Metabolic triumvirate

These nutrients act as one system: without B12, folate becomes trapped in its methylated form and cannot participate in DNA synthesis, leading to megaloblastic anaemia . Deficiency of any of these components disrupts cell division and leads to fatigue, pallor and reduced exercise tolerance.

Dietary intake and absorption of iron

An adult consumes around 10–20 mg of iron per day, but only 1–2 mg (3–15 %) is absorbed. Absorption occurs in two stages:

• Gastric phase. The acidic environment of the stomach liberates iron from food and reduces inorganic iron from the ferric (Fe³⁺) to the ferrous (Fe²⁺) state, which can be transported . Without adequate acid secretion (e.g. in atrophic gastritis or prolonged use of proton pump inhibitors) iron absorption falls dramatically. This explains why taking iron tablets often causes nausea but fails to raise ferritin.

• Intestinal phase. In the duodenum, ferrous iron is taken up through the DMT1 transporter. Haem iron from meat is absorbed more rapidly and efficiently via the HCP1 transporter because it is already in the reduced form.

Diet and medications influence absorption. Ascorbic acid (vitamin C) enhances iron solubility and protects it from oxidation. Phytates (grains and legumes), tea and coffee polyphenols, excessive calcium and acid-suppressing drugs diminish absorption . Clinical observations show that patients in whom iron “doesn’t get absorbed” often have hypochlorhydria – reduced stomach acidity.

Transport and regulation of iron

Once inside enterocytes, iron binds to transferrin, which carries it to the bone marrow for haemoglobin synthesis. Excess iron is stored in ferritin (liver, spleen, bone marrow). The key regulator is the hormone hepcidin, produced by the liver. During inflammation, infection or iron overload, hepcidin levels rise; it binds to the only known iron exporter – ferroportin – and triggers its internalisation . As a result, iron cannot leave enterocytes and macrophages, accumulates in ferritin and hypoferraemia develops . When the demand for red blood cells increases (anaemia, hypoxia), hepcidin synthesis falls, the amount of ferroportin increases, and iron is released into the bloodstream .

This explains the phenomenon of anaemia of chronic inflammation: in chronic infections and autoimmune diseases, elevated hepcidin blocks iron release from stores despite normal or high ferritin levels . In such a situation, simply taking iron supplements is useless – it is essential to remove the inflammatory trigger.

Iron recycling

The body recycles iron almost completely: every day, macrophages in the spleen and liver return about 25 mg of iron to the circulation by breaking down old erythrocytes . This is more than ten times the amount absorbed from food. Persistent ferritin deficiency is therefore more often due to impaired recycling or blocked release (e.g. due to inflammation) than to low intake.

Absorption and stores of folate and vitamin B12

Folic acid (vitamin B9) is absorbed in the jejunum and rapidly used: the liver contains about 5 mg of folate, enough for 3–4 months . Folate deficiency can occur with inadequate intake (alcoholism, malnutrition), pregnancy, chronic haemolysis or diseases of the small intestine such as coeliac disease or tropical sprue.

Vitamin B12 is obtained from animal products. Its absorption involves three stages: gastric acid releases B12 from food; in the duodenum it binds to intrinsic factor (IF); and in the terminal ileum the “B12 – IF” complex is absorbed . Only a small fraction of B12 is absorbed passively along the entire small bowel. The liver contains 2–3 mg of cobalamin, a reserve that lasts 2–4 years .

Folate–B12 interplay: the methyl trap

Folate supplies one‑carbon units for DNA synthesis. In methylation reactions vitamin B12 serves as a cofactor for methionine synthase, which converts 5‑methyltetrahydrofolate back to tetrahydrofolate (THF). When B12 is deficient, folate becomes trapped as 5‑methyl‑THF and cannot convert back to THF . This results in methionine deficiency and disrupted DNA synthesis, so bone marrow cells enlarge but do not divide; the blood shows large immature red cells and hypersegmented neutrophils . This type of anaemia is called megaloblastic. Beyond haematopoiesis, B12 deficiency causes neurological symptoms (paraesthesias, balance disorders) that are not corrected by folate alone .

Why anaemia persists despite good diet and supplements

The ineffectiveness of standard iron therapy often results from disruptions in absorption, transport or regulation.

Chronic inflammation and elevated hepcidin

In chronic infections, autoimmune processes or obesity, the cytokine IL‑6 stimulates the liver to produce hepcidin. Hepcidin binds to ferroportin and causes its degradation, leading to iron retention in macrophages and enterocytes . Ferritin may be normal or high, but iron remains unavailable to the bone marrow. To restore erythropoiesis, one must identify and remove the source of inflammation – for example by treating gastrointestinal infections, microbiota imbalances, inflammatory bowel disease or dental disease.

Low stomach acidity and atrophic gastritis

Atrophic gastritis and prolonged use of proton pump inhibitors reduce the production of hydrochloric acid, preventing the conversion of Fe³⁺ to the absorbable Fe²⁺ form. A review of autoimmune atrophic gastritis notes that under these conditions iron (especially from non‑meat sources) precipitates and is not absorbed . Studies also show that in patients with pernicious anaemia, adding gastric juice restores iron absorption . Therefore, correcting hypochlorhydria (treating Helicobacter pylori, avoiding long‑term PPIs, using bitters or betaine HCl under medical supervision) may be more effective than increasing iron dosage.

Coeliac disease and gluten intolerance

Coeliac disease is an autoimmune condition in which gluten causes villous atrophy of the small intestine. This leads to impaired absorption of iron, folate and vitamin B12 . Reviews note that anaemia is often the first symptom of coeliac disease and its pathogenesis involves a combination of iron, folate and/or vitamin B12 deficiency . In such patients B12 may not be absorbed because of low gastric acidity, bacterial overgrowth or ileal damage . Diagnosis includes testing for tissue transglutaminase antibodies (tTG‑IgA) and total IgA; treatment is a strict gluten‑free diet. As the intestinal mucosa heals, ferritin levels usually rise gradually.

Incorrect iron supplementation

Iron supplementation often fails not because of dosage, but because of how it is taken.

Non-heme iron (the type used in most supplements) requires an acidic environment and must be reduced to Fe²⁺ to be absorbed through the DMT1 channel. When iron is taken:

• with inhibitors → absorption drops by up to 90%

• with enhancers → absorption increases significantly

  
  

Conclusion

Effective erythropoiesis requires the coordinated activity of iron, folate and vitamin B12. The body recycles almost all iron from old red blood cells, and iron absorption and mobilisation are tightly regulated by the hormone hepcidin and the protein ferroportin. Development of anaemia is more often related to disrupted stomach acidity, inflammation or damage to the small intestinal mucosa than to inadequate intake.

With persistent low ferritin it is important to search for root causes – treat gastritis, eradicate H. pylori, rule out coeliac disease and reduce inflammation – and to correct B12 and folate deficiencies. A systemic approach can restore energy and quality of life without indiscriminate iron supplementation.

✉️ Need personalised guidance?

If you’re struggling with persistent low ferritin, exhaustion, hair loss, or unexplained anaemia even while supplementing, it may be due to impaired absorption, inflammation, or B12–folate imbalance — not because you aren’t taking enough iron.

Book a consultation here. Together, we can determine why your iron isn’t rising and build a tailored protocol that works for your biochemistry, not generic advice

References:

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• Crider, K.S. et al. (2012) ‘Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folate’s Role’, Advances in Nutrition, 3(1), pp. 21–38. Available at: https://doi.org/10.3945/an.111.000992

• Froese, D.S., Fowler, B. and Baumgartner, M.R. (no date) ‘Vitamin B12, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation’. Available at: https://doi.org/10.1002/jimd.12009

• Halfdanarson, T.R., Litzow, M.R. and Murray, J.A. (2007) ‘Hematologic manifestations of celiac disease’, Blood, 109(2), pp. 412–421. Available at: https://doi.org/10.1182/blood-2006-07-031104

• Hariz, A. and Bhattacharya, P.T. (2025) ‘Megaloblastic Anemia’, StatPearls. Treasure Island (FL): StatPearls Publishing. Available at: http://www.ncbi.nlm.nih.gov/books/NBK537254/

• Pantopoulos, K. (2024) ‘Oral iron supplementation: new formulations, old questions’, Haematologica, 109(9), pp. 2790–2801. Available at: https://doi.org/10.3324/haematol.2024.284967

• Piskin, E. et al. (2022) ‘Iron Absorption: Factors, Limitations, and Improvement Methods’, ACS Omega, 7(24), pp. 20441–20456. Available at: https://doi.org/10.1021/acsomega.2c01833

• Schmidt, P.J. (2015) ‘Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation’, The Journal of Biological Chemistry, 290(31), pp. 18975–18983. Available at: https://doi.org/10.1074/jbc.R115.650150

• Wang, C.-Y. and Babitt, J.L. (2016) ‘Hepcidin Regulation in the Anemia of Inflammation’, Current Opinion in Hematology, 23(3), pp. 189–197. Available at: https://doi.org/10.1097/MOH.0000000000000236

• West, A.R. and Oates, P.S. (2008) ‘Mechanisms of heme iron absorption: Current questions and controversies’, World Journal of Gastroenterology, 14(26), pp. 4101–4110. Available at: https://doi.org/10.3748/wjg.14.4101