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PA14.1-2 | Iron Deficiency Anaemia: Pathogenesis to Lab Diagnosis — Part 2
Clinical Features: What the Patient Shows You
IDA presents in two layers: general anaemia features (any anaemia) + IDA-specific epithelial changes (reflect chronic iron deficiency in rapidly dividing epithelial cells).
Plummer-Vinson Syndrome: Anatomy, Radiological Findings, and Diagnostic Approach
Angular Cheilitis in Iron Deficiency Anaemia
A. General Anaemia Features (non-specific):
- Pallor (skin, conjunctiva, palmar creases) — most sensitive sign
- Fatigue, lethargy, reduced exercise tolerance
- Exertional dyspnoea — the Hb can't deliver enough O₂ for the metabolic demand of exercise
- Tachycardia, palpitations — compensatory increase in cardiac output
- Headache, poor concentration
- In severe/rapid anaemia: systolic flow murmur (hyperdynamic circulation)
B. IDA-Specific Features (epithelial — iron is needed for cell proliferation and enzyme function):
| Feature | Description | Mechanism |
|---|---|---|
| Koilonychia | Spoon-shaped nails — concave curvature | Iron required for nail plate formation; brittle, thin nails deform outward |
| Angular cheilitis | Cracking/erythema at mouth corners | Epithelial atrophy, secondary Candida/bacterial superinfection |
| Atrophic glossitis | Smooth, red, painful tongue — loss of papillae | Papillae (rapidly dividing) require iron; tongue appears beefy red |
| Pica | Craving for non-nutritive substances | Pagophagia (ice) is most specific for IDA; also clay, dirt, chalk |
| Dysphagia | Difficulty swallowing solids | Plummer-Vinson syndrome (see below) |
Plummer-Vinson Syndrome (Patterson-Kelly in the UK):
The triad: IDA + post-cricoid dysphagia + oesophageal webs (thin mucosal folds at the cricopharyngeal junction).
- Occurs predominantly in middle-aged women
- Diagnosed by barium swallow or oesophagoscopy
- Clinical importance: Plummer-Vinson syndrome carries a 10–15% risk of developing squamous cell carcinoma of the pharynx or upper oesophagus. It is a premalignant condition. Must be followed up and the webs dilated.
Plummer-Vinson Syndrome and Paediatric Effects of Iron Deficiency
Paediatric features:
- Developmental delay (iron is essential for myelination and neurotransmitter synthesis)
- Behavioural changes: irritability, reduced attention span
- Breath-holding spells in toddlers (mechanism debated but association is well-established)
- School-age children: reduced cognitive performance
In an infant or toddler with IDA, treat promptly — cognitive effects may not fully reverse even after Hb normalises.
SELF-CHECK
A 28-year-old woman, teacher, vegetarian diet, heavy periods, presents with 3-month fatigue. Hb 7.8 g/dL, MCV 68 fL, MCHC 28 g/dL. Peripheral smear shows pencil cells and target cells. What is your NEXT investigation to confirm the diagnosis before starting treatment?
A. A. Serum ferritin and iron studies (serum iron, TIBC, transferrin saturation)
B. B. Bone marrow biopsy with Perls Prussian blue stain
C. C. Haemoglobin electrophoresis to exclude thalassemia trait
D. D. Reticulocyte count and reticulocyte production index
Reveal Answer
Answer: A. A. Serum ferritin and iron studies (serum iron, TIBC, transferrin saturation)
Option A is correct. The clinical picture (menorrhagia, vegetarian diet, microcytic hypochromic anaemia with pencil cells and target cells) is highly suggestive of IDA. The next step is to confirm IDA with iron studies. Serum ferritin (<15 ng/mL) is the gold-standard marker for depleted iron stores (if no concurrent inflammation). A low serum iron + elevated TIBC + low transferrin saturation (<15%) completes the diagnosis. Bone marrow (B) is rarely needed and invasive — reserved when iron studies are inconclusive. Haemoglobin electrophoresis (C) is important in the differential when IDA is confirmed but treatment fails, or when thalassemia trait is suspected — flag forward to SDL 3. Reticulocyte count (D) supports the diagnosis (low RPI indicates production failure) but does not confirm IDA specifically.
Laboratory Diagnosis: The Full Workup
Approach lab diagnosis of IDA systematically: CBC → Iron Studies → Peripheral Smear → Reticulocyte Index → Bone Marrow (rarely). Always end with the question: Why does this patient have IDA?
1. Complete Blood Count (CBC):
| Parameter | Finding in IDA | Normal range |
|---|---|---|
| Haemoglobin | ↓ (<12 g/dL women, <13 g/dL men) | Women 12–16, Men 13–17 g/dL |
| MCV | ↓ <80 fL (microcytic) | 80–100 fL |
| MCH | ↓ <27 pg (hypochromic) | 27–33 pg |
| MCHC | ↓ <31 g/dL | 31–36 g/dL |
| RDW | ↑ >14.5% (early, before MCV drops) | 11.5–14.5% |
| Platelet count | Often ↑ (reactive thrombocytosis, especially in chronic blood loss IDA) | 150,000–400,000/µL |
| WBC | Normal | — |
2. Iron Studies — the diagnostic panel:
| Test | IDA | ACD | Thalassemia trait |
|---|---|---|---|
| Serum iron | ↓ | ↓ | Normal/↑ |
| TIBC (Total Iron Binding Capacity) | ↑ | ↓ or normal | Normal |
| Transferrin saturation | ↓ <15% | <15% (variable) | Normal/↑ |
| Serum ferritin | ↓ <15 ng/mL | Normal/↑ (APR) | Normal/↑ |
| Serum sTfR (soluble transferrin receptor) | ↑ | Normal | ↑ (if iron-deficient component) |
Ferritin caveat — the acute-phase trap: Ferritin is an acute-phase reactant. In IDA coexisting with infection, inflammation, liver disease, or malignancy, ferritin can be falsely normal or even elevated. A ferritin of 50 ng/mL in a patient with active rheumatoid arthritis does NOT exclude IDA. Use sTfR (elevated in IDA, normal in ACD) when ferritin is uninterpretable.
The TIBC logic: The liver upregulates transferrin production when iron stores are low (trying to capture more iron from the gut). High TIBC = 'empty trucks looking for iron.' In ACD and inflammation, TIBC is suppressed (the body holds onto iron as an antimicrobial defence via hepcidin).
3. Peripheral Blood Smear:
Laboratory Diagnosis of Iron Deficiency Anemia: Systematic Workup Approach
Findings in IDA:
- Microcytic RBCs: smaller than a normal lymphocyte nucleus
- Hypochromia: central pallor >1/3 of cell diameter
- Anisopoikilocytosis: variation in size (aniso) and shape (poikilo)
- Pencil cells (cigar cells): elongated thin cells — more specific for IDA than other microcytic anaemias
- Target cells: bell-shaped RBCs with central haemoglobin density
- Elliptocytes: occasional
→ For a dedicated smear interpretation exercise, proceed to SDL 4 (Peripheral Smear Workshop).
4. Reticulocyte Count and Index:
- Reticulocyte count: usually low or low-normal (not elevated despite anaemia)
- Reticulocyte Production Index (RPI): <2 → confirms hypoproliferative (production failure) anaemia
- RPI formula: (Reticulocyte % × Hb/Normal Hb) ÷ Maturation factor
This distinguishes IDA (production failure) from haemolytic anaemia (high retic count, high RPI).
5. Bone Marrow Examination (rarely indicated):
Reserved for diagnostically challenging cases (e.g., ferritin uninterpretable, concurrent haematological malignancy suspected).
- Erythroid hyperplasia (↑ erythroid precursors, reduced M:E ratio from 3:1 to 1:1)
- Micronormoblasts (small, haemoglobin-deficient erythroid precursors)
- Perls Prussian blue stain: absent stainable iron in macrophages — this is the gold-standard definitive test for absent iron stores
- Absent ring sideroblasts (present in sideroblastic anaemia — important differential in SDL 3)
Bone Marrow Perls Stain in Iron Deficiency Anemia
The 'Find-the-Cause' Workup Tree:
``
IDA CONFIRMED → ASK: Who is this patient?
│
├── Reproductive-age woman
│ └── Is there menorrhagia/abnormal uterine bleeding?
│ ├── YES → Pelvic USS, coagulation screen, gynaecology referral
│ └── NO → Check dietary history, coeliac serology, stool OBT
│
├── Infant/child
│ └── Dietary history (breastfed? cow's milk? iron-containing formula?)
│ Exclude hookworm in endemic areas
│
├── Pregnant woman
│ └── Nutritional + increased demand — confirm with ferritin
│ Ensure iron supplementation started
│
├── Elderly man OR post-menopausal woman
│ └── MANDATORY GI evaluation
│ ├── Stool occult blood test (x3)
│ ├── Upper GI endoscopy (OGD): peptic ulcer, gastric carcinoma, coeliac
│ └── Colonoscopy: colorectal carcinoma, polyps, angiodysplasia
│ ⚠️ Do not attribute to diet without excluding GI malignancy
│
└── Any adult with malabsorption symptoms
└── Coeliac serology (anti-TTG IgA), duodenal biopsy
H. pylori breath test or serology
CLINICAL PEARL
Ferritin is an acute-phase reactant — use sTfR when the clinical picture doesn't match. In a patient with IDA plus active infection, rheumatoid arthritis, liver disease, or malignancy, ferritin may be 'falsely normal' — e.g., 80 ng/mL — because inflammation drives ferritin synthesis independent of iron stores. In these situations, the soluble transferrin receptor (sTfR) is invaluable: it is elevated in IDA (tissue iron deficiency drives sTfR upregulation on erythroid precursors) but NORMAL in anaemia of chronic disease (ACD). The sTfR/log ferritin ratio (Thomas plot) is particularly useful in separating pure ACD from IDA+ACD overlap — a common scenario in patients with chronic kidney disease, inflammatory bowel disease, or malignancy.
SELF-CHECK
A 45-year-old woman with Hb 9.0 g/dL and MCV 70 fL is referred from the rheumatology clinic where she is being treated for active rheumatoid arthritis. Her serum ferritin is 90 ng/mL. Based on this result alone, can you exclude iron deficiency anaemia?
A. A. Yes — ferritin 90 ng/mL is well above the IDA cutoff of 15 ng/mL, so IDA is excluded
B. B. No — ferritin is an acute-phase reactant; it may be falsely elevated by active inflammation, and IDA cannot be excluded
C. C. Yes — microcytic anaemia with ferritin >30 ng/mL is diagnostic of anaemia of chronic disease
D. D. No — IDA cannot be excluded without a bone marrow biopsy in any anaemic patient
Reveal Answer
Answer: B. B. No — ferritin is an acute-phase reactant; it may be falsely elevated by active inflammation, and IDA cannot be excluded
Option B is correct. Ferritin is an acute-phase reactant synthesised in the liver (like CRP, fibrinogen). In active inflammation — including active rheumatoid arthritis — ferritin rises independently of iron stores. A ferritin of 90 ng/mL in this context may represent genuinely depleted iron stores with an 'inflammation-inflated' ferritin. In active RA or other inflammatory conditions, IDA is not excluded until ferritin falls below approximately 50–100 ng/mL (the cutoff shifts upward in inflammation). The correct next step is to request serum iron, TIBC, transferrin saturation, and/or sTfR. Option C is incorrect — microcytic anaemia + elevated ferritin + active inflammation is consistent with both ACD and IDA+ACD overlap; you need the full iron panel to distinguish them. Option D is incorrect — bone marrow is a last resort, not a routine step.
Management: Treat the Iron, Find the Cause
Iron Replacement Therapy Management in Microcytic Anemia
Iron replacement corrects the anaemia. Finding and treating the cause prevents recurrence.
Oral Iron Therapy (first-line):
| Preparation | Elemental iron per tablet | Recommended dose |
|---|---|---|
| Ferrous sulphate 200 mg | 65 mg elemental iron | 1 tablet TDS (three times daily) |
| Ferrous gluconate 300 mg | 36 mg elemental iron | 1-2 tablets TDS |
| Ferrous fumarate 200 mg | 65 mg elemental iron | 1 tablet TDS |
How to give oral iron:
- Take between meals (empty stomach maximises absorption; acidic environment favours Fe²⁺)
- Take with vitamin C (ascorbic acid 250 mg) — reduces Fe³⁺ to absorbable Fe²⁺, increases absorption 2–3×
- Avoid with tea, coffee, milk, antacids, PPIs, calcium supplements (all reduce absorption)
- Duration: 3–6 months AFTER Hb normalises to replenish body stores (not just until Hb is normal)
Common side effects (counsel the patient):
- GI: nausea, epigastric pain, constipation, diarrhoea
- Black stools (harmless — do not confuse with melaena)
- Liquid iron may stain teeth (rinse after)
Monitoring response — the therapeutic test:
| Timepoint | Expected finding |
|---|---|
| Day 3–5 | Reticulocytosis (retic count rises — the first sign of response) |
| Week 2–4 | Hb rises 1–2 g/dL |
| Week 8 | Hb approaches normal |
| Month 4–6 | Ferritin normalises (stores replete) — STOP iron here |
Failure to respond to oral iron → rethink:
1. Non-compliance (most common) — ask directly
2. Ongoing blood loss outpacing replacement
3. Malabsorption (undiagnosed coeliac, post-gastrectomy)
4. Wrong diagnosis (thalassemia trait, ACD, sideroblastic — see SDL 3)
5. Concurrent deficiency (B12/folate) masking the retic response
Parenteral Iron (IV route):
Indicated when oral iron fails, is not tolerated, or when rapid Hb restoration is needed.
| Indication | Example |
|---|---|
| Oral iron intolerance | Severe GI side effects |
| Malabsorption | Post-gastrectomy, active IBD, coeliac disease |
| Chronic kidney disease on haemodialysis | Functional IDA + EPO therapy |
| Severe/symptomatic IDA needing rapid response | Pre-op, second/third trimester |
| Ongoing blood loss > oral replacement capacity | GI malignancy, menorrhagia |
Formulations: Iron sucrose (Venofer), Ferric carboxymaltose (Ferinject — can give full replacement dose in one infusion), Low molecular weight iron dextran.
Dietary advice:
- Increase haem iron (meat, fish, poultry)
- Increase non-haem iron (dark green leafy vegetables, legumes, fortified cereals)
- Always pair non-haem iron foods with vitamin C (citrus, amla, tomato)
- Avoid tea/coffee within 1 hour of iron-rich meals
Treat the underlying cause — always:
- Menorrhagia: gynaecological referral (uterine fibroids, hormonal, coagulation workup)
- GI blood loss: appropriate endoscopy and surgical/oncological management
- Malabsorption: gluten-free diet (coeliac), H. pylori eradication, acid supplementation (post-gastrectomy)
- Hookworm: anthelmintic therapy (albendazole)
SELF-CHECK
A 55-year-old male underwent a partial gastrectomy for peptic ulcer disease 3 years ago. He now has confirmed IDA (Hb 9.1 g/dL, ferritin 8 ng/mL). He has been on ferrous sulphate 200 mg TDS for 6 weeks but his Hb has only risen by 0.3 g/dL. What is the most appropriate next step?
A. A. Double the dose of oral ferrous sulphate and continue for another 6 weeks
B. B. Switch to intravenous iron (e.g., ferric carboxymaltose) and co-administer vitamin C
C. C. Perform bone marrow biopsy to confirm IDA before changing therapy
D. D. Add folic acid supplementation and recheck Hb in 4 weeks
Reveal Answer
Answer: B. B. Switch to intravenous iron (e.g., ferric carboxymaltose) and co-administer vitamin C
Option B is correct. This patient has post-gastrectomy IDA with documented failure to respond to oral iron. The mechanism is clear: partial gastrectomy reduces gastric acid secretion, impairing the conversion of dietary Fe³⁺ to absorbable Fe²⁺, and the operation bypasses or limits the duodenum (the primary iron absorption site). In this context, oral iron absorption is fundamentally impaired regardless of dose. IV iron (ferric carboxymaltose or iron sucrose) bypasses the absorptive defect entirely and delivers iron directly to transferrin. Option A (doubling oral dose) will not overcome the absorptive block and increases GI side effects. Option C (bone marrow biopsy) is not indicated — the diagnosis is confirmed (ferritin 8 ng/mL), and the clinical question is about treatment failure. Option D (folic acid) addresses folate deficiency, not the iron absorption problem — and there is no clinical suggestion of folate deficiency here.