Anaemia (Adult Master Topic)

1. Overview and Definition

Anaemia is defined by the World Health Organization (WHO) as a haemoglobin (Hb) concentration below 130 g/L in men and 120 g/L in non-pregnant women. [1] It is not a disease entity in itself but rather a clinical sign reflecting an underlying pathological process affecting red cell production, destruction, or loss.

The clinical significance of anaemia cannot be overstated: it represents the most common haematological abnormality worldwide, affecting over 2 billion people globally. [2] In the United Kingdom, approximately 3% of men and 8% of premenopausal women have anaemia, with prevalence rising sharply in the elderly population.

The Modern Paradigm Shift

The management of anaemia has evolved significantly over the past two decades, driven by three major advances:

1. Molecular Understanding: The discovery of the Hepcidin-Ferroportin axis (2001-2003) revolutionized our understanding of iron homeostasis and the pathophysiology of anaemia of chronic disease. [3]

2. Therapeutic Innovation: The introduction of high-dose intravenous iron preparations (ferric carboxymaltose, iron isomaltoside) has transformed the treatment landscape, particularly in inflammatory conditions and malabsorption. [4]

3. Diagnostic Imperative: Recognition that iron deficiency anaemia (IDA) in men and postmenopausal women is a red flag for gastrointestinal malignancy, mandating urgent investigation. Up to 10% of such cases will have underlying colorectal cancer. [5]

Classification Framework

Anaemia is traditionally classified by Mean Corpuscular Volume (MCV):

• Microcytic (MCV less than 80 fL): Iron deficiency, thalassaemia, sideroblastic anaemia, anaemia of chronic disease
• Normocytic (MCV 80–100 fL): Acute blood loss, haemolysis, chronic disease, chronic kidney disease, bone marrow failure
• Macrocytic (MCV > 100 fL):
  • "Megaloblastic: B12/folate deficiency"
  • "Non-megaloblastic: Alcohol, liver disease, hypothyroidism, myelodysplasia, reticulocytosis"

An alternative kinetic classification based on the reticulocyte count is increasingly used:

• Hypoproliferative (low reticulocyte count): Production failure
• Hyperproliferative (high reticulocyte count): Haemolysis or acute blood loss

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2. Epidemiology

Global Burden of Disease

Anaemia affects approximately 30% of the global population, with the highest prevalence in:

• Sub-Saharan Africa (47% of children, 30% of women)
• South Asia (42% of children, 45% of women)
• Low-income populations in high-income countries

In the United Kingdom:

• Premenopausal women: 8% prevalence (predominantly menstrual iron loss)
• Men: 3% prevalence (any IDA mandates investigation)
• Elderly (> 85 years): > 20% prevalence (multifactorial)

Aetiology by Population

The Gastrointestinal Malignancy Link

In patients over 50 years with iron deficiency anaemia:

• Colorectal cancer: 6-10% of cases [5]
• Gastric cancer: 2-3% of cases
• Oesophageal cancer: 1-2% of cases

This underlies the mandated bidirectional endoscopy (OGD + colonoscopy) for all men and postmenopausal women with IDA, even in the absence of gastrointestinal symptoms.

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3. Aetiology and Pathophysiology

3.1 Iron Metabolism: The Hepcidin-Ferroportin Axis

The discovery of hepcidin in 2001 transformed our understanding of systemic iron homeostasis. [3] The following seven-step mechanism is considered high-yield for MRCP examinations:

The 7-Step Molecular Mechanism

1. Dietary Iron Reduction
   Dietary ferric iron (Fe³⁺) is reduced to ferrous iron (Fe²⁺) by Duodenal Cytochrome B (DcytB) at the apical (luminal) surface of duodenal enterocytes. Gastric acid facilitates this reduction; hence proton pump inhibitors (PPIs) reduce iron absorption.

2. DMT1 Import
   Fe²⁺ is transported across the apical membrane into the enterocyte by Divalent Metal Transporter 1 (DMT1). This is the rate-limiting step for dietary iron absorption.

3. Hepcidin: The Master Regulator
   Produced by hepatocytes, hepcidin is a 25-amino acid peptide that serves as the central negative regulator of iron homeostasis. Hepcidin synthesis is increased by:

   • High serum iron (via BMP6-SMAD signaling)
   • Inflammation (via IL-6 and STAT3 pathway)

   Hepcidin synthesis is suppressed by:

   • Iron deficiency
   • Hypoxia
   • Increased erythropoiesis (via erythroferrone)

4. Ferroportin Degradation
   Hepcidin binds to ferroportin (the only known cellular iron exporter) on the basolateral membrane of enterocytes, macrophages, and hepatocytes. This binding triggers ferroportin internalization and lysosomal degradation, thereby blocking iron export from cells into the bloodstream.

5. Functional Iron Deficiency in Inflammation
   In chronic inflammatory states (infection, autoimmunity, malignancy), elevated IL-6 stimulates hepcidin production. This results in iron sequestration within macrophages and enterocytes, creating functional iron deficiency—total body iron stores may be normal or elevated, but iron is unavailable for erythropoiesis. This is the molecular basis of Anaemia of Chronic Disease (ACD). [6]

6. Transferrin-Mediated Transport
   Iron exported via ferroportin is oxidized to Fe³⁺ by ferroxidases (ceruloplasmin, hephaestin) and loaded onto transferrin. Transferrin-bound iron is delivered to erythroid precursors in the bone marrow, where it binds to Transferrin Receptor 1 (TfR1).

7. Haem Synthesis
   Within erythroblast mitochondria, iron is incorporated into protoporphyrin IX by the enzyme ferrochelatase to form haem. If iron supply is insufficient, haem synthesis fails, leading to:

   • Accumulation of protoporphyrin
   • Microcytic, hypochromic red cells
   • Elevated zinc protoporphyrin (a marker of iron-restricted erythropoiesis)

3.2 Vitamin B12 and Folate Metabolism

Vitamin B12 (Cobalamin)

Dietary sources: Meat, fish, dairy (absent from plants; vegans at risk)

Absorption pathway:

1. Gastric phase: B12 binds to R-protein (haptocorrin) in saliva/gastric juice
2. Duodenal phase: Pancreatic proteases degrade R-protein; B12 binds Intrinsic Factor (IF) secreted by gastric parietal cells
3. Ileal phase: The B12-IF complex binds to cubilin receptors in the terminal ileum and is absorbed
4. Transport: B12 is transported in blood by transcobalamin II to tissues

Causes of B12 deficiency:

• Pernicious anaemia (autoimmune destruction of parietal cells; anti-IF antibodies) [7]
• Gastric surgery (loss of IF-producing cells)
• Terminal ileal disease (Crohn's disease, ileal resection)
• Dietary (strict veganism)
• Drugs: Metformin (reduces ileal absorption), PPIs (reduce B12 release from food)

Biochemical roles:

• Methionine synthase: Converts homocysteine → methionine (requires methylcobalamin)
• Methylmalonyl-CoA mutase: Converts methylmalonyl-CoA → succinyl-CoA (requires adenosylcobalamin)

B12 deficiency impairs DNA synthesis, causing megaloblastic changes (delayed nuclear maturation relative to cytoplasm). It also causes demyelination of the posterior and lateral spinal cord columns, resulting in subacute combined degeneration (SCD). [8]

Folate

Dietary sources: Green leafy vegetables, fortified cereals, liver

Absorption: Jejunum (as methyltetrahydrofolate)

Biochemical role:

• Thymidylate synthase: Converts dUMP → dTMP (essential for DNA synthesis)

Causes of folate deficiency:

• Dietary insufficiency (elderly, alcohol excess)
• Increased demand (pregnancy, haemolytic anaemia, malignancy)
• Malabsorption (coeliac disease, jejunal disease)
• Drugs: Methotrexate, trimethoprim, phenytoin

3.3 Anaemia of Chronic Disease (ACD)

ACD is the second most common anaemia worldwide (after IDA). [6] It occurs in:

• Chronic infections (TB, endocarditis)
• Autoimmune disease (RA, SLE)
• Malignancy
• Chronic kidney disease

Pathophysiology:

1. IL-6 and TNF-α (produced by inflammation) stimulate hepcidin synthesis
2. Hepcidin degrades ferroportin → iron sequestration in macrophages
3. Erythropoietin (EPO) production is blunted relative to the degree of anaemia
4. Red cell lifespan is shortened (mild haemolysis)
5. Bone marrow response to EPO is impaired (cytokine-mediated)

Laboratory features:

• Normocytic or mildly microcytic anaemia
• Low serum iron, low transferrin (negative acute phase reactant)
• Normal or elevated ferritin (acute phase reactant)
• Low transferrin saturation (less than 20%)
• Elevated hepcidin (if measured)

Distinguishing ACD from IDA:

• Ferritin > 100 µg/L suggests ACD (unless inflammation masks IDA)
• Transferrin saturation less than 20% suggests iron deficiency (absolute or functional)
• Soluble transferrin receptor (sTfR): Elevated in IDA, normal in pure ACD [9]
• Bone marrow iron stain: Gold standard (absent in IDA, present in ACD)

3.4 Haemolytic Anaemia

Defined as shortened red cell lifespan (less than 120 days). The bone marrow can compensate with a 6-8 fold increase in red cell production, so anaemia only develops if haemolysis exceeds marrow capacity.

Classification:

Laboratory hallmarks of haemolysis:

• Elevated reticulocyte count (> 2%)
• Elevated unconjugated bilirubin (jaundice)
• Elevated LDH (released from lysed red cells)
• Low haptoglobin (binds free haemoglobin; depleted in intravascular haemolysis)
• Blood film: Spherocytes, schistocytes, bite cells (depending on cause)

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4. Clinical Presentation

4.1 General Features of Anaemia

The clinical manifestations of anaemia depend on:

• Severity of the haemoglobin drop
• Rapidity of onset (acute vs. chronic)
• Patient's cardiorespiratory reserve

Symptoms

• Fatigue and lethargy (most common)
• Exertional dyspnoea (reduced oxygen-carrying capacity)
• Palpitations (compensatory tachycardia)
• Headache, dizziness, lightheadedness
• Chest pain (angina may be precipitated in patients with coronary artery disease)

Signs

• Pallor (conjunctival, palmar creases)
• Tachycardia and systolic flow murmur (high-output state)
• Bounding pulse (wide pulse pressure due to reduced blood viscosity)
• Signs of cardiac failure (in severe anaemia; high-output cardiac failure)

4.2 Specific Stigmata by Aetiology

4.3 Red Flags

The following presentations demand urgent investigation:

1. Severe symptomatic anaemia (Hb less than 70 g/L): Risk of high-output cardiac failure; consider transfusion
2. Iron deficiency in men or postmenopausal women: Assume GI malignancy until proven otherwise
3. Neurological deficits: B12 deficiency causing subacute combined degeneration (irreversible if untreated)
4. Pancytopenia: Suggests bone marrow failure (aplastic anaemia, MDS, leukaemia)
5. Dark urine + jaundice: Acute intravascular haemolysis (PNH, AIHA, G6PD crisis)
6. Rapid onset with haemodynamic instability: Acute GI bleed, splenic rupture
7. Macrocytosis with unexplained cytopenias: Suspect MDS, especially in elderly

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5. Investigations: The Diagnostic Algorithm

5.1 First-Line Tests

Full Blood Count (FBC) and Blood Film

Key parameters:

• Haemoglobin: Confirms anaemia
• MCV: Classification (microcytic, normocytic, macrocytic)
• RDW (Red Cell Distribution Width): Elevated in iron deficiency (mixed cell sizes)
• Reticulocyte count: Differentiates production failure from increased destruction/loss [10]

Blood film findings:

• Microcytic, hypochromic cells: Iron deficiency, thalassaemia
• Target cells: Thalassaemia, liver disease, post-splenectomy
• Spherocytes: Hereditary spherocytosis, AIHA
• Schistocytes (fragmented cells): MAHA (TTP, HUS, DIC, prosthetic valve)
• Hypersegmented neutrophils (> 5 lobes): Megaloblastic anaemia (B12/folate deficiency)
• Tear-drop cells (dacrocytes): Myelofibrosis, severe iron deficiency
• Howell-Jolly bodies: Post-splenectomy, hyposplenism (coeliac, sickle cell)
• Basophilic stippling: Lead poisoning, thalassaemia

Reticulocyte Count

The reticulocyte count is a marker of bone marrow erythropoietic activity. Normal range: 0.5-2.0%.

Corrected reticulocyte count (adjusts for severity of anaemia):

\text{Corrected retic count} = \text{Reticulocyte \%} \times \frac{\text{Patient Hb}}{\text{Normal Hb}}

5.2 Microcytic Anaemia (MCV less than 80 fL)

Iron Studies

Ferritin caveats:

• Ferritin is an acute phase reactant; may be falsely elevated in inflammation
• In patients with chronic disease, ferritin > 100 µg/L does NOT exclude iron deficiency
• Use transferrin saturation less than 20% as additional marker of iron deficiency in this context [9]

Haemoglobin Electrophoresis

Indicated when:

• MCV is disproportionately low for the degree of anaemia (suggests thalassaemia trait)
• Family history of thalassaemia or ethnic origin (Mediterranean, South Asian, African)

Findings:

• β-thalassaemia trait: Elevated HbA₂ (> 3.5%), normal or mildly elevated HbF
• α-thalassaemia trait: Normal HbA₂ and HbF (diagnosis often by exclusion or genetic testing)

5.3 Macrocytic Anaemia (MCV > 100 fL)

Vitamin B12 and Folate Levels

Causes of B12 deficiency (less than 150 ng/L):

• Pernicious anaemia (anti-IF antibodies in 50-70%, anti-parietal cell antibodies in 90%) [7]
• Gastric surgery (gastrectomy, bariatric surgery)
• Terminal ileal disease (Crohn's disease, ileal resection)
• Dietary (strict veganism)
• Drugs (metformin, PPIs)

Causes of folate deficiency (less than 2 µg/L):

• Dietary insufficiency (elderly, alcoholism)
• Increased demand (pregnancy, haemolysis)
• Malabsorption (coeliac disease)
• Drugs (methotrexate, trimethoprim, phenytoin)

Additional tests for B12 deficiency:

• Anti-intrinsic factor antibodies: Highly specific (98%) for pernicious anaemia, but low sensitivity (50-70%)
• Serum methylmalonic acid (MMA): Elevated in B12 deficiency (more sensitive than B12 level alone)
• Serum homocysteine: Elevated in both B12 and folate deficiency

Blood film:

• Hypersegmented neutrophils (> 5 lobes in > 5% of neutrophils): Pathognomonic for megaloblastic anaemia
• Macro-ovalocytes: Large, oval red cells

Non-Megaloblastic Macrocytosis

If B12 and folate are normal, consider:

• Alcohol excess (direct toxic effect on marrow)
• Liver disease (altered lipid metabolism affects RBC membrane)
• Hypothyroidism (reduced metabolic rate)
• Myelodysplastic syndrome (MDS): Especially if cytopenias, dysplastic changes on film
• Reticulocytosis: Young red cells are larger (check if patient recently treated for anaemia or has haemolysis)
• Drugs: Azathioprine, hydroxyurea, zidovudine

5.4 Normocytic Anaemia (MCV 80-100 fL)

Initial Approach

1. Reticulocyte count:

   • High: Suggests haemolysis or acute blood loss
   • Low: Suggests production failure

2. Specific tests:

   • Renal function (eGFR): CKD is a common cause of normocytic anaemia (reduced EPO production)
   • Inflammatory markers (CRP, ESR): Suggests ACD
   • Thyroid function (TSH): Hypothyroidism
   • Haemolysis screen (if reticulocytes elevated):
     • LDH (↑), unconjugated bilirubin (↑), haptoglobin (↓)
     • Direct Coombs test (AIHA)
     • Blood film (schistocytes, spherocytes)

3. Bone marrow biopsy (if unexplained):

   • Aplastic anaemia, MDS, leukaemia, myelofibrosis, marrow infiltration (lymphoma, carcinoma)

5.5 Haemolysis Screen

If reticulocyte count is elevated and haemolysis suspected:

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6. Management: Evidence-Based Protocols

6.1 Iron Deficiency Anaemia (IDA)

Step 1: Identify and Treat the Underlying Cause

Red flag: Iron deficiency in men or postmenopausal women is GI malignancy until proven otherwise. [5]

Mandatory investigations:

• Bidirectional endoscopy (OGD + colonoscopy): Detects colorectal cancer in 6-10%, gastric cancer in 2-3%
• Coeliac serology (anti-TTG, anti-EMA): Coeliac disease is present in 4-6% of IDA cases
• Urine dipstick: Haematuria (renal/bladder pathology)

In premenopausal women:

• If menorrhagia is the likely cause, gynaecological assessment and treatment
• If menstrual loss is normal, still investigate for GI pathology (coeliac disease in particular)

Step 2: Iron Replacement

Oral iron (first-line):

• Ferrous sulfate 200 mg (65 mg elemental iron) once daily or alternate days [11]
• Rationale for alternate-day dosing: Daily dosing causes hepcidin elevation, reducing absorption of subsequent doses. Alternate-day dosing allows hepcidin to fall, improving overall absorption and reducing side effects.
• Side effects: Nausea, constipation, dark stools (affects 30-40%)
• Expected response: Hb rise of 10-20 g/L per week; reticulocyte count peaks at 7-10 days
• Duration: Continue for 3 months after Hb normalizes to replete stores

Intravenous iron (second-line or first-line in specific situations):

• Indications:

  • Intolerance to oral iron (persistent GI side effects)
  • Malabsorption (coeliac disease, IBD, post-gastric bypass)
  • Chronic kidney disease (oral iron poorly absorbed; hepcidin elevated)
  • Inflammatory bowel disease (hepcidin-mediated functional deficiency)
  • Pregnancy (third trimester; oral iron insufficient to meet demand)
  • Preoperative optimization (elective surgery with expected blood loss)

• Preparations:

  • "Ferric carboxymaltose (Ferinject): 1000 mg single dose (15 min infusion)"
  • "Iron isomaltoside (Monofer): Up to 20 mg/kg single dose"
  • Low risk of anaphylaxis (less than 0.1% with newer preparations)

• Evidence: The FIND-CKD trial demonstrated superiority of IV iron over oral iron in CKD patients with IDA. [12] The PREVENTT trial showed reduced transfusion rates with preoperative IV iron in elective surgery. [13]

Step 3: Monitor Response

• Reticulocyte count: Should rise within 7-10 days
• Hb: Recheck at 2-4 weeks (expect 10-20 g/L rise per week)
• Ferritin: Recheck after 3 months of treatment (target > 30 µg/L to confirm store repletion)

Failure to respond: Consider:

• Non-compliance
• Continued blood loss
• Malabsorption
• Incorrect diagnosis (thalassaemia, sideroblastic anaemia)
• Co-existent B12/folate deficiency

6.2 Vitamin B12 Deficiency

Replacement Regimen

Standard protocol (British Society for Haematology guidelines): [14]

• Hydroxocobalamin 1 mg IM:
  • "Without neurological features: 3 injections per week for 2 weeks, then 3-monthly maintenance"
  • "With neurological features (subacute combined degeneration): Alternate-day injections until no further improvement, then 2-monthly maintenance"

Critical warning: If both B12 and folate are low, always replace B12 first (or simultaneously). Giving folate alone can precipitate or worsen subacute combined degeneration.

Oral B12:

• Cyanocobalamin 50-150 µg daily can be used for dietary deficiency (vegans) or after initial IM loading
• NOT suitable for pernicious anaemia or malabsorption (absorption requires intrinsic factor)

6.3 Folate Deficiency

Folic acid 5 mg daily for 4 months (or until Hb normalizes and stores repleted)

Special populations:

• Pregnancy: Prophylactic folic acid 400 µg daily (pre-conception to 12 weeks) to prevent neural tube defects
• High-risk pregnancy (anti-epileptics, previous NTD): 5 mg daily
• Chronic haemolytic anaemia: Lifelong folic acid 5 mg daily (increased red cell turnover depletes folate)

6.4 Anaemia of Chronic Disease (ACD)

Primary strategy: Treat the underlying inflammatory condition

Iron replacement:

• Oral iron: Generally ineffective (hepcidin blocks absorption)
• IV iron: May be effective, particularly if transferrin saturation less than 20%

Erythropoiesis-Stimulating Agents (ESAs):

• Indications:

  • Chronic kidney disease (Hb less than 100 g/L; target 100-120 g/L to minimize cardiovascular risk) [15]
  • Cancer-related anaemia (chemotherapy-induced; Hb less than 100 g/L)
  • Rheumatoid arthritis (rarely used; only if severe symptomatic anaemia unresponsive to disease-modifying therapy)

• Preparations:

  • Epoetin alfa/beta (short-acting; 2-3 times per week)
  • Darbepoetin alfa (long-acting; once weekly or fortnightly)

• Risks: Increased venous thromboembolism (VTE) risk and potential tumour progression in cancer patients (ESAs should NOT be used if Hb > 100 g/L) [16]

• Evidence: The TREAT trial in CKD patients showed no benefit and potential harm from targeting Hb > 130 g/L with ESAs (increased stroke risk). [15]

6.5 Blood Transfusion

Indications

Acute symptomatic anaemia:

• Haemodynamic instability (tachycardia, hypotension)
• Severe symptoms (angina, dyspnoea at rest)
• Hb less than 70 g/L with symptoms

Chronic anaemia:

• Generally, transfusion is NOT indicated unless:
  • Hb less than 70 g/L with severe symptoms
  • Acute coronary syndrome or severe cardiac disease (consider if Hb less than 80 g/L)

Transfusion Thresholds

Evidence from the TRICC trial (critically ill patients): [17]

• Restrictive strategy (transfuse if Hb less than 70 g/L): Non-inferior to liberal strategy, with lower mortality in less severely ill patients
• Liberal strategy (transfuse if Hb less than 100 g/L): No benefit; increased risk of volume overload

Current NICE guidelines (NG24): [18]

• Hb less than 70 g/L: Consider transfusion
• Hb 70-80 g/L: Consider transfusion if symptomatic or acute coronary syndrome
• Hb > 80 g/L: Transfusion generally not indicated unless acute bleeding or severe cardiac disease

Transfusion Process

• Pre-transfusion: Group and save (G&S) or crossmatch; consent patient; baseline observations
• Rate: 1 unit over 2-4 hours (slower if cardiac failure risk)
• Monitoring: Observations at 0, 15 min, then hourly
• Expected rise: 10-15 g/L per unit transfused

Complications

• Acute: Transfusion reactions (febrile, allergic, haemolytic), TRALI (transfusion-related acute lung injury), TACO (transfusion-associated circulatory overload)
• Delayed: Iron overload (in chronic transfusion; requires chelation), alloimmunization, infections (rare with modern screening)

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7. Specific Anaemia Subtypes

7.1 Thalassaemia

β-Thalassaemia Trait:

• MCV less than 70 fL, Hb mildly reduced (100-120 g/L)
• HbA₂ > 3.5% on electrophoresis
• Key feature: MCV is disproportionately low for degree of anaemia (MCV less than 70, Hb > 100)
• Management: No treatment required; genetic counselling if partner also carrier

α-Thalassaemia Trait:

• MCV 70-80 fL, Hb mildly reduced or normal
• Normal HbA₂ and HbF (diagnosis often by exclusion or genetic testing)
• Management: No treatment required

Thalassaemia Major:

• Transfusion-dependent from infancy
• Requires lifelong regular transfusions + iron chelation
• Complications: Iron overload (cardiac, hepatic, endocrine), alloimmunization

7.2 Sideroblastic Anaemia

Pathophysiology: Defective haem synthesis → iron accumulates in mitochondria, forming ring sideroblasts (visible on bone marrow iron stain)

Causes:

• Congenital: X-linked (ALAS2 mutation)
• Acquired: Myelodysplastic syndrome (refractory anaemia with ring sideroblasts, RARS)
• Reversible: Alcohol, lead poisoning, drugs (isoniazid, chloramphenicol), copper deficiency

Laboratory:

• Microcytic or dimorphic anaemia
• High ferritin, high transferrin saturation
• Bone marrow: ≥15% ring sideroblasts

Management:

• Treat underlying cause (stop alcohol, remove lead exposure)
• Pyridoxine (vitamin B6): Trial in congenital cases (some respond)
• Transfusion support if severe

7.3 Aplastic Anaemia

Definition: Pancytopenia due to bone marrow failure (hypocellular marrow)

Causes:

• Idiopathic (70%)
• Acquired: Drugs (chloramphenicol, NSAIDs, gold), viruses (EBV, hepatitis), pregnancy, PNH
• Congenital: Fanconi anaemia

Presentation:

• Anaemia, infections (neutropenia), bleeding (thrombocytopenia)

Diagnosis: Bone marrow biopsy (hypocellular, less than 25% cellularity)

Management:

• Severe aplastic anaemia (neutrophils less than 0.5, platelets less than 20, reticulocytes less than 20):
  • Haematopoietic stem cell transplant (HSCT) if less than 40 years, matched donor
  • Immunosuppression (anti-thymocyte globulin + ciclosporin) if older or no donor
• Supportive: Transfusions, antibiotics, G-CSF

7.4 Myelodysplastic Syndrome (MDS)

Definition: Clonal haematopoietic disorder characterized by cytopenias and dysplastic changes in bone marrow, with risk of transformation to acute myeloid leukaemia (AML)

Presentation:

• Elderly patient (median age 70)
• Macrocytic anaemia, often with neutropenia and/or thrombocytopenia
• Blood film: Dysplastic features (hypogranular neutrophils, hypolobated megakaryocytes)

Diagnosis: Bone marrow biopsy (dysplasia in ≥10% of cells in ≥1 lineage; less than 20% blasts)

Risk stratification: IPSS-R score (based on blast %, cytogenetics, cytopenias)

Management:

• Low-risk MDS: Supportive (transfusions, ESAs, growth factors)
• High-risk MDS: Azacitidine (hypomethylating agent), consider HSCT if fit

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8. Prognosis and Complications

8.1 Iron Deficiency Anaemia

Prognosis:

• Excellent if underlying cause identified and treated
• Hb normalizes within 2 months in most cases
• 10-year survival depends on underlying cause (e.g., colorectal cancer has poor prognosis if advanced)

Complications:

• High-output cardiac failure (if severe chronic anaemia)
• Restless legs syndrome (improves with iron replacement)
• Impaired cognitive function (especially in children)

8.2 B12 Deficiency

Prognosis:

• Haematological abnormalities resolve within 1-2 months of treatment
• Neurological recovery: Variable; early treatment crucial to prevent irreversible damage
  • "If treated within 3 months of symptom onset: 90% full recovery"
  • "If treated after 1 year: Only 50% show improvement"

Complications:

• Subacute combined degeneration: Irreversible if untreated
• Increased risk of gastric cancer (in pernicious anaemia; loss of acid promotes bacterial overgrowth and nitrosamine formation)

8.3 Anaemia of Chronic Disease

Prognosis: Depends on underlying disease

Complications:

• Increased morbidity and mortality in CKD, heart failure, cancer
• Impaired quality of life

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9. Examination Scenarios

9.1 Single Best Answer (SBA) Questions

Question 1

A 70-year-old male presents with fatigue. Blood tests show Hb 95 g/L, MCV 72 fL, ferritin 45 µg/L. He has no gastrointestinal symptoms. What is the most appropriate next step?

• A) Start ferrous sulfate 200 mg TDS
• B) Repeat FBC in 3 months
• C) Urgent OGD and colonoscopy
• D) Hb electrophoresis
• E) Check B12 and folate levels

Answer: C
In an elderly male, iron deficiency anaemia (even with "low-normal" ferritin, as inflammation may falsely elevate it) must be assumed to be due to gastrointestinal blood loss until proven otherwise. GI malignancy is the critical diagnosis to exclude; up to 10% will have colorectal cancer. Bidirectional endoscopy is mandatory, even in the absence of GI symptoms.

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Question 2

What is the molecular mechanism behind anaemia of chronic disease that prevents the use of stored iron?

• A) Downregulation of transferrin
• B) IL-6 mediated rise in hepcidin, degrading ferroportin
• C) Loss of erythropoietin receptors
• D) Direct inhibition of heme oxygenase
• E) B12 malabsorption in the terminal ileum

Answer: B
Inflammation (via IL-6) stimulates hepatic production of hepcidin, which binds to ferroportin (the only cellular iron exporter) on macrophages and enterocytes, causing its internalization and degradation. This traps iron intracellularly, creating functional iron deficiency despite normal or elevated total body iron stores.

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Question 3

A 55-year-old woman with rheumatoid arthritis has Hb 90 g/L, MCV 75 fL, ferritin 150 µg/L. What is the most useful test to determine if she has true iron deficiency?

• A) Serum iron
• B) Total iron-binding capacity (TIBC)
• C) Transferrin saturation
• D) Bone marrow biopsy
• E) Reticulocyte count

Answer: C
In patients with chronic inflammatory disease, ferritin is an acute phase reactant and may be falsely elevated. Transferrin saturation less than 20% is the most useful marker to identify iron deficiency (absolute or functional) in this context. A bone marrow biopsy with iron stain is the gold standard but is invasive and rarely performed.

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Question 4

A 28-year-old vegan presents with Hb 80 g/L, MCV 110 fL, and paraesthesia in both feet. Blood film shows hypersegmented neutrophils. Which treatment regimen is most appropriate?

• A) Oral cyanocobalamin 50 µg daily
• B) Hydroxocobalamin 1 mg IM alternate days until no further improvement
• C) Folic acid 5 mg daily for 4 months
• D) Ferrous sulfate 200 mg daily
• E) Blood transfusion

Answer: B
This patient has B12 deficiency with neurological involvement (subacute combined degeneration causing peripheral neuropathy). The correct treatment is hydroxocobalamin 1 mg IM alternate days until no further improvement, then 2-monthly maintenance. Oral B12 is insufficient in this context, and delaying treatment risks irreversible neurological damage.

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9.2 Viva Scenario: The "Normal" Ferritin Trap

Examiner: "A patient with rheumatoid arthritis has Hb 90 g/L, MCV 75 fL, and ferritin 150 µg/L. Are they iron deficient?"

Candidate Response:

1. Acknowledge ambiguity:
   "I cannot definitively determine from the ferritin alone, as it is an acute phase reactant and is likely falsely elevated by the underlying inflammation from rheumatoid arthritis."

2. Next investigation:
   "I would check the transferrin saturation (TSAT). If it is less than 20%, this suggests absolute or functional iron deficiency despite the 'normal' ferritin."

3. Advanced marker (if asked):
   "An alternative would be to measure soluble transferrin receptor (sTfR), which is elevated in true iron deficiency but unaffected by inflammation."

4. Management decision:
   "If TSAT is less than 20%, I would consider a trial of IV iron (as oral iron is poorly absorbed in the context of elevated hepcidin due to inflammation). If TSAT is > 20%, the anaemia is likely pure anaemia of chronic disease, and I would optimize management of the underlying RA."

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9.3 Clinical Case: Subacute Combined Degeneration

Presentation:
A 68-year-old woman with a history of hypothyroidism presents with a 6-month history of progressive weakness and numbness in her feet. She has difficulty walking and reports her legs feel "wobbly." Examination reveals loss of vibration sense and proprioception in the lower limbs, absent ankle jerks, and extensor plantar responses bilaterally.

Blood tests:

• Hb 85 g/L, MCV 118 fL
• Blood film: Macro-ovalocytes, hypersegmented neutrophils
• B12: 60 ng/L (low)
• Folate: Normal
• Thyroid function: Normal (on levothyroxine)

Question: What is the diagnosis, and what is the most important immediate management step?

Answer:

Diagnosis: Subacute combined degeneration of the spinal cord due to vitamin B12 deficiency (likely pernicious anaemia, given age and association with autoimmune hypothyroidism).

Pathophysiology:
B12 deficiency causes demyelination of the posterior columns (vibration, proprioception) and lateral corticospinal tracts (UMN signs: extensor plantars). The combination of peripheral neuropathy (absent ankle jerks) and UMN signs is pathognomonic.

Immediate management:

1. Hydroxocobalamin 1 mg IM alternate days until no further neurological improvement (may take weeks to months), then 2-monthly maintenance
2. Urgent neurology referral for MRI spine (to exclude cord compression) and further assessment
3. Do NOT wait for anti-IF antibodies before starting treatment; neurological damage can become irreversible within weeks

Further investigations:

• Anti-intrinsic factor antibodies (confirm pernicious anaemia)
• Anti-parietal cell antibodies
• Consider OGD (to assess gastric atrophy, exclude gastric cancer)

Prognosis:

• Haematological recovery: Excellent (within 1-2 months)
• Neurological recovery: Depends on duration of symptoms before treatment. If treated within 3 months: 90% full recovery. If delayed > 1 year: Only 50% show improvement.

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10. Patient Explanation (Lay Summary)

"Anaemia means your blood has a low level of haemoglobin—the substance in red blood cells that carries oxygen around your body. Think of your red blood cells as little trucks delivering oxygen to your muscles, brain, and organs. If you don't have enough trucks, or if the trucks are missing parts, you feel tired, breathless, and weak.

There are many reasons why anaemia happens. The most common is iron deficiency—iron is like the fuel for building new red blood cells. Women often lose iron through heavy periods, while in men and older women, it's usually due to slow bleeding from the stomach or bowel, which we need to investigate carefully.

Another common cause is vitamin B12 or folate deficiency. These vitamins are essential for building healthy red blood cells. B12 deficiency can also affect your nerves, causing numbness and tingling in your feet and hands.

Sometimes, anaemia is caused by long-term illnesses like kidney disease, arthritis, or infections. In these cases, your body locks away iron so it can't be used to make new red blood cells, even though you have plenty stored.

Our job is not just to replace what's missing (iron, B12, or folate) but to find out why it's missing in the first place—for example, by checking your stomach and bowel for any problems, or testing for conditions that affect absorption like coeliac disease.

Most cases of anaemia can be treated successfully with tablets or injections, and you should start to feel better within a few weeks. However, it's very important that we investigate the underlying cause to make sure there's nothing serious going on."

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11. Key Takeaways for MRCP Candidates

1. IDA in men and postmenopausal women = GI malignancy until proven otherwise → Mandatory bidirectional endoscopy

2. Hepcidin is the master regulator of iron homeostasis. IL-6 (inflammation) → ↑ Hepcidin → Ferroportin degradation → Functional iron deficiency (ACD)

3. Ferritin is an acute phase reactant. In chronic disease, ferritin > 100 µg/L does NOT exclude iron deficiency. Use transferrin saturation less than 20% as additional marker.

4. MCV disproportionately low for degree of anaemia (e.g., MCV less than 70, Hb > 100) → Think thalassaemia trait, not iron deficiency.

5. Hypersegmented neutrophils on blood film = Megaloblastic anaemia (B12 or folate deficiency)

6. If both B12 and folate are low, always replace B12 first (or simultaneously) to avoid precipitating subacute combined degeneration.

7. Subacute combined degeneration: Loss of vibration/proprioception + UMN signs (extensor plantars). Treat urgently with IM hydroxocobalamin alternate days until no further improvement. Neurological damage can be irreversible if delayed.

8. Reticulocyte count differentiates:

   • High (> 2%): Haemolysis or acute blood loss (marrow responding)
   • Low (less than 0.5%): Production failure (IDA, ACD, aplastic anaemia, B12/folate deficiency)

9. Oral iron: Alternate-day dosing is as effective as daily dosing and better tolerated (reduces hepcidin spikes)

10. IV iron preferred in: IBD, CKD, malabsorption, third-trimester pregnancy, intolerance to oral iron

11. Transfusion threshold: Hb less than 70 g/L (restrictive strategy) is non-inferior to liberal strategy and reduces complications (TRICC trial)

12. ESAs in CKD: Target Hb 100-120 g/L. Targeting > 130 g/L increases stroke risk (TREAT trial)

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12. References

1. WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. Geneva, World Health Organization, 2011. (WHO/NMH/NHD/MNM/11.1).

2. Kassebaum NJ, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood. 2014;123(5):615-624. [PMID: 24297872]

3. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102(3):783-788. [PMID: 12869498]

4. Rognoni C, et al. Efficacy and safety of ferric carboxymaltose and other formulations in iron-deficient patients: a systematic review and network meta-analysis. Clin Drug Investig. 2016;36(3):177-194. [PMID: 26692004]

5. Goddard AF, et al. Guidelines for the management of iron deficiency anaemia. Gut. 2011;60(10):1309-1316. [PMID: 21561874]

6. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011-1023. [PMID: 15758012]

7. Toh BH, et al. Pernicious anemia. N Engl J Med. 1997;337(20):1441-1448. [PMID: 9358142]

8. Healton EB, et al. Neurologic aspects of cobalamin deficiency. Medicine (Baltimore). 1991;70(4):229-245. [PMID: 1648656]

9. Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015;372(19):1832-1843. [PMID: 25946282]

10. Hoffbrand AV, Moss PAH. Hoffbrand's Essential Haematology, 8th Edition. Wiley-Blackwell, 2020.

11. Stoffel NU, et al. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Lancet Haematol. 2017;4(11):e524-e533. [PMID: 29032957]

12. Macdougall IC, et al. Intravenous iron in patients undergoing maintenance hemodialysis. N Engl J Med. 2019;380(5):447-458. [PMID: 30365356]

13. Richards T, et al. Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial. Lancet. 2020;396(10259):1353-1361. [PMID: 33069326]

14. Devalia V, et al. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol. 2014;166(4):496-513. [PMID: 24942828]

15. Pfeffer MA, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019-2032. [PMID: 19880844]

16. Bennett CL, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008;299(8):914-924. [PMID: 18314434]

17. Hébert PC, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340(6):409-417. [PMID: 9971864]

18. NICE. Blood transfusion. NICE guideline [NG24]. November 2015. Available at: https://www.nice.org.uk/guidance/ng24

19. Cappellini MD, et al. Iron deficiency anaemia revisited. J Intern Med. 2020;287(2):153-170. [PMID: 31665543]

20. Pasricha SR, et al. Iron deficiency. Lancet. 2021;397(10270):233-248. [PMID: 33285139]

21. Green R, et al. Vitamin B12 deficiency. Nat Rev Dis Primers. 2017;3:17040. [PMID: 28660890]

22. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med. 2013;368(2):149-160. [PMID: 23301732]

23. Chaparro CM, Suchdev PS. Anemia epidemiology, pathophysiology, and etiology in low- and middle-income countries. Ann N Y Acad Sci. 2019;1450(1):15-31. [PMID: 31008520]

24. Lopez A, et al. Iron deficiency anaemia. Lancet. 2016;387(10021):907-916. [PMID: 26314490]

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Last Updated: 2026-01-06 | MedVellum Editorial Team
Citation Count: 24
Target Examination: MRCP, FRACP, Postgraduate Haematology