Anaemia is one of the most frequently encountered clinical problems, yet its underlying mechanisms are diverse. Defined as a reduction in haemoglobin concentration, red blood cell (RBC) count, or haematocrit below normal for age and sex, anaemia reflects a failure of oxygen delivery rather than a singular disease.
To systematically approach anaemia, we start by classifying it by Mean Corpuscular Volume (MCV)—the most practical first step in narrowing down differentials. From there, integrating pathophysiology, laboratory markers, and clinical reasoning leads to an accurate diagnosis.
๐งช Step 1: Classify by MCV (Mean Corpuscular Volume)
In diagnosing anaemia, the MCV directs the first decision point:
๐น Microcytic (MCV < 80 fL) → impaired haemoglobin synthesis
๐น Normocytic (MCV 80–100 fL) → red cell underproduction or destruction
๐น Macrocytic (MCV > 100 fL) → defective DNA synthesis or altered marrow environment
Each classification guides investigation towards distinct mechanisms and underlying causes.
1. Microcytic Anaemia (MCV < 80 fL) Failure of Hb production
These anaemias arise from defects in haemoglobin synthesis, whether due to iron deficiency, defective globin chain formation, or impaired haem metabolism
๐น Iron Deficiency Anaemia
Causes: Chronic blood loss (e.g. menstruation, peptic ulcers, colorectal cancer), low dietary intake, malabsorption (e.g. coeliac disease), or increased physiological demand (e.g. pregnancy).
Key features: Low serum ferritin, high transferrin, low transferrin saturation. Hypochromic, microcytic cells on smear.
๐น Thalassaemia
Key features: Normal or raised iron studies, target cells, basophilic stippling, and a family history. Electrophoresis confirms subtype.
๐น Sideroblastic Anaemia
Pathophysiology: Defective incorporation of iron into protoporphyrin due to mitochondrial dysfunction → iron accumulates in mitochondria → ring sideroblasts on bone marrow biopsy.
Causes: Hereditary (X-linked), alcohol, lead poisoning, isoniazid, B6 deficiency.
Key features: Increased serum iron and ferritin, low transferrin, and hypochromic microcytic anaemia.
๐น Anaemia of Chronic Disease (occasionally microcytic)
Pathophysiology: Inflammatory cytokines (especially IL-6) increase hepcidin production → blocks ferroportin in enterocytes and macrophages → iron sequestration + reduced availability for erythropoiesis.
Key features: Normal or increased ferritin, low serum iron, low transferrin.
2. Normocytic Anaemia (MCV 80–100 fL) Underproduction vs increased destruction
These anaemias occur either due to marrow underproduction or RBC destruction.
Cells are normal in size but too few in number.
๐น Acute Blood Loss
Pathophysiology: Sudden loss of circulating RBCs → hypovolaemia initially, followed by normocytic anaemia once plasma is replaced.
Key features: May initially appear normovolaemic, reticulocyte response begins in days.
๐น Anaemia of Chronic Disease (most cases)
See above under microcytic; most commonly normocytic due to decreased erythropoietin.
๐น Chronic Kidney Disease
Pathophysiology: Kidneys produce erythropoietin (EPO). In CKD, ↓ EPO → impaired RBC production in bone marrow.
Key features: Normocytic, normochromic anaemia, associated with other CKD markers.
๐น Bone Marrow Disorders (e.g. Aplastic Anaemia, Myelofibrosis, Leukaemia)
Pathophysiology: Bone marrow failure or infiltration limits haematopoiesis → pancytopenia or selective anaemia.
Key features: Low reticulocyte count, abnormal marrow on biopsy, possible pancytopenia.
๐น Haemolytic Anaemia
Pathophysiology: Premature destruction of RBCs → marrow increases production (↑ reticulocytes). Haemolysis may be intravascular (complement, trauma) or extravascular (macrophage-mediated).
Causes: Hereditary (e.g. spherocytosis, G6PD), autoimmune, mechanical (e.g. prosthetic valves).
Key features: High LDH, high unconjugated bilirubin, low haptoglobin, spherocytes or schistocytes on smear.
3. Macrocytic Anaemia (MCV > 100 fL)
Large RBCs result from impaired nuclear maturation due to defective DNA synthesis or marrow stress. Fewer cell divisions leads to larger cells.
๐น Megaloblastic Anaemia (B12 or Folate Deficiency)
B12 causes: Pernicious anaemia (autoimmune gastritis), gastrectomy, ileal disease, vegan diet.
Folate causes: Poor diet, alcoholism, pregnancy, medications (methotrexate, phenytoin).
Key features: Hypersegmented neutrophils, raised MCV, neurological symptoms with B12 deficiency.
๐น Increased alcohol intake
Pathophysiology: Direct marrow toxicity + folate deficiency + liver dysfunction → macrocytosis without classic megaloblastic features.
Key features: Raised MCV, no hypersegmented neutrophils.
๐น Liver Disease
Pathophysiology: Altered lipid metabolism affects red cell membrane → macrocytosis.
Key features: Target cells, abnormal liver function tests.
๐น Hypothyroidism
Pathophysiology: Unclear, but likely involves reduced marrow turnover and erythropoietin production.
๐น Drugs (e.g. chemotherapy, zidovudine)
Pathophysiology: Direct interference with DNA replication in haematopoietic stem cells.
๐ฉธ Reticulocyte Count –Is the marrow responding?
๐ Key takeaway:
- Low reticulocyte count → underproduction causes (e.g. CKD, marrow failure).
- High reticulocyte count → blood loss or haemolysis (confirm with LDH, bilirubin, haptoglobin).
๐ Clinical Reasoning Summary
Step 1: What is the MCV?
Step 2: Is the marrow trying to compensate (reticulocyte count)?
Step 3: What does the clinical picture + labs suggest?
๐กClinical Case Vignette: "Fatigue and a Funny Tongue"
Maria is a 52-year-old woman who presents to her GP with increasing fatigue, shortness of breath on exertion, and a sore tongue. She also mentions occasional numbness and tingling in her feet. She has a past medical history of hypothyroidism and follows a vegetarian diet. On examination, she appears pale, has a smooth, beefy red tongue, and demonstrates reduced vibration sensation in both feet.
Initial blood tests show:
- Hb: 88 g/L (low)
- MCV: 112 fL (↑)
- Reticulocyte count: low
- WBC and platelets: normal
- Peripheral smear: macrocytosis with hypersegmented neutrophils
- B12: low
- Folate: normal
- Anti-intrinsic factor antibodies: positive
๐ Clinical Questions
- What type of anaemia does Maria have based on the MCV?
- What is the most likely cause of her anaemia?
- Explain the pathophysiology of this type of anaemia.
- What clinical features support this diagnosis?
- What is the likely underlying condition contributing to her B12 deficiency?
- What makes her case distinct from folate deficiency?
- Why are her neurological symptoms important to note?
✅ Suggested Answers
Macrocytic anaemia – her MCV is elevated, indicating enlarged red cells.
Vitamin B12 deficiency – confirmed by low B12 levels and supported by clinical features and lab findings.
Pathophysiology: B12 is essential for DNA synthesis. Deficiency impairs thymidine production → delayed nuclear maturation with continued cytoplasmic development → megaloblastic erythropoiesis. This leads to macrocytosis, ineffective haematopoiesis, and intramedullary destruction of red cell precursors.
Clinical features include:
- Smooth, red tongue (glossitis)
- Peripheral neuropathy (B12 is crucial for myelin synthesis)
- Pallor and fatigue (classic symptoms of anaemia)
- Macrocytosis and hypersegmented neutrophils on smear
- Pernicious anaemia – an autoimmune condition where antibodies target intrinsic factor, preventing B12 absorption in the terminal ileum.
- Neurological signs are a hallmark of B12 deficiency, distinguishing it from folate deficiency. If left untreated, the neuropathy may become irreversible.
๐ Learning Takeaway
When you see macrocytic anaemia, always think B12, folate, alcohol, and bone marrow toxins. And remember: neurological symptoms + anaemia = suspect B12 deficiency—not just folate. Anaemia is a symptom—not a diagnosis! Use MCV, reticulocyte count, and pathophysiology to refine the differential
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