi et al. (n=18 mostly anaemic TB patients) found that fractional iron absorption from 6 mg labelled ferrous sulphate was negligible before treatment (0.8%) but increased 10- and 20-fold to 8% and 15.2% after 2 months and 6 months of TB treatment, respectively. Hepcidin decreased by 70% at 2 weeks, and anaemia prevalence dropped from 89% to 22%.
**Clinical Implications:** Anaemia of infection generally resolves with effective TB drug treatment as inflammation subsides. IDA, especially when persisting after TB treatment, may require iron supplementation. Based on current evidence, iron supplementation should be initiated only upon completion of TB drug treatment when absorption is most efficient, and only for patients who remain anaemic. Moderate iron supplementation within an 'iron benefit window' may be beneficial, but exceeding this limit may promote bacterial growth. More clinical trials are needed to determine optimal dosage, timing, and conditions for iron supplementation in TB patients.