Iron deficiency anemia

01Definition and overview

Iron deficiency anaemia is anaemia caused by too little iron to make haemoglobin. It is the last of three stages: first the stores empty (a low ferritin, a normal blood count), then the supply to the marrow falls short (a falling transferrin saturation), and only then does the haemoglobin fall, with small, pale red cells. Iron deficiency without anaemia is commoner still and can cause tiredness on its own. Iron deficiency is always the result of something else, so the diagnosis has two halves: proving the deficiency, and finding its cause.

What anaemia is

Anaemia is a haemoglobin concentration below the normal range for age, sex and pregnancy: a sign, never a final diagnosis. Haemoglobin is reported in g/L in the UK and in g/dL in much of Europe (130 g/L is 13 g/dL). As a concentration it moves with the plasma volume: it is falsely normal in the first hours after a sudden bleed, falsely low when the plasma expands (pregnancy, fluid overload) and falsely high in dehydration.

The WHO revised its cut-offs in 2024, lowering the threshold for children aged 6 to 23 months and giving the second trimester of pregnancy, when the plasma volume expands most, its own. The measured haemoglobin is adjusted for altitude (from 500 m) and for smoking, but not for ethnicity or inflammation. Laboratories flag results against their own reference ranges, which differ a little.

How anaemias are sorted

The red cell indices of the blood count point to the cause before any other test:

• Mean cell volume (MCV), the average red cell size, normally about 80 to 96 fL (up to 100 fL in some laboratories).
• Mean cell haemoglobin (MCH), normally 27 to 32 pg. A low MCH (hypochromia) is probably the more reliable sign of iron deficiency, as it depends less on the analyser and the age of the sample.
• Red cell distribution width (RDW): wide in iron deficiency and mixed deficiencies, usually normal in thalassaemia trait.
• Reticulocytes, the youngest red cells, normally about 0.5 to 2.5 per cent (50 to 100 × 10⁹/L): low when the marrow cannot keep up, high when it is replacing cells lost or destroyed, or when treatment works.

02Etiology and pathophysiology

What anaemia does to the body

Less haemoglobin carries less oxygen. The body defends the oxygen supply in four ways, which is why a slowly developing anaemia can be well tolerated:

1. 1

   More oxygen unloaded

   Red cells make more 2,3-bisphosphoglycerate, which shifts the oxygen dissociation curve to the right, so more oxygen is released in the tissues.
2. 2

   Blood redirected

   Flow is diverted from the skin, gut and kidneys to the brain and heart, one reason for pallor.
3. 3

   A faster circulation

   Heart rate and stroke volume rise and the cardiac output climbs; flow murmurs appear, and a diseased heart may fail.
4. 4

   More red cells

   The kidney senses the lack of oxygen and releases erythropoietin, which drives the marrow, provided it has iron, vitamin B12 and folate.

The speed of the fall matters more than the level: losing a litre of blood suddenly can cause shock, while a haemoglobin that falls slowly to 70 g/L may cause only breathlessness on the stairs.

Iron in the body

of iron in an adult man, two thirds of it in haemoglobin

4gof iron in an adult man, two thirds of it in haemoglobin

recycled from old red cells by macrophages, the marrow's main supply

20mg a dayrecycled from old red cells by macrophages, the marrow's main supply

absorbed from food, about a tenth of what the diet holds, matching what is lost

1–2mg a dayabsorbed from food, about a tenth of what the diet holds, matching what is lost

Iron moves in an almost closed loop, and the little that is lost leaves in shed gut and skin cells. There is no regulated way to excrete iron, so the body controls its iron at absorption.

• Absorption is in the duodenum and upper jejunum. Haem iron from meat and fish is absorbed far better than plant iron. Non-haem iron is mostly ferric (Fe³⁺); a reductase turns it into ferrous iron (Fe²⁺), which the transporter DMT1 carries into the enterocyte. Acid helps; tea, coffee, calcium, phytates in cereals and acid-suppressing drugs hinder.
• The enterocyte keeps the iron as ferritin, lost when the cell is shed, or exports it through ferroportin, the only known cellular iron exporter, which macrophages and liver cells use too.
• Transferrin carries iron in plasma to the erythroblasts, normally with about a third of its sites filled (the transferrin saturation); the total iron-binding capacity (TIBC) in effect measures transferrin.
• Ferritin stores iron in liver and macrophages, and the little in serum reflects the stores. Haemosiderin, its insoluble breakdown product, stains blue with Perls' reaction.

Hepcidin, the master switch

Hepcidin, a peptide hormone from the liver, binds ferroportin and makes the cell destroy it, so iron stays locked in enterocytes (and leaves when they are shed) and in macrophages. It rises when the stores are full and in inflammation, driven by interleukin-6, and falls with iron deficiency, hypoxia and active erythropoiesis.

• In chronic inflammation, high hepcidin traps iron in macrophages despite full stores: the anaemia of inflammation, and the reason oral iron is poorly absorbed in active inflammatory disease.
• A dose of oral iron raises hepcidin for about a day and blocks absorption of the next, so one dose a day, or on alternate days, works as well as more frequent dosing.
• Too little hepcidin lets iron flood in, in hereditary haemochromatosis and in thalassaemia.

Causes of iron deficiency

Most iron deficiency is blood loss. A millilitre of blood carries about half a milligram of iron, so a few millilitres a day, unseen in the stool, can outrun absorption; normal periods alone cost about 0.5 to 0.7 mg a day across the month.

Anticoagulants and antiplatelet drugs make a lesion bleed rather than explain the loss, and iron deficiency is often multifactorial, so neither ends the search for a cause in an older patient.

Whatever the cause, once iron runs short haem synthesis slows; erythroblasts are thought to keep dividing while they wait for haemoglobin, so the cells come out small and pale. Iron enzymes in muscle, brain and epithelia suffer too, which explains tiredness, restless legs and the changes in nails, tongue and mouth.

03Clinical features

Any anaemia

• Symptoms: tiredness, breathlessness on exertion, palpitations, headache, dizziness, poor concentration; with heart disease or in old age, angina, claudication, heart failure or confusion. Many with a slow anaemia have none.
• Signs: pallor of the conjunctivae and palms (a poor guide), a fast pulse, a systolic flow murmur and, when severe, high-output heart failure.
• Clues to the cause: jaundice in haemolysis, leg ulcers in sickle cell disease, lymph nodes or a big spleen in lymphoma and leukaemia, bruising in marrow failure, neuropathy in vitamin B12 deficiency.

Iron deficiency

Most patients have only the anaemia, or nothing. Long-standing deficiency, now less common, adds its own signs:

• Koilonychia (spoon-shaped nails), brittle nails and hair loss.
• Angular cheilitis and atrophic glossitis (a smooth, sore tongue).
• Restless legs syndrome, which improves with iron.
• Pica, a craving for ice (pagophagia), earth or starch.
• Plummer–Vinson (Paterson–Brown-Kelly) syndrome: difficulty swallowing from a web in the upper oesophagus, with glossitis; rare now, and it carries a risk of postcricoid cancer.
• In children, slower development; in pregnancy, a link with preterm birth and low birth weight.

The history looks for the cause: diet, periods (length, flooding, clots), pregnancies, blood donation, NSAIDs and anticoagulants, bowel symptoms and weight loss, gut surgery, nosebleeds, blood in the urine, a family history of bowel cancer, and where the patient has lived.

04Diagnosis and management

Confirming iron deficiency

• Full blood count: low haemoglobin, MCV below 80 fL, MCH below 27 pg, wide RDW; platelets often raised, reticulocytes low for the anaemia.
• Blood film: small, pale cells of varied size and shape, with elongated pencil cells.
• Serum ferritin: the single most useful test.

ferritin below this means empty stores, almost certain iron deficiency

15µg/Lferritin below this means empty stores, almost certain iron deficiency

ferritin below this means low stores, the usual working threshold, also in pregnancy

30µg/Lferritin below this means low stores, the usual working threshold, also in pregnancy

ferritin below this is a practical cut-off for investigation in UK guidance

45µg/Lferritin below this is a practical cut-off for investigation in UK guidance

transferrin saturation below this means too little iron reaches the marrow

20per centtransferrin saturation below this means too little iron reaches the marrow

Finding the cause

1. 1

   Everyone

   A history and examination, a urine test for blood (kidney and bladder cancers bleed), and coeliac disease serology (tissue transglutaminase IgA with total IgA): coeliac disease is found in 3 to 5 per cent of people with iron deficiency anaemia.
2. 2

   Men and postmenopausal women

   Gastroscopy and colonoscopy, usually at one session, even when aspirin or a hiatus hernia seems to explain the loss, with duodenal biopsies if coeliac serology is positive or not done, and in older patients, in whom serology misses more. CT colonography if colonoscopy is unsuitable. Colonoscopy is deferred only if a cancer is found in the upper gut.
3. 3

   Premenopausal women

   Coeliac serology and attention to the periods. Endoscopy only at 50 or over, without periods, with red flag symptoms, with a strong family history (colorectal cancer in two first-degree relatives, or in one before 50), or with deficiency that recurs or is out of proportion to the periods.
4. 4

   Still unexplained

   If both endoscopies are clear and the anaemia fails to respond or recurs: capsule endoscopy of the small bowel (angioectasia, Crohn's disease, NSAID damage, tumours), imaging of the urinary tract, and repeat endoscopy if the views were poor.

• In men and postmenopausal women, investigation finds a likely cause in the gut in about a third, a cancer in 8 to 10 per cent, and lesions in both the upper and the lower gut in 1 to 10 per cent. Young men are investigated the same way; in pregnancy, endoscopy is kept for pointers to gut disease.
• A faecal immunochemical test (FIT) helps set the urgency of referral in UK primary care, but a negative result does not replace endoscopy in iron deficiency anaemia.
• Helicobacter pylori and atrophic gastritis reduce stomach acid and with it iron absorption. European consensus recommends looking for and eradicating H. pylori in unexplained iron deficiency anaemia, though whether eradication improves the response to iron is less certain.

The other microcytic anaemias

• Anaemia of inflammation, the commonest anaemia in hospital: interleukin-6 raises hepcidin, which locks iron in macrophages, the erythropoietin response is blunted, and red cells live a little less long. It is treated through the disease (rheumatoid arthritis, for example), with intravenous iron when true deficiency coexists.
• Thalassaemia trait: a Mentzer index (MCV divided by the red cell count) below 13 favours it, as a rough guide. An HbA2 of about 3.5 per cent or more confirms beta trait; alpha trait has a normal HbA2. Iron deficiency lowers the HbA2 and can hide beta trait. Carriers need no treatment, and partners are offered testing before a pregnancy (see haemolytic anaemias).
• Sideroblastic anaemia: iron piles up in the mitochondria of erythroblasts and rings the nucleus. The X-linked form (ALAS2, the pyridoxine-dependent first enzyme of haem synthesis) may respond to pyridoxine; in adults most cases are a myelodysplastic syndrome, which can progress to acute myeloid leukaemia; alcohol, lead, isoniazid and copper deficiency are reversible causes.
• Lead poisoning blocks haem synthesis: a mild microcytic or normocytic anaemia with basophilic stippling, colic, a motor neuropathy and, in children, learning problems.

Oral iron

Iron is started as soon as the deficiency is confirmed, alongside the search for the cause, unless a colonoscopy is days away.

• One tablet a day (50 to 100 mg of elemental iron), on an empty stomach, away from tea, coffee, milk, antacids and calcium; food can cut absorption by up to three quarters. Vitamin C is no longer advised, since a large trial found no gain, and modified-release forms, which release iron beyond the duodenum, are not recommended.
• If one tablet a day is not tolerated, one on alternate days is absorbed better per dose and may cause fewer side effects; ferric maltol or intravenous iron are the other options.
• Side effects: nausea, upper abdominal pain, constipation or diarrhoea, and harmless black stools. Iron reduces the absorption of levothyroxine, tetracyclines, quinolones and bisphosphonates, so they are taken hours apart.
• Iron tablets are dangerous to small children: an overdose causes vomiting, gut bleeding, shock and liver failure. They are kept out of reach; desferrioxamine is the antidote.

The response is checked at 2 to 4 weeks: a rise of 10 g/L or more at 2 weeks, or of 20 g/L or into the normal range at 4 weeks, is adequate. Once the haemoglobin is normal, iron continues for about 3 months to refill the stores, and blood counts every few months for a year or two catch a recurrence. No rise means tablets not taken, a wrong diagnosis, continuing bleeding, poor absorption, another deficiency alongside (vitamin B12, folate), or kidney or marrow disease.

Intravenous iron

Intravenous iron refills the stores in one or two visits, but the haemoglobin rises at much the same pace as with tablets, which therefore stay first for most patients. It is chosen from the start for continuing heavy bleeding, malabsorption from gut disease, iron deficiency with active inflammation, or when tablets cannot be taken; and later for intolerance or failure of oral iron, or when the anaemia must be corrected quickly, as before surgery.

• It is avoided in the first trimester of pregnancy and withheld in bacteraemia.
• Hypophosphataemia: ferric carboxymaltose raises FGF23, which makes the kidney waste phosphate and lowers calcitriol. In two head-to-head trials the phosphate fell below 0.65 mmol/L in about three quarters of patients given ferric carboxymaltose, against under a tenth given ferric derisomaltose. It is usually silent and passes in weeks, but repeated doses and risk factors (inflammatory bowel disease, vitamin D deficiency, malabsorption, osteoporosis) can cause bone pain, weakness, osteomalacia and fractures, easily blamed on the iron deficiency, so the phosphate is checked in those at risk. In September 2026 the European Medicines Agency began a review of this harm with all injectable irons, after reports of serious cases with ferric carboxymaltose even after one or two doses and in people without known risk factors; its outcome is pending.

Transfusion

Transfusion is rarely needed: it is kept for severe symptoms or a failing circulation, aiming at 70 to 90 g/L (80 to 100 g/L with unstable coronary disease). One unit holds only about 200 mg of iron, so iron is still given afterwards.

Special situations

• Pregnancy: in UK guidance anaemia is a haemoglobin below 110 g/L in the first trimester, below 105 g/L later and below 100 g/L after delivery, and a ferritin below 30 µg/L confirms deficiency. Some fall is normal, as the plasma volume expands more than the red cells (see maternal adaptations). A trial of oral iron is both test and treatment; intravenous iron is considered from the second trimester if tablets fail or are not tolerated, or little time is left before delivery.
• Chronic kidney disease: iron deficiency is a transferrin saturation of 20 per cent or less with a ferritin of 100 µg/L or less (200 µg/L or less on haemodialysis), and iron is replaced before erythropoiesis-stimulating agents, intravenously on haemodialysis.
• Heart failure: iron deficiency affects 40 to 70 per cent of patients. With a reduced ejection fraction, intravenous iron (ferric carboxymaltose or ferric derisomaltose) improves symptoms, exercise capacity and quality of life and may reduce admissions; oral iron does not, and with a preserved ejection fraction the evidence is scarce. European guidance now defines iron deficiency in heart failure by a transferrin saturation below 20 per cent.
• Inflammatory bowel disease: intravenous iron comes first in active disease, after intolerance of oral iron, or with a haemoglobin below 100 g/L; otherwise oral iron, at 100 mg of elemental iron a day or less.
• After a Roux-en-Y gastric bypass, about a quarter of patients have iron deficiency anaemia at 2 years; long-term iron is usual, but another cause is still sought.

05Epidemiology

Anaemia affected about 1.9 billion people in 2021, close to a quarter of the world (24.3 per cent, down from 28.2 per cent in 1990), and dietary iron deficiency was its leading cause. The burden is greatest in children under 5 and in women, and in sub-Saharan Africa and South Asia, where poor diets, hookworm, malaria and frequent pregnancies combine.

In high-income countries such as the UK, iron deficiency anaemia affects about 2 to 5 per cent of adult men and postmenopausal women and 5 to 12 per cent of otherwise healthy premenopausal women, and iron deficiency without anaemia is commoner still. Anaemia rises with age, to more than a fifth of people over 85, though iron deficiency explains only part of it.

06Prognosis

Iron deficiency itself is easily treated: the reticulocytes rise within a week, the haemoglobin usually returns to normal within a couple of months, and tiredness and restless legs often improve sooner. The outlook is that of the cause, which is why the cause is always sought.

After clear endoscopies and a full response, the deficiency still recurs in about 12 to 25 per cent; recurrence leads to small bowel and urinary tract investigation, and to long-term iron when the cause cannot be removed (angioectasia, atrophic gastritis, gut surgery). Untreated, iron deficiency is associated with slower development in infancy, preterm birth and less reserve for bleeding at delivery in pregnancy, and more symptoms and admissions in heart failure and kidney disease.