GC076 Pallor: Diagnosis Of Anaemia; Nutritional Anaemia; Anaemia Of Systemic Diseases
Pallor indicating anaemia is systematically diagnosed by evaluating hemoglobin levels and red cell indices to distinguish nutritional deficiencies (iron, B12, folate) from anaemia secondary to chronic systemic diseases such as infections, renal failure, or malignancies.
This lecture by Prof Anskar Leung covers the foundational approach to anaemia — arguably the single most examined haematology topic in HKUMed summative exams. The lecture walks you from bedside (pallor → clinical presentation) through bench (MCV-based classification → blood film) to diagnosis (nutritional deficiencies, anaemia of chronic disease, and systemic causes). It is structured around four pillars: [1]
- Clinical presentation and physical examination of the anaemic patient
- Investigations and causes of anaemia (the MCV classification framework)
- Nutritional anaemia (iron deficiency, vitamin B12 deficiency / pernicious anaemia, folate deficiency)
- Anaemia of chronic illness (the hepcidin story)
Why this matters clinically: Anaemia is not a diagnosis — it's a sign. The lecture teaches you to use it as a springboard to find the underlying cause, which could be anything from NSAID-induced GI bleeding to multiple myeloma to Fanconi anaemia. Every single case in the lecture ends with "what is the next investigation?" — this is exactly how exam questions are framed. [1]
How this fits into exams: Past papers consistently test the MCV-based differential, iron studies interpretation (IDA vs. ACD), features of pernicious anaemia, and clinical vignettes requiring you to pick the correct next investigation. [3][4][5]
Core Concepts and Mechanisms
Anaemia = reduction in haemoglobin concentration below the normal range for age and sex. The WHO defines it as Hb < 13 g/dL (males) and < 12 g/dL (females). However, in clinical practice and exam stems, the lab reference range provided should be your guide.
Why does it matter? Haemoglobin carries oxygen. Less Hb → less O₂ delivery → the body compensates (increased cardiac output, tachycardia, 2,3-DPG shift of the oxygen-dissociation curve). When compensation fails → symptoms.
Every anaemia falls into one (or more) of three categories: [1]
- Decreased RBC production — the factory is broken
- Increased RBC destruction — the product is being destroyed too fast
- Blood loss — the product is leaking out
This is the single most important framework. When you see any anaemia question, the first thing your brain should do is sort it into one of these three bins.
Clinical Presentations of Anaemia
Acute and severe anaemia: Shortness of breath, palpitation, dizziness or syncope, symptoms of cardiac ischaemia [1]
Chronic and insidious anaemia: Fatigue, decreased exercise tolerance, pale-looking [1]
Symptoms related to the cause: menorrhagia, passage of tarry stool, bone pain [1]
Why the difference? In acute anaemia (e.g. massive GI bleed), the body has no time to compensate — you get haemodynamic instability. In chronic anaemia (e.g. slow iron depletion), compensatory mechanisms kick in (↑ 2,3-DPG, ↑ cardiac output), so the patient may tolerate Hb as low as 5-6 g/dL with only fatigue.
Physical examination findings and what they suggest: [1]
Physical Finding Suggests Uraemic look Anaemia of renal failure Jaundice Haemolysis Early greying + glossitis Pernicious anaemia Shock / tachycardia Acute blood loss Isolated splenomegaly Hypersplenism Lymphadenopathy + hepatosplenomegaly Haematological malignancy Abnormal abdominal mass Carcinoma
Additional examination findings from supporting sources: [2]
- Koilonychia (spoon-shaped nails) → severe iron deficiency anaemia (rarely seen today)
- Pallor of conjunctivae → best site to check for anaemia clinically
- Pallor of palmar creases → unreliable sign but often mentioned
- Angular cheilitis → iron or B12 deficiency
- Glossitis (beefy-red tongue) → B12 / folate deficiency
- Petechiae / purpura → if concurrent thrombocytopenia (consider aplastic anaemia, leukaemia, or megaloblastic anaemia with pancytopenia)
Exam Trap
Palmar erythema is NOT a feature of iron deficiency anaemia — it is associated with chronic liver disease, pregnancy, thyrotoxicosis, and polycythaemia. This was directly tested in the 2020 summative MCQ Q7: "Which of the following physical signs is NOT associated with iron deficiency anaemia? → Answer: Palmar erythema." [3]
Causes of Anaemia — The Complete Classification
Causes of decreased RBC production: [1]
- Nutritional: Iron, B12, folate deficiency
- Bone marrow disorders: Aplastic anaemia, pure red cell aplasia, neoplastic diseases
- Bone marrow suppression: Drugs, chemotherapy, irradiation
- Reduced trophic hormones: Erythropoietin (renal failure), thyroid hormone (hypothyroidism)
- Anaemia of chronic disease
Intrinsic RBC defects: [1]
- Enzyme deficiencies (e.g. G6PD deficiency)
- Haemoglobin defects (e.g. thalassaemias, haemoglobinopathies)
- Membrane defects (e.g. hereditary spherocytosis, elliptocytosis)
Extrinsic RBC defects: [1]
- Liver disease and hypersplenism
- Infections (e.g. malaria)
- Autoimmune haemolytic anaemia (warm- or cold-reacting, drug-induced)
- Microangiopathy (e.g. prosthetic valve leak, TTP, DIC)
- Transfusion reactions (e.g. ABO incompatibility)
Sites: Gastrointestinal tract, genital tract, soft tissue [1]
This is the table you must have cold for exams. The lecture explicitly provides this framework:
Classification of anaemia based on MCV: [1]
| Microcytic (MCV < 80 fL) | Normocytic (MCV 80–99 fL) | Macrocytic (MCV > 100 fL) |
|---|---|---|
| Thalassaemia | Anaemia of chronic disease | Aplastic anaemia |
| Iron deficiency | Anaemia of renal disease | Chronic liver disease |
| Sideroblastic anaemia | Acute blood loss | Chemotherapy / Alcohol |
| Dimorphic anaemia | Haemolytic anaemia | Vitamin B12 or folate deficiency |
| Myelodysplasia |
Key Points on MCV Classification
- Anaemia of chronic disease is usually normocytic normochromic, but can occasionally be microcytic (especially if severe or long-standing). The lecture lists it under both microcytic and normocytic — the exam expects you to know it is predominantly normocytic.
- Dimorphic anaemia = two populations of RBCs (e.g. concurrent iron deficiency + B12 deficiency after gastrectomy) — the MCV may appear "normal" because the micro and macro populations average out, but the RDW will be high.
- Haemolytic anaemia is listed under normocytic — this is because the MCV may be raised slightly due to reticulocytosis (reticulocytes are larger), but it is not a true macrocytic anaemia.
The lecture provides a visual gallery. You must be able to recognize these and know what they mean: [1]
| Morphology | Clinical Significance |
|---|---|
| Hypochromic microcytic | Iron deficiency, thalassaemia |
| Macroovalocytes | Megaloblastic anaemia (B12 / folate deficiency) |
| Hypersegmented neutrophils | Megaloblastic anaemia (≥5 lobes in neutrophil) |
| Spherocytes | Hereditary spherocytosis, autoimmune haemolytic anaemia |
| Elliptocytes | Hereditary elliptocytosis, iron deficiency (pencil cells are a variant) |
| Schizocytes / schistocytes | Microangiopathic haemolytic anaemia (TTP, DIC, prosthetic valve) |
| Tear-drop cells (dacrocytes) | Myelofibrosis, marrow infiltration |
| Rouleaux formation | ↑ globulins (e.g. multiple myeloma, chronic inflammation) |
| Agglutination | Cold agglutinin disease |
| Polychromasia | Reticulocytosis (active marrow response) |
| Echinocytes (burr cells) | Uraemia, artifact |
| Spur cells (acanthocytes) | Liver disease, abetalipoproteinaemia |
| Bite cells | G6PD deficiency (Heinz bodies "bitten out" by splenic macrophages) |
| Malaria parasites | Malaria infection |
| Pencil cells | Iron deficiency anaemia |
Iron Metabolism and Iron Deficiency Anaemia
Key numbers: [1]
- Total body iron: ~3–4 grams (2 g in Hb, 1 g in stores)
- Daily intake: ~1 mg absorbed
- Daily loss: ~1 mg (via desquamated cells, minor GI loss)
- 2 grams in circulating RBC haemoglobin
- 1 gram in stores (ferritin, haemosiderin in macrophages/liver)
The key concept is that iron is recycled — senescent RBCs are phagocytosed by macrophages, iron is released and loaded onto transferrin (as di-ferric transferrin), which delivers it to erythroid precursors for new haemoglobin synthesis. Only ~1 mg per day enters/exits the body. This is why chronic blood loss is the most common cause of iron deficiency — you lose iron with each mL of blood lost, and the gut can only absorb 1-2 mg/day maximally.
Non-heme iron absorption requires: [1]
- Acidity in the stomach (Fe³⁺ → Fe²⁺ requires acid environment)
- Conditions that impair absorption:
- Gastrectomy
- Prolonged PPI use
- Autoimmune gastritis
- Once absorbed, iron binds to transferrin for transport
Why acid? Dietary non-heme iron is in the ferric (Fe³⁺) form. It needs to be reduced to ferrous (Fe²⁺) by duodenal cytochrome B (Dcytb) in an acidic environment before it can be absorbed via DMT1 on the apical surface of duodenal enterocytes. Without stomach acid, this step fails.
The most common cause of iron deficiency anaemia is: Chronic blood loss [1]
This is directly from a lecture MCQ. The logic: since the iron cycle is nearly closed, and dietary intake barely covers basal losses, even modest chronic bleeding (e.g. occult GI bleed, menorrhagia) will progressively deplete iron stores.
Common causes by system:
- GI tract: Peptic ulcer, gastritis (including NSAID-induced), colorectal carcinoma, angiodysplasia, oesophageal varices, hookworm
- Genital tract: Menorrhagia, pregnancy
- Malabsorption: Coeliac disease, gastrectomy, chronic PPI use
- Dietary: Rarely the sole cause in adults (more relevant in paediatrics — excessive cow's milk intake)
Iron deficiency anaemia vs Anaemia of chronic disease — The critical comparison: [1]
| Parameter | Iron Deficiency Anaemia | Anaemia of Chronic Disease |
|---|---|---|
| Clinical picture | Suggesting iron deficiency | Suggesting chronic disease |
| Severity | Could be severe | Generally modest |
| RBC morphology | Hypochromic microcytic | Normochromic normocytic |
| Serum iron | Reduced | Reduced |
| Transferrin / TIBC | Increased | Decreased / no change |
| Transferrin saturation | Reduced | Reduced |
| Ferritin | Reduced | Normal or increased |
| Soluble transferrin receptor | Elevated | Normal |
| Serum hepcidin | Normal | Elevated |
The Most Useful Test to Distinguish IDA from ACD
The lecture MCQ asks: "Which is most useful in distinguishing IDA from ACD?" → Answer: Serum ferritin level [1]
This is because:
- In IDA, stores are truly depleted → ferritin is LOW
- In ACD, stores are adequate but sequestered → ferritin is NORMAL or HIGH (it's also an acute phase reactant, so it rises in inflammation)
- Serum iron is LOW in BOTH → not helpful for distinction
- TIBC is the mirror image of transferrin — raised in IDA (body upregulates transferrin to scavenge more iron) but normal/low in ACD
- Hepcidin is elevated in ACD (see below) but this test is not routinely available clinically
Functional Iron Deficiency
From the Case 4 scenario and CKD notes: patients on erythropoietin-stimulating agents (ESAs) can develop functional iron deficiency — they have adequate stores but cannot mobilize iron fast enough to keep up with the accelerated erythropoiesis driven by ESA. The MCV drops, and they become refractory to ESA. This is different from true IDA (depleted stores) and from ACD (inflammation-mediated sequestration). Treatment: IV iron supplementation. [1][6]
Anaemia of Chronic Disease (ACD)
Causes of anaemia of chronic disease: [1]
- Infections
- Cancer
- Autoimmune diseases
- Chronic rejection after solid-organ transplantation
- Chronic kidney disease and inflammation
Proposed mechanisms of anaemia of chronic illness: [1]
- Infection / inflammation → cytokines + LPS → ↑ hepcidin production by the liver
- Hepcidin ↓ iron absorption in gut mucosa (blocks ferroportin on enterocytes)
- Hepcidin ↓ iron release from macrophages (blocks ferroportin on macrophages)
- Net effect: iron is trapped in the reticuloendothelial system → unavailable for erythropoiesis → anaemia
The hepcidin story from first principles:
- Ferroportin is the ONLY known iron exporter on cell surfaces (enterocytes, macrophages, hepatocytes)
- Hepcidin (produced by liver) binds to ferroportin → ferroportin is internalized and degraded
- In inflammation, IL-6 is the key driver of hepcidin transcription (via JAK-STAT3 pathway)
- Result: iron is "locked" inside cells even though total body iron is normal or elevated
- This explains why ferritin is normal/high (iron stores are full) but serum iron is low (iron can't get out)
The lecture diagram shows hepcidin blocking both: [1]
- Macrophage iron release (recycling pathway)
- Gut mucosal iron absorption (intake pathway)
- Blunted EPO response: Cytokines (TNF-α, IL-1, IFN-γ) suppress erythropoietin production and reduce erythroid progenitor responsiveness
- Shortened RBC survival: Inflammatory state mildly shortens RBC lifespan
- Direct marrow suppression: Some cytokines inhibit erythroid precursors
Vitamin B12 and Folate Deficiency — Megaloblastic Anaemia
Which is the most important source of vitamin B12? → Animal and dairy products [1]
Sources include: fish, meat, poultry, eggs, dairy products, fortified cereals, nutritional yeasts, fermented soybean, supplements [1]
Why animal products? B12 is synthesized only by microorganisms. Animals accumulate it in their tissues. Humans cannot absorb enough B12 from gut bacterial synthesis alone (bacteria produce it in the colon, past the absorption site in the terminal ileum).
The pathway: [1]
- B12 in food → released by gastric acid and pepsin
- Binds to R-protein (haptocorrin) in saliva/stomach
- In duodenum, pancreatic proteases cleave R-protein
- B12 binds to Intrinsic Factor (IF) (secreted by gastric parietal cells)
- B12-IF complex absorbed at the terminal ileum via cubilin receptor
Pathophysiology of B12 deficiency:
- Deficient/defective IF or release in stomach (pernicious anaemia, gastrectomy)
- Defective absorption of B12-IF complex at terminal ileum (Crohn's disease, ileal resection, bacterial overgrowth)
Which is the most common cause of vitamin B12 deficiency anaemia? → Pernicious anaemia [1]
Pernicious anaemia = autoimmune destruction of gastric parietal cells → loss of intrinsic factor → inability to absorb B12. It is NOT dietary deficiency (though strict veganism can also cause B12 deficiency, it takes years because the liver stores enough B12 for 3-4 years).
Other causes: prolonged PPI use (reduces B12 release from food, but does not impair IF-mediated absorption as dramatically), metformin (uncertain mechanism, possibly interferes with calcium-dependent B12-IF absorption in terminal ileum), IBD affecting terminal ileum, bacterial overgrowth (bacteria consume B12).
Two key intracellular reactions: [1]
- Methylmalonyl CoA → Succinyl CoA (requires adenosylcobalamin in mitochondria)
- Deficiency → ↑ methylmalonic acid (MMA) → explains neurological damage
- Homocysteine → Methionine (requires methylcobalamin in cytoplasm)
- This reaction also converts methyl-THF → THF (tetrahydrofolate)
- THF is needed for DNA synthesis (thymidylate synthesis)
- Deficiency → ↑ homocysteine + impaired DNA synthesis → megaloblastic change
The "methyl-folate trap": When B12 is deficient, methyl-THF cannot be converted to THF. Folate gets "trapped" as methyl-THF and cannot participate in DNA synthesis. This is why B12 deficiency causes megaloblastic anaemia even when folate levels are adequate (and why giving folate alone to a B12-deficient patient can partially correct the anaemia but will NOT fix the neuropathy — and may actually worsen it by diverting remaining B12 away from neurological functions).
From the lecture diagram: [1]
- Transcobalamin II (TCII): delivers B12 to cells via TCII receptor → endocytosis → lysosome → active B12 released for intracellular reactions
- Transcobalamin III (TCIII) / Haptocorrin: carries most circulating B12 but delivers it mainly to the liver
Clinical features: [1]
- Incidental finding of macrocytic anaemia
- Anaemia symptoms (fatigue, SOB)
- Early greying of hairs
- Mild jaundice (intramedullary haemolysis — defective erythroblasts die in marrow)
- Glossitis: beefy-red tongue
- Angular stomatitis
- Neuropathy: subacute combined degeneration of the cord (SCDC)
Why jaundice? The megaloblastic erythropoiesis is ineffective — many erythroblasts die within the marrow before maturing (= intramedullary haemolysis). This releases unconjugated bilirubin and LDH. This is NOT classic extravascular or intravascular haemolysis — it's ineffective erythropoiesis.
SCDC from first principles: B12 deficiency → ↑ methylmalonic acid → abnormal fatty acid incorporation into neuronal myelin → demyelination of the dorsal columns (proprioception, vibration) and lateral corticospinal tracts (motor — UMN pattern). Clinically: sensory ataxia, paresthesias → spasticity → paraplegia → incontinence. This can occur WITHOUT anaemia or macrocytosis. [7]
Key laboratory findings: [1]
- Pancytopenia (all lineages affected because DNA synthesis is impaired in all rapidly dividing cells)
- Macrocytic anaemia (MCV often > 110 fL)
- Intramedullary haemolysis: elevated unconjugated bilirubin and LDH
- Blood film: hypersegmented neutrophils and macroovalocytes
High Yield: Hypersegmented Neutrophils
A neutrophil with ≥5 lobes (or > 5% of neutrophils with 5 lobes) is considered hypersegmented. This is virtually pathognomonic for megaloblastic anaemia (B12 or folate deficiency). In an exam, if you see macrocytic anaemia + hypersegmented neutrophils on blood film → think megaloblastic anaemia FIRST.
Investigations: [1]
- Serum Vitamin B12 level — first-line screening test
- Serum holotranscobalamin — more sensitive measure of B12 bioavailability
- Serum and red cell folate level — to exclude concurrent folate deficiency
- Anti-parietal cell antibody — sensitive but less specific (detectable in small proportion of normal individuals)
- Anti-intrinsic factor antibody — specific but less sensitive (some patients with PA may be negative)
- Upper endoscopy — to look for atrophic gastritis and carcinoma of stomach (PA patients have ↑ risk of gastric carcinoma)
- Schilling test — historical interest only, obsolete in HK
- Bone marrow examination — NOT routinely needed, except when laboratory findings incompatible with PA
The commonly used test for investigation of B12 deficiency: Serum total vitamin B12 level [1]
Anti-Parietal Cell Ab vs Anti-IF Ab
| Anti-Parietal Cell Ab | Anti-Intrinsic Factor Ab | |
|---|---|---|
| Sensitivity | High (~90%) | Lower (~50-70%) |
| Specificity | Lower (found in elderly, other autoimmune diseases) | High (~95%) |
| Clinical use | Screening | Confirmatory |
If the exam asks for the most specific test → anti-IF antibody. If it asks for the most sensitive → anti-parietal cell antibody. [1]
Sources: Green leafy vegetables, fruits, fortified cereals, liver — unlike B12, folate stores last only ~4 months.
Causes of folate deficiency:
- Inadequate dietary intake (alcoholism, anorexia, poor diet)
- Malabsorption (coeliac disease, tropical sprue, IBD, gastric bypass)
- Increased requirements (pregnancy, chronic haemolytic anaemia, exfoliative skin disease, haemodialysis)
- Drug-induced: Methotrexate (DHFR inhibitor), trimethoprim, anticonvulsants (phenytoin, carbamazepine, valproate)
Clinical features: Similar to B12 deficiency (macrocytic anaemia, glossitis, angular cheilitis) BUT:
- Mouth ulcers are more common in folate deficiency
- Neurological features (SCDC) are much less prominent — mainly ascribed to B12 deficiency
From Case 4 in the lecture: [1]
A patient with poorly controlled DM and HTN presenting with normochromic normocytic anaemia → check serum creatinine → 890 umol/L → the cause is reduced erythropoietin [1]
Why? The peritubular interstitial cells of the kidney cortex are the main source of erythropoietin (EPO). As CKD progresses, these cells are destroyed → EPO production falls → anaemia. This is typically a normochromic normocytic anaemia and correlates with the severity of CKD (prevalence: 1% at eGFR 60, 9% at eGFR 30, 33-67% at eGFR 15). [6]
Treatment: ESAs (erythropoiesis-stimulating agents, e.g. epoetin, Mircera) via subcutaneous injection. Target Hb ~10-11.5 g/dL. [6]
Complications of ESA therapy (from Case 4):
- After starting EPO, if MCV drops and Hb doesn't improve → think functional iron deficiency (cannot mobilize stores fast enough) or true iron deficiency from occult bleeding
- Rare: development of anti-EPO antibodies → pure red cell aplasia
Lecture Case Studies — Worked Examples
These cases are extremely exam-relevant as they model the exact question style used in HKUMed summative MCQs: [1]
- 70M, malaise, low back pain, pallor
- Hb 5.7, MCV 88, WBC 5.2, Plt 92. Blood film: Rouleaux
- Rouleaux = ↑ globulins (immunoglobulins stack RBCs)
- Next test of diagnostic value → Serum globulin (will be grossly elevated)
- Then → Serum protein electrophoresis (SPEP) to detect M-band
- Lesson: Rouleaux + bone pain + normocytic anaemia in elderly = think myeloma
- 60F, dizziness, unsteady gait
- Hb 5.7, MCV 128, WBC 2.0, Plt 59 (pancytopenia), Retic 3%, Bili 100, LDH 1890
- Next investigation → Peripheral blood smear (shows hypersegmented neutrophils + macroovalocytes)
- Then → All of: Serum B12, Anti-IF Ab, Anti-Parietal Cell Ab, Serum and red cell folate
- After diagnosis of PA → Upper endoscopy (to look for atrophic gastritis and gastric carcinoma, NOT bone marrow, NOT Schilling's test)
- Lesson: Very high MCV + pancytopenia + raised LDH/bilirubin = megaloblastic anaemia → PA until proven otherwise
- 60F, metallic mitral valve (chronic rheumatic valve disease), on warfarin
- Hb 6.7, MCV 99, Plt 259, Bili 60, LDH 690
- Next → Peripheral blood smear (will show schistocytes / schizocytes)
- Then → Echocardiogram (assess prosthetic valve function, paravalvular leak)
- Lesson: Anaemia + raised LDH/bilirubin + prosthetic valve = mechanical haemolysis. The blood film clinches it.
- 53M, poorly controlled DM + HTN, ankle oedema, pale
- Hb 6.7, MCV 88, normochromic normocytic
- Next → Serum creatinine (890 → renal failure → reduced EPO)
- After EPO replacement × 3 months: Hb only 7.7 but MCV dropped to 68 → now microcytic
- Causes of persistent anaemia → Iron deficiency from occult bleeding AND functional iron deficiency
- Lesson: EPO drives erythropoiesis but needs iron as substrate. If iron is insufficient, the marrow cannot respond.
- 78M, OA, on NSAIDs, malaise/SOB/dizziness
- Hb 8.5, MCV 70, WBC 14, Plt 719. Blood film: hypochromic microcytic + pencil cells
- Next → Serum iron level (found to be low, with low transferrin saturation and raised TIBC = IDA)
- Then → Upper endoscopy (found bleeding gastritis)
- Cause → NSAID intake for OA
- Lesson: Microcytic anaemia in elderly = IDA until proven otherwise → always look for GI source. Reactive thrombocytosis is common in IDA.
Reactive Thrombocytosis in IDA
Platelet count of 719 × 10⁹/L — this is reactive thrombocytosis seen in iron deficiency. Mechanism: thrombopoietin (TPO) shares structural homology with erythropoietin. In IDA, increased EPO may cross-stimulate TPO receptors. Also, iron deficiency itself upregulates megakaryopoiesis. Do NOT confuse this with a myeloproliferative neoplasm.
- 19M, immigrant from China, short stature, worsening malaise
- Hb 7.5, MCV 103, WBC 2.0, Plt 109. Blood film: macrocytic anaemia + dysplastic neutrophils
- Cafe-au-lait spots and abnormal thumbs on examination (slide images)
- Relevant history → Were siblings similarly affected? (autosomal recessive inheritance)
- Diagnostic test → Demonstration of chromosome breaks (chromosomal fragility test with diepoxybutane/mitomycin C)
- Most worrisome complication → Leukaemia transformation (AML)
- Lesson: Young patient + short stature + pancytopenia + café-au-lait spots + radial/thumb anomalies = think inherited bone marrow failure syndrome → Fanconi anaemia
The lecture shows a slide on "Examples of iron restricted erythropoiesis" [1]
This concept unifies three scenarios where the marrow cannot get enough iron to make Hb properly:
- Absolute iron deficiency (IDA) — stores are empty
- Functional iron deficiency (ACD, CKD on ESA) — stores are full but iron is trapped
- Iron maldistribution — iron in the wrong compartment (e.g. sideroblastic anaemia where iron accumulates in mitochondria as ring sideroblasts)
All three lead to hypochromic microcytic red cells eventually, though functional iron deficiency and ACD are usually normocytic in mild/moderate stages.
Exam Intelligence
- "Which physical sign is NOT associated with IDA?" → Palmar erythema [3]
- "32F with pancytopenia and macrocytosis, pale, no HSM → most likely diagnosis?" → Distinguish between aplastic anaemia vs pernicious anaemia. Key: in PA you get macrocytosis + elevated LDH/bilirubin; in aplastic, the marrow is empty but LDH/bili are normal. [3][5]
- "What is the most useful test to differentiate IDA from ACD?" → Serum ferritin [1]
- "Elderly with macrocytic anaemia, glossitis, thyroid disease history, pancytopenia, very high LDH → diagnosis?" → Pernicious anaemia [5]
- "Young woman with low MCV, mild anaemia, low platelets but otherwise well → diagnosis?" → Thalassaemia intermedia with hypersplenism [3]
| Trap | Correct Understanding |
|---|---|
| Assuming all microcytic anaemia = IDA | Could be thalassaemia trait — check Mentzer index (MCV/RBC: > 13 = IDA, < 13 = thal trait) or Hb electrophoresis |
| Thinking ACD is always normocytic | Can be microcytic in severe/chronic cases |
| Ordering Schilling test | Obsolete — upper endoscopy is the answer for PA workup |
| Giving folate alone for megaloblastic anaemia | Dangerous if B12 deficiency exists — can mask anaemia while neuropathy worsens |
| Confusing elevated LDH/bilirubin in PA with haemolysis | It's INTRAMEDULLARY haemolysis (ineffective erythropoiesis), not peripheral haemolysis |
| Assuming ferritin always reflects iron stores | Ferritin is an acute phase reactant — can be falsely normal/elevated in ACD even with concurrent iron depletion |
-
MCQ: A 65-year-old man with chronic rheumatoid arthritis on NSAIDs presents with fatigue. Hb 8.0 g/dL, MCV 72 fL, ferritin 8 µg/L, TIBC 85 µmol/L, serum iron 4 µmol/L. What is the most likely cause of his anaemia?
- Answer: Iron deficiency anaemia (low ferritin = truly depleted stores; NSAID use → GI blood loss; NOT ACD because ferritin is LOW)
-
MCQ: Which of the following blood film findings is most characteristic of megaloblastic anaemia?
- Answer: Hypersegmented neutrophils and macroovalocytes
-
SAQ: List 4 causes of microcytic anaemia.
- Markscheme: Iron deficiency anaemia, thalassaemia, sideroblastic anaemia, anaemia of chronic disease (when severe/prolonged). Some also accept lead poisoning.
-
SAQ: Explain the role of hepcidin in anaemia of chronic disease.
- Markscheme: Inflammation (via IL-6) → ↑ hepcidin → binds ferroportin on macrophages and enterocytes → iron sequestered in RES + decreased gut absorption → functional iron deficiency → ↓ erythropoiesis → anaemia
-
Clinical vignette: 60-year-old woman with dizziness, unsteady gait, Hb 5.7, MCV 128, WBC 2.0, Plt 59, LDH 1890, Bili 100. What investigation would you order first? Why?
- Answer: Peripheral blood smear. To look for macroovalocytes and hypersegmented neutrophils to confirm megaloblastic anaemia before proceeding to B12/folate levels and antibody testing.
High Yield Summary
Anaemia is classified by MCV: microcytic ( < 80), normocytic (80-99), macrocytic ( > 100). The most common cause of IDA is chronic blood loss. IDA vs ACD is distinguished by ferritin (low in IDA, normal/high in ACD), TIBC (high in IDA, low/normal in ACD), and hepcidin (normal in IDA, elevated in ACD). Pernicious anaemia is the most common cause of B12 deficiency; it presents with macrocytic anaemia, pancytopenia, hypersegmented neutrophils, macroovalocytes, raised LDH/bilirubin from intramedullary haemolysis, and can cause subacute combined degeneration of the cord. Anti-IF antibody is specific; anti-parietal cell antibody is sensitive. After diagnosing PA, perform upper endoscopy for atrophic gastritis and gastric carcinoma screening. In CKD, anaemia is due to reduced EPO — treat with ESAs but watch for functional iron deficiency. On blood film: Rouleaux → myeloma; schistocytes → microangiopathic haemolytic anaemia; tear-drop cells → myelofibrosis; bite cells → G6PD deficiency. Always ask: "What is the CAUSE of the anaemia?" — it is a sign, not a diagnosis.
Active Recall - Pallor: Diagnosis of Anaemia; Nutritional Anaemia; Anaemia of Systemic Diseases
[1] Lecture slides: GC 076. Pallor_diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (all pages) [2] Senior notes: Ryan Ho Haemtology.pdf (p5, p50); Ryan Ho Fundamentals.pdf (p120, p393) [3] Past papers: 2020 Fourth Summative Assessment MCQ paper.pdf (Q7, Q30, Q31) [4] Senior notes: Block A - Pallor_ diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (p1) [5] Past papers: 2023 Fourth Summative MCQ.pdf (Q33) [6] Senior notes: Ryan Ho Urogenital.pdf (p106); Block A - Chronic Kidney Disease and its Complications.pdf (p12) [7] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1326, p1311)
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