Medicine chapters
Iron deficiency, anaemia of chronic disease (hepcidin) and sideroblastic anaemia
The causes, features, iron studies and treatment of iron deficiency anaemia, how hepcidin produces the anaemia of chronic disease, and how sideroblastic anaemia differs.
- Iron deficiency is the commonest anaemia worldwide; it is usually due to blood loss and shows a low ferritin with a high TIBC.
- In anaemia of chronic disease, hepcidin (driven by IL-6) blocks ferroportin and traps iron in macrophages: ferritin is normal or high and TIBC is low.
- Sideroblastic anaemia is a defect of haem synthesis with ring sideroblasts on Perls' stain and iron overload.
On this page
Overview
A microcytic hypochromic anaemia has small (MCV below 80 fL), pale (MCH below 27 pg) red cells. The four causes to remember are:
- Iron deficiency (by far the commonest; the leading cause of anaemia in the world).
- Anaemia of chronic disease (usually normocytic, becomes microcytic when longstanding).
- Thalassaemia trait (a globin defect; covered in its own chapter).
- Sideroblastic anaemia (a haem synthesis defect).
The exam tests iron studies, the role of hepcidin and the treatment of iron deficiency.
Small red cells come from a shortage of one of the three parts of haemoglobin: iron (iron deficiency, chronic disease), haem ring (sideroblastic, lead) or globin (thalassaemia).
Iron physiology in brief
- Dietary iron is mostly ferric (Fe3+), which is poorly absorbed. Ferrous (Fe2+) iron and haem iron (from meat) are absorbed better.
- Absorption takes place mainly in the duodenum. DMT1 carries iron into the enterocyte; ferroportin exports it into plasma.
- In plasma, iron travels on transferrin, which is normally about one-third saturated.
- Stores are held as ferritin (soluble) and haemosiderin (insoluble, seen with Perls' stain) in macrophages and liver.
- Vitamin C and gastric acid help absorption. Tea (tannins), phytates and antacids reduce it.
- The body has no active route to excrete iron. Balance is controlled only at the point of absorption.
- Daily losses are small (about 0.5–1 mg). Needs rise in growth and pregnancy.
Hepcidin: the master regulator
- A small peptide made by the liver.
- It binds ferroportin and causes it to be taken into the cell and destroyed.
- Result: less iron leaves gut cells and macrophages, so plasma iron falls.
- Raised by inflammation (IL-6) and by iron loading.
- Lowered by iron deficiency, anaemia and hypoxia (so absorption increases).
- In thalassaemia, the hormone erythroferrone from stressed erythroblasts suppresses hepcidin, so these patients absorb too much iron even without transfusion.
- In hereditary haemochromatosis, mutations (e.g. HFE) cut hepcidin production, so iron absorption is excessive.
High hepcidin = iron trapped (anaemia of chronic disease). Low hepcidin = iron flooding in (haemochromatosis, thalassaemia).
Iron deficiency anaemia
Causes
| Mechanism | Examples |
|---|---|
| Blood loss (commonest) | Heavy periods; gut bleeding from peptic ulcer, NSAIDs, large bowel cancer or polyps, angiodysplasia; hookworm in low income countries |
| Increased needs | Pregnancy, infancy, adolescent growth, prematurity |
| Poor absorption | Coeliac disease, gastrectomy, achlorhydria, H. pylori |
| Poor intake | Vegetable-based diet, delayed weaning, elderly |
- In premenopausal women, menstrual loss is the usual cause. A monthly loss well above 100 mL usually outstrips what the gut can absorb.
- In men and postmenopausal women, assume gastrointestinal blood loss until proven otherwise, and look for a bowel or stomach cancer.
- In Pakistan, poor diet, repeated pregnancies and hookworm are common contributors.
Unexplained iron deficiency in a man or an older woman is a red flag for bowel cancer. Investigate the gut (upper endoscopy and colonoscopy); do not just prescribe iron.
Clinical features
General features of anaemia: tiredness, breathlessness, palpitations, pallor. Signs specific to longstanding iron deficiency:
- Koilonychia (spoon-shaped nails) and brittle nails.
- Angular stomatitis and atrophic glossitis (smooth tongue).
- Brittle hair.
- Pica (craving for ice, clay or soil).
- Plummer–Vinson (Paterson–Brown–Kelly) syndrome: iron deficiency with a post-cricoid oesophageal web causing dysphagia and glossitis. It carries a risk of post-cricoid squamous carcinoma.
Ask about diet, periods (duration, clots, number of pads), NSAID use, blood in the stool, weight loss and change in bowel habit.
Investigations
- Full blood count: low Hb, low MCV and MCH, and a raised RDW (cells vary in size).
- Blood film: microcytic hypochromic cells, anisocytosis (size variation), poikilocytosis (shape variation), pencil cells.
- Serum ferritin: reflects stores. A low ferritin confirms iron deficiency. Normal ranges in Kumar and Clark are about 30–300 μg/L in men and 15–200 μg/L in women.
- Serum iron: low, but it fluctuates through the day and is not useful alone.
- TIBC (transferrin): raised, because the liver makes more transferrin when iron is short.
- Transferrin saturation: low; iron deficiency is regularly present below about 19%.
- Soluble transferrin receptor: raised in iron deficiency but normal in chronic disease; useful when both may coexist.
- Erythrocyte protoporphyrin: raised (there is no iron to put into the haem ring).
- Bone marrow (rarely needed): absent stainable iron.
- Find the cause: stool for ova (hookworm), coeliac serology, upper GI endoscopy and colonoscopy, gynaecological assessment.
Serum iron 6 μmol/L, TIBC 80 μmol/L
Saturation = 6 ÷ 80 × 100 = 7.5%
Well below 19%, with a high TIBC → fits iron deficiency
Ferritin is an acute-phase protein. In infection, inflammation, cancer or liver disease it may be normal or high even when iron stores are empty. Look at TIBC, transferrin saturation and soluble transferrin receptor.
Order of change as iron runs out
- Stores fall first: ferritin drops, TIBC rises.
- Then serum iron and transferrin saturation fall.
- Then a normocytic anaemia appears.
- Finally the cells become microcytic and hypochromic.
Treatment
Treat the cause and replace iron.
Oral iron (first line):
- Ferrous sulphate 200 mg tablets; each gives 60 mg elemental iron. The traditional dose is one tablet three times daily, but once daily or alternate-day dosing may be absorbed as well and is better tolerated (each dose briefly raises hepcidin).
- Take on an empty stomach, ideally with orange juice (vitamin C). Avoid tea with the dose.
- Side effects: nausea, epigastric pain, constipation or diarrhoea, black stools.
- Expect Hb to rise by about 10 g/L per week and a reticulocyte response within about a week.
- Continue for some months after Hb is normal to refill the stores (the whole course can take about 6 months).
Hb 80 g/L, target 130 g/L, expected rise about 10 g/L per week
Time = (130 − 80) ÷ 10 = 5 weeks for the Hb to normalise
Then continue iron to replenish stores
Failure to respond to oral iron: think of
- poor compliance (commonest);
- ongoing bleeding;
- wrong diagnosis (e.g. thalassaemia trait, chronic disease);
- malabsorption (coeliac disease, atrophic gastritis);
- a mixed deficiency (folate or B12 as well).
Parenteral (intravenous) iron: used when oral iron is not tolerated, in malabsorption, in inflammatory bowel disease, in chronic kidney disease (with erythropoietin) and late in pregnancy when time is short. Preparations include iron sucrose, ferric carboxymaltose and low-molecular-weight iron dextran (test dose needed because of anaphylactoid reactions). It refills stores faster, but the Hb does not rise faster than with oral iron. Stop oral iron while giving IV iron.
Blood transfusion is kept for severe symptomatic anaemia, heart failure or active bleeding.
A response to iron is the final proof of iron deficiency: reticulocytes rise within days and Hb climbs by about 10 g/L a week.
Anaemia of chronic disease (anaemia of inflammation)
Causes
- Chronic infections: tuberculosis, infective endocarditis, osteomyelitis, HIV.
- Chronic inflammation: rheumatoid arthritis, SLE, Crohn's disease, polymyalgia rheumatica.
- Malignancy.
- It is one of the commonest anaemias in hospital patients.
Mechanism: the role of hepcidin
- Inflammatory cytokines, especially IL-6, make the liver produce more hepcidin.
- Hepcidin destroys ferroportin.
- Iron is locked inside macrophages and gut cells and cannot reach the marrow.
- Other effects: the erythropoietin response is blunted and red cell survival is slightly shortened.
The body is "hiding" iron from bacteria; the cost is anaemia.
Findings
- Mild to moderate anaemia, usually normocytic normochromic; microcytic when longstanding.
- Serum iron low, TIBC low (or normal), transferrin saturation low.
- Ferritin normal or raised (stores are full and ferritin is also an acute-phase protein).
- Soluble transferrin receptor normal.
- Marrow: iron present in macrophages but not in developing red cells.
Treatment
- Treat the underlying disease.
- Oral iron does not help (hepcidin blocks absorption). IV iron may help some patients.
- Erythropoietin is used in chronic kidney disease and sometimes in inflammatory disease.
- Transfuse if severe and symptomatic.
A patient with rheumatoid arthritis on NSAIDs can have both chronic disease and iron deficiency from gut bleeding. A ferritin in the low-normal range in an inflamed patient may still mean iron deficiency.
Sideroblastic anaemia
What it is
A failure to make haem (protoporphyrin) in the red cell precursor. Iron enters the mitochondria but cannot be used. Iron-loaded mitochondria form a ring of granules around the nucleus: the ring sideroblast, seen on Perls' (Prussian blue) stain of the marrow. Ring sideroblasts are the diagnostic feature.
Causes
| Type | Causes |
|---|---|
| Inherited | X-linked defect of δ-ALA synthase, the first, pyridoxine-dependent enzyme of haem synthesis (mainly affects males); rarer autosomal recessive forms |
| Acquired (commonest in adults) | Myelodysplastic syndrome (primary acquired form); alcohol; lead poisoning; isoniazid (pyridoxine antagonist); other drugs; myeloproliferative disease |
Findings
- Anaemia that does not respond to ordinary haematinics.
- Film often dimorphic (a mixture of small pale cells and normal or large cells). MCV is low in the inherited form but often raised in the acquired (myelodysplastic) form.
- Serum iron and ferritin high, transferrin saturation high: an iron-overloaded state.
- Lead poisoning also shows basophilic stippling.
Treatment
- Remove the cause (stop alcohol, isoniazid, lead exposure).
- Pyridoxine helps some patients, especially inherited forms; give it to patients on isoniazid as prevention.
- Folic acid if deficient; transfusion and iron chelation for severe cases.
Isoniazid causes sideroblastic anaemia (and peripheral neuropathy) by depleting vitamin B6. Pyridoxine is the cofactor for ALA synthase.
Iron studies at a glance
| Test | Iron deficiency | Chronic disease | Thalassaemia trait | Sideroblastic |
|---|---|---|---|---|
| MCV | Low | Normal or low | Very low for the Hb | Low (inherited) or high (acquired) |
| Serum iron | Low | Low | Normal | High |
| TIBC | High | Low | Normal | Normal |
| Ferritin | Low | Normal or high | Normal | High |
| Soluble transferrin receptor | High | Normal | Normal or high | Normal or high |
| Marrow iron | Absent | Present (in macrophages) | Present | Present, ring sideroblasts |
| RDW | High | Normal | Usually normal | Often high (dimorphic) |
In iron deficiency the empty transport lorries (transferrin/TIBC) are sent out in large numbers; in chronic disease the warehouse (ferritin) is locked and fewer lorries are sent.
Expect: the commonest cause of iron deficiency in different age and sex groups; signs such as koilonychia and Plummer–Vinson syndrome; the iron study pattern (ferritin, TIBC, saturation) that separates iron lack from chronic disease, thalassaemia trait and sideroblastic anaemia; ferritin as an acute-phase reactant; hepcidin, IL-6 and ferroportin; elemental iron in ferrous sulphate, the expected Hb rise and causes of non-response; indications for IV iron; and ring sideroblasts, Perls' stain, ALA synthase and the isoniazid–pyridoxine link.
Quick revision
- Microcytic causes: iron deficiency, chronic disease, thalassaemia trait, sideroblastic anaemia.
- Iron deficiency: low ferritin, high TIBC, low saturation, high RDW, pencil cells.
- Iron deficiency in a man or postmenopausal woman: scope the gut.
- Ferrous sulphate 200 mg = 60 mg elemental iron; Hb rises about 10 g/L per week.
- Non-response: poor compliance, ongoing loss, wrong diagnosis, malabsorption.
- Chronic disease: IL-6 → hepcidin up → ferroportin destroyed → iron trapped; ferritin normal or high, TIBC low.
- Sideroblastic: ring sideroblasts on Perls' stain; high ferritin and iron; causes include alcohol, lead, isoniazid, MDS; try pyridoxine.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Pathoma: Fundamentals of Pathology).
FAQ
What is the single best test for iron deficiency?
Serum ferritin; a low value confirms depleted stores, but a normal value does not exclude deficiency in an inflamed patient.
Why is TIBC low in anaemia of chronic disease but high in iron deficiency?
TIBC mostly reflects transferrin; the liver makes more transferrin when iron is short, but makes less during chronic inflammation.
What does hepcidin do?
It is a liver peptide that destroys the iron exporter ferroportin, so iron stays trapped in gut cells and macrophages and plasma iron falls.
Does intravenous iron raise haemoglobin faster than oral iron?
No; it refills stores faster, but the haemoglobin rises at about the same rate.
What is a ring sideroblast?
An erythroblast with a collar of iron-packed mitochondria circling its nucleus, seen with Perls' stain in sideroblastic anaemia.