Iron, B12 and Folate Metabolism
Iron, vitamin B12, and folate are essential nutrients required for effective red blood cell production and haemoglobin synthesis. Deficiency in any of these nutrients leads to anaemia, but each produces distinct physiological changes and clinical consequences. Understanding how these nutrients are absorbed, transported, stored, and utilised provides crucial insight into anaemia management, dietary counselling, and interpretation of pathology results. For nurses, this knowledge underpins safe supplementation and recognition of deficiency states.
What You Need to Know
Iron is a critical component of haemoglobin. Dietary iron is absorbed primarily in the duodenum and proximal small intestine. It circulates bound to transferrin and is stored in ferritin molecules within the liver, spleen, and bone marrow. The body regulates iron absorption carefully because humans cannot actively excrete excess iron; deficiency is common, whereas overload can be toxic. Iron overload, or haemochromatosis, causes iron to deposit int orgains (mainly the liver, heart, and prancreas), leading to toxic damage, chronic fatigue, joint pain, bronze-coloured skin, and a higher risk of diabetes, heart failure, and liver cancer.
Vitamin B12 (cobalamin) is required for DNA synthesis during RBC production. It is absorbed in the ileum but only when bound to intrinsic factor, a protein produced by parietal cells in the stomach. Because B12 stores are large and turnover is slow, deficiency develops gradually.
Folate is essential for DNA synthesis and cell division. It is absorbed in the jejunum and must be consumed regularly because body stores are limited. Folate deficiency develops more rapidly than B12 deficiency.
Beyond the Basics
Iron balance in the body is regulated almost entirely at the level of absorption rather than excretion. Hepcidin, a peptide hormone synthesised by the liver, is the central regulator of this process. It controls the activity of ferroportin, the iron export channel found on enterocytes in the duodenum, macrophages that recycle iron from old red blood cells, and hepatocytes that store iron. When hepcidin levels are high, ferroportin is internalised and degraded, trapping iron within cells and reducing the amount released into the circulation.
Inflammation has a profound effect on this system. Pro-inflammatory cytokines, particularly interleukin-6, stimulate hepcidin production even when total body iron is low. This leads to reduced intestinal absorption and impaired release of iron from macrophages (macrophages recycle old red blood cells and release iron), resulting in functional iron deficiency. In this state, iron is present in the body but unavailable for erythropoiesis, contributing to anaemia of chronic disease. This explains why oral iron supplementation is often ineffective in inflammatory conditions and why ferritin levels may be normal or elevated despite low serum iron.
Iron Deficiency vs Anaemia of Chronic Disease
Understanding hepcidin physiology helps distinguish iron deficiency anaemia from anaemia of chronic disease. In true iron deficiency, hepcidin levels are suppressed, allowing maximal absorption of dietary iron and increased mobilisation from stores. Laboratory findings typically include low ferritin, low transferrin saturation, and elevated total iron-binding capacity.
In contrast, anaemia of chronic disease is characterised by normal or high ferritin, reflecting preserved or increased iron stores, but low serum iron and transferrin saturation. The bone marrow is effectively starved of iron due to hepcidin-mediated sequestration. Clinically, this distinction is critical, as management focuses on treating the underlying inflammatory condition rather than aggressive iron replacement alone.
Vitamin B12 Absorption: A Multistep Process
Vitamin B12 absorption is one of the most complex processes in human nutrition and depends on the coordinated function of several organs. In the mouth, B12 initially binds to haptocorrin (also called R-protein) secreted in saliva. In the acidic environment of the stomach, this binding protects B12 from degradation. Parietal cells simultaneously secrete intrinsic factor, although B12 does not bind to it immediately.
Once the B12-haptocorrin complex reaches the duodenum, pancreatic enzymes degrade haptocorrin, releasing free B12. At this point, B12 binds to intrinsic factor, forming a stable complex that is resistant to digestion. This complex travels intact to the terminal ileum, where it binds to specific receptors on enterocytes and is absorbed via receptor-mediated endocytosis. Any disruption along this pathway can significantly impair absorption.
Causes and Consequences of B12 Deficiency
Conditions that reduce gastric acid secretion, such as long-term proton pump inhibitor use or atrophic gastritis, impair the initial release of B12 from food proteins. Pernicious anaemia results from autoimmune destruction of parietal cells or intrinsic factor itself, making absorption impossible regardless of dietary intake. Surgical procedures involving the stomach or terminal ileum, as well as inflammatory conditions like Crohn’s disease affecting the ileum, further increase the risk of deficiency.
Vitamin B12 plays a critical role in DNA synthesis and myelin formation. Deficiency leads to ineffective erythropoiesis and macrocytic anaemia, but it also causes progressive neurological damage. Peripheral neuropathy, loss of proprioception, cognitive changes, and even irreversible spinal cord degeneration can occur if deficiency is prolonged. Importantly, treating folate deficiency alone in an undiagnosed B12 deficiency may correct anaemia while allowing neurological damage to progress unnoticed.
Folate Metabolism and Vulnerability to Deficiency
Folate absorption occurs primarily in the proximal small intestine and is more vulnerable to dietary insufficiency than B12 because body stores are limited. Alcohol interferes with folate absorption, hepatic storage, and enterohepatic circulation, making deficiency common in chronic alcohol use. Several medications, including methotrexate and some anticonvulsants, directly inhibit folate metabolism or absorption.
Like B12, folate is essential for DNA synthesis and cell division. Deficiency leads to impaired nuclear maturation in rapidly dividing cells, particularly within the bone marrow. This results in macrocytosis and megaloblastic anaemia, characterised by large, fragile red blood cells and ineffective erythropoiesis. Unlike B12 deficiency, folate deficiency does not cause neurological symptoms, which is a key clinical distinction.
Clinical Connections
Iron deficiency anaemia
Iron deficiency anaemia produces small, pale red blood cells and usually results from chronic blood loss rather than inadequate intake in adults. Heavy menstruation, gastrointestinal bleeding, pregnancy, and malabsorption are common causes. Patients may present with:
fatigue, pallor, exertional dyspnoea, brittle nails, hair thinning, glossitis, and pica (craving ice, clay, or starch). Because iron deficiency is often the first sign of occult gastrointestinal disease, identifying and treating the source of blood loss is as important as replacing the iron itself.
Iron replacement can be given orally or intravenously. Iron infusions (intravenous iron) are used when deficiency is severe, absorption is poor, or rapid replenishment is needed, such as in chronic kidney disease, inflammatory bowel disease, ongoing blood loss, or when oral iron is poorly tolerated. Unlike oral iron, IV iron bypasses the gut and allows full replacement of iron stores over a short period, supporting effective red blood cell production without relying on gastrointestinal absorption.
Vitamin B12 deficiency
Vitamin B12 deficiency causes megaloblastic anaemia and neurological injury because B12 is essential for both DNA synthesis and myelin formation. Patients may develop:
paraesthesia, gait disturbance, memory changes, mood disturbance, and glossitis even before anaemia becomes severe.
Pernicious anaemia, caused by autoimmune destruction of intrinsic factor, prevents intestinal B12 absorption and requires lifelong parenteral B12 therapy, usually by intramuscular injection.
Folate deficiency
Folate deficiency also produces megaloblastic anaemia but does not cause neurological damage. It commonly occurs in malnutrition, alcoholism, malabsorption, and pregnancy. Because folate supplementation can correct the anaemia while allowing neurological injury from B12 deficiency to worsen, B12 status must always be assessed before folate treatment.
Folate deficiency in pregnancy, particularly in early gestation, increases the risks of neural tube defects (such as spina bifida), low birth weight and placental issues. Supplementation to prevent such risks should begin at least one month before conception and throughout the first trimester. Supplementation pre-conception is essential, because neural tube defects are more likely to occur in the first few weeks of gestation, often before women know they are pregnant.
Concept Check
Why does iron deficiency produce microcytic anaemia while B12 deficiency produces macrocytic anaemia?
What role does intrinsic factor play in vitamin B12 absorption?
How does chronic inflammation contribute to anaemia of chronic disease?
Which symptoms are unique to B12 deficiency?
Why is folate particularly important during pregnancy?