Microcytic Anaemia

Iron Deficiency Anaemia

Pathophysiology and staging

Iron deficiency anaemia (IDA) is the final haematological manifestation of a negative iron balance. Total body iron is approximately 3–4 g in adults, with two-thirds in haemoglobin, 10–15% in myoglobin and enzymes, and the remainder stored as ferritin or haemosiderin. Daily obligatory losses are small, around 1 mg/day in men and postmenopausal women, but rise with menstruation, pregnancy, lactation, blood donation, gastrointestinal bleeding, malabsorption, or inflammatory gastrointestinal disease. Dietary absorption occurs predominantly in the duodenum and proximal jejunum: haem iron is absorbed more efficiently than non-haem iron, which requires reduction from Fe³⁺ to Fe²⁺ via duodenal cytochrome b and transport through divalent metal transporter 1. Ferroportin exports iron into plasma; hepcidin, produced by the liver, internalises and degrades ferroportin, thereby reducing iron egress from enterocytes and macrophages.

Stage	Biochemical pattern	Blood film / indices	Clinical relevance
Iron depletion	Low ferritin; normal Hb, MCV, serum iron	Usually normal	Earliest detectable phase
Iron-deficient erythropoiesis	Low ferritin, low transferrin saturation; rising TIBC	May develop low MCH before low MCV	Reticulocyte Hb content falls early
Established IDA	Low ferritin, low serum iron, high TIBC, low transferrin saturation	Microcytosis, hypochromia, anisopoikilocytosis, pencil cells	Symptomatic anaemia; search for cause mandatory

Diagnostic approach and exam-relevant thresholds

The hallmark is microcytic, hypochromic anaemia, but early IDA may be normocytic. A low mean corpuscular haemoglobin (MCH <27 pg) is often more sensitive than MCV. Thrombocytosis may accompany IDA and can be substantial; leucocyte count is usually normal. Reticulocytes are inappropriately low until iron is replaced. The British Society of Gastroenterology (BSG) 2021 guideline recommends confirming iron deficiency with iron studies before investigation, unless urgent treatment is required.

Test	Typical IDA result	Key numerical interpretation
Serum ferritin	Low	<15 microgram/L is highly specific; <30 microgram/L improves sensitivity; in inflammation, IDA remains likely if <45–50 microgram/L, and possible up to 100 microgram/L with TSAT <20%
Serum iron	Low	Diurnal variation; not diagnostic alone
TIBC / transferrin	High	Contrasts with anaemia of chronic disease, where transferrin is low or normal
Transferrin saturation	Low	<16–20% supports iron-restricted erythropoiesis
Soluble transferrin receptor	High	Useful when inflammation confounds ferritin; rises in IDA but not usually in pure inflammatory anaemia
Reticulocyte Hb content	Low	CHr or Ret-He <29 pg suggests functional iron deficiency

Serum ferritin is the single best initial test: meta-analyses suggest ferritin <15 microgram/L has specificity exceeding 95%, whereas a cut-off around 30 microgram/L gives sensitivity approximately 90% with specificity around 85%. Ferritin is an acute-phase reactant, so C-reactive protein, liver disease, malignancy, chronic kidney disease, and infection must be considered. Bone marrow iron staining is rarely required but remains the reference standard.

Aetiology and mandatory investigation

In adult men and postmenopausal women, IDA is gastrointestinal blood loss until proven otherwise. BSG 2021 recommends bidirectional endoscopy in men and postmenopausal women with newly diagnosed IDA, with urgent cancer pathway referral where appropriate. Coeliac disease occurs in approximately 3–5% of adults investigated for IDA; tissue transglutaminase IgA plus total IgA should be checked, recognising reduced sensitivity in older adults. Premenopausal women commonly have menstrual loss, but endoscopic investigation is appropriate when anaemia is severe or recurrent, there are gastrointestinal symptoms, age is >50 years, family history is significant, or coeliac testing is positive. In refractory or recurrent IDA after negative endoscopy, consider capsule endoscopy for small-bowel angioectasia, Crohn disease, NSAID enteropathy, and malignancy.

Treatment: oral and intravenous iron

The aim is correction of haemoglobin and repletion of stores. Oral ferrous salts are first-line when tolerated. A typical adult regimen is ferrous sulfate 200 mg once daily, providing approximately 65 mg elemental iron; alternatives include ferrous fumarate 210 mg once daily, providing approximately 68 mg elemental iron, or ferrous gluconate 300 mg once daily, providing approximately 35 mg elemental iron. BSG advises once-daily dosing initially; if not tolerated, reduce to alternate-day dosing or use another preparation. Alternate-day dosing has a physiological basis: oral iron induces hepcidin for about 24 hours, reducing subsequent absorption; stable isotope studies by Stoffel et al. showed higher fractional absorption with alternate-day dosing than consecutive daily dosing.

Preparation	Example adult dose	Elemental iron	Exam point
Ferrous sulfate	200 mg orally once daily	~65 mg	Common first-line; gastrointestinal intolerance frequent
Ferrous fumarate	210 mg orally once daily	~68 mg	Similar efficacy to sulfate
Ferrous gluconate	300 mg orally once daily	~35 mg	Often better tolerated, lower elemental dose
Ferric carboxymaltose	Up to 1,000 mg IV per infusion	Dose by weight/Hb deficit	Risk of hypophosphataemia via FGF23-mediated renal phosphate wasting
Iron isomaltoside/derisomaltose	Up to 20 mg/kg IV	Total-dose replacement possible	Useful when rapid repletion needed

A response is expected within days: reticulocytosis at 5–10 days and haemoglobin rise by approximately 10 g/L after 2 weeks, or 20 g/L within 3–4 weeks. Failure suggests non-adherence, ongoing bleeding, malabsorption, incorrect diagnosis, inflammation-mediated functional deficiency, or mixed pathology. Continue oral iron for approximately 3 months after Hb normalisation to replenish stores. Absorption is reduced by calcium, tea, coffee, proton-pump inhibitors, antacids, and tetracyclines/quinolones; vitamin C may increase absorption but is not routinely required. Intravenous iron is indicated for intolerance or failure of oral therapy, malabsorption, ongoing blood loss, inflammatory bowel disease flare, chronic kidney disease, late pregnancy, or need for rapid correction. Red cell transfusion should be reserved for haemodynamic instability, active bleeding, or severe symptomatic anaemia; it does not replace iron repletion.

Anaemia of Chronic Disease

Anaemia of chronic disease, more accurately termed anaemia of inflammation, is a hypoproliferative anaemia driven by immune-mediated iron sequestration and impaired erythropoiesis. It is typically normocytic and normochromic initially, but becomes microcytic in a substantial minority, especially with prolonged inflammation or coexistent absolute iron deficiency. Common settings include chronic infection, autoimmune disease, malignancy, chronic kidney disease, inflammatory bowel disease and critical illness.

Pathophysiology

The central mediator is hepcidin, a 25-amino-acid hepatic peptide upregulated predominantly by IL-6 via JAK/STAT3 signalling. Hepcidin binds ferroportin, the only known cellular iron exporter, causing its internalisation and degradation. This reduces iron release from macrophages and enterocytes, producing functional iron deficiency: total body iron stores may be normal or increased, but iron is unavailable for erythropoiesis.

• Iron sequestration: low serum iron and low transferrin saturation despite normal/high ferritin; marrow iron is present but poorly mobilised.
• Reduced erythropoietin response: inflammatory cytokines blunt renal EPO production and impair marrow responsiveness to EPO; this is especially important in CKD.
• Direct erythroid suppression: TNF-α, IL-1 and interferon-γ inhibit erythroid progenitors and shorten red cell survival from approximately 120 days to around 60–90 days.
• Altered iron transport proteins: transferrin, a negative acute-phase reactant, falls; ferritin, a positive acute-phase reactant, rises.

Laboratory Pattern and Diagnostic Interpretation

The anaemia is usually mild to moderate, commonly with haemoglobin 80–110 g/L; severe anaemia should prompt evaluation for bleeding, haemolysis, marrow infiltration, renal failure or combined nutritional deficiency. Reticulocytes are inappropriately low. The peripheral blood film may be unremarkable or show mild microcytosis and hypochromia.

Parameter	Anaemia of chronic disease	Iron deficiency anaemia	Exam relevance
Serum iron	Low	Low	Not discriminatory alone
TIBC/transferrin	Low or normal	High	Key discriminator
Transferrin saturation	Low, often <20%	Low, often <15%	Functional versus absolute deficiency
Ferritin	Normal/high, commonly >100 micrograms/L	Low; <15 micrograms/L highly specific	Ferritin rises with inflammation
Soluble transferrin receptor	Normal or mildly raised	Raised	Useful when CRP is elevated
Bone marrow iron	Present or increased	Absent	Gold standard but rarely required

In inflammatory states, a ferritin threshold of <30 micrograms/L remains strongly suggestive of absolute iron deficiency, whereas many guidelines use <100 micrograms/L as compatible with iron deficiency when inflammation, CKD or heart failure is present. A ferritin >100 micrograms/L with TSAT <20% suggests functional iron restriction. CRP should be interpreted alongside ferritin. The soluble transferrin receptor/log ferritin index may help identify combined iron deficiency and inflammation, although cut-offs vary by assay.

Clinical Contexts

In rheumatoid arthritis, inflammatory bowel disease and chronic infection, anaemia severity often parallels inflammatory activity. In malignancy, anaemia may reflect inflammation, marrow involvement, chemotherapy, renal impairment or occult bleeding. In CKD, relative EPO deficiency overlaps with hepcidin-mediated iron restriction; reduced renal clearance of hepcidin further worsens functional iron deficiency.

Management

The primary treatment is control of the underlying inflammatory disorder. Haematinics should not be given reflexively: oral iron is often ineffective because hepcidin blocks intestinal absorption, but iron replacement is appropriate where absolute deficiency coexists.

Intervention	Typical indication	Exam-level details
Treat inflammation	Autoimmune disease, infection, malignancy	Effective anti-inflammatory or antimicrobial therapy may normalise hepcidin and improve Hb over weeks
Oral iron	Combined absolute deficiency and mild inflammation	Ferrous sulfate 200 mg once daily or alternate-day dosing may improve tolerability; response expected Hb rise about 10 g/L over 2–3 weeks if absorption adequate
Intravenous iron	CKD, IBD, heart failure, intolerance or failure of oral iron	Preparations include ferric carboxymaltose 500–1000 mg per infusion or iron sucrose 100–200 mg repeated; avoid during active bacteraemia
Erythropoiesis-stimulating agents	Selected CKD or chemotherapy-associated anaemia	Use with iron repletion; target Hb generally not normalisation
Red cell transfusion	Symptomatic severe anaemia or instability	Restrictive thresholds commonly Hb 70–80 g/L, modified by ischaemic heart disease, bleeding and symptoms

For CKD, contemporary practice avoids full correction of haemoglobin. ESA therapy is usually considered when Hb is persistently around <100 g/L after iron optimisation, aiming for approximately 100–120 g/L rather than normal values. Trials such as CHOIR and TREAT showed increased cardiovascular and thrombotic risk with higher Hb targets, particularly around 130 g/L. ESA examples include epoetin alfa 50–100 units/kg subcutaneously 1–3 times weekly or darbepoetin alfa 0.45 micrograms/kg weekly, adjusted to response. In cancer, ESAs are generally restricted to chemotherapy-associated anaemia when cure is not the treatment intent because of thromboembolic and potential tumour-progression concerns.

For MRCP, the classic diagnostic clue is: low serum iron, low TIBC, normal/high ferritin and low reticulocyte count in a patient with chronic inflammation. The common trap is missing combined iron deficiency, where ferritin may be “normal” despite depleted stores because it is elevated by inflammation.

Sideroblastic Anaemia

Definition and core pathobiology

Sideroblastic anaemia is a disorder of defective mitochondrial haem synthesis in erythroid precursors, producing iron-laden mitochondria arranged around the nucleus: ring sideroblasts. The anaemia may be microcytic, normocytic, macrocytic, or dimorphic; in MRCP questions, microcytosis with normal or raised iron stores should prompt consideration of sideroblastic anaemia rather than iron deficiency.

The key lesion is failure to incorporate iron into protoporphyrin IX to form haem. Iron enters mitochondria but cannot be effectively utilised, causing mitochondrial iron accumulation, ineffective erythropoiesis, raised serum iron, raised ferritin and raised transferrin saturation. A ring sideroblast is classically defined on Perls’ Prussian blue stain as an erythroblast with ≥5 iron granules encircling at least one-third of the nuclear circumference.

Classification and causes

Category	Mechanism	Typical clues
Congenital	Most commonly ALAS2 mutation, X-linked; impaired delta-aminolaevulinic acid synthase, the first and rate-limiting step of haem synthesis	Male patient, lifelong microcytosis, family history, variable response to pyridoxine
Clonal acquired	Myelodysplastic neoplasm with ring sideroblasts, commonly associated with SF3B1 mutation	Older patient, macrocytosis or dimorphic film, cytopenias, dysplasia, raised ferritin
Reversible acquired	Toxic or metabolic inhibition of haem synthesis or mitochondrial function	Alcohol, isoniazid, linezolid, chloramphenicol, lead, zinc-induced copper deficiency, vitamin B6 deficiency

Alcohol is a common reversible cause and may produce vacuolated erythroid precursors and ring sideroblasts; abnormalities may improve within weeks of abstinence. Isoniazid causes functional pyridoxine deficiency by forming hydrazones with pyridoxal phosphate. Lead inhibits delta-aminolaevulinic acid dehydratase and ferrochelatase, causing sideroblastic erythropoiesis with basophilic stippling and abdominal, neurological or renal manifestations.

Laboratory pattern and diagnostic approach

The hallmark is anaemia with iron repletion or overload. Typical biochemistry shows low or normal MCV, raised serum iron, raised ferritin, raised transferrin saturation and low/normal total iron-binding capacity. This contrasts with iron deficiency anaemia, where ferritin and transferrin saturation are low. Blood film may show hypochromia, anisopoikilocytosis, Pappenheimer bodies, basophilic stippling in lead toxicity, or a dimorphic red cell population following transfusion or in clonal disease.

Investigation	Sideroblastic anaemia pattern	Exam significance
Ferritin	Usually raised; normal adult reference often approximately 30–300 micrograms/L in men and 15–200 micrograms/L in women	Raised ferritin with microcytosis argues against uncomplicated iron deficiency
Transferrin saturation	Often raised; normal approximately 20–45%	Persistent elevation suggests iron-loading erythropoiesis
Bone marrow iron stain	Ring sideroblasts present	Required for morphological confirmation
Molecular testing	SF3B1, ALAS2, broader myeloid panel if clonal disease suspected	Determines classification, prognosis and therapy

In contemporary WHO/ICC classifications, myelodysplastic neoplasm with SF3B1 mutation is recognised as a distinct entity. Historically, MDS with ring sideroblasts required ≥15% ring sideroblasts, or ≥5% if an SF3B1 mutation was present. In an older patient with unexplained sideroblastic anaemia, marrow morphology, cytogenetics and next-generation sequencing are therefore central, not optional.

Prognosis and scoring in clonal sideroblastic anaemia

For MDS-associated sideroblastic anaemia, prognosis is assessed using IPSS-R and increasingly IPSS-M, incorporating marrow blasts, cytogenetics, depth of cytopenias and molecular lesions. Isolated SF3B1-mutated disease often follows a relatively indolent course with prominent anaemia and low transformation risk, but adverse co-mutations, excess blasts, complex karyotype, severe neutropenia or thrombocytopenia alter management.

Management

Treatment depends on reversibility, congenital versus clonal disease, and the burden of anaemia or iron overload.

• Remove reversible causes: stop alcohol and culprit drugs where possible; treat copper deficiency, zinc excess or lead exposure.
• Pyridoxine: give vitamin B6 in suspected congenital ALAS2-related disease or drug-induced deficiency. Typical therapeutic dosing is 50–200 mg orally daily; higher chronic doses risk sensory neuropathy. Isoniazid prophylaxis commonly uses pyridoxine 10–50 mg daily.
• Lead poisoning: chelation is guided by blood lead level and symptoms. Succimer is often used orally in less severe cases; severe encephalopathy requires parenteral therapy such as dimercaprol plus calcium disodium EDTA under specialist toxicology supervision.
• Transfusion support: red cell transfusion is used for symptomatic anaemia, often targeting symptom relief rather than a fixed haemoglobin. Chronic transfusion creates secondary iron overload.
• Iron chelation: consider in lower-risk MDS with ongoing transfusion dependence, ferritin persistently >1000 micrograms/L, usually after approximately 20–25 units of red cells, and expected survival >1–2 years. Deferasirox film-coated tablets are commonly started at about 14 mg/kg once daily, adjusted to ferritin trend and renal/hepatic toxicity.
• Erythropoiesis-stimulating agents: in lower-risk MDS, response is most likely when endogenous erythropoietin is ≤500 IU/L and transfusion burden is low. Regimens include epoetin alfa 30,000–40,000 units weekly or darbepoetin alfa 150–300 micrograms every 1–3 weeks.
• Luspatercept: an activin receptor ligand trap enhancing late erythroid maturation. In the MEDALIST trial in lower-risk MDS with ring sideroblasts after ESA failure, luspatercept achieved transfusion independence for ≥8 weeks in 38% versus 13% with placebo. Dose is 1 mg/kg subcutaneously every 3 weeks, titrated to 1.75 mg/kg.

Exam traps include assuming all microcytosis is iron deficiency, giving iron to a patient with raised ferritin and transferrin saturation, and missing MDS in an older patient with “microcytic anaemia” plus neutropenia, thrombocytopenia or macrocytic/dimorphic red cells.