• IDA is the most common cause of anaemia worldwide and the most common nutritional deficiency globally.
• WHO estimates > 1.2 billion people are affected.
• It accounts for approximately 50% of all anaemia cases.

• Present in ~20% of females, especially at childbearing age ^[2][3].
• Most common cause of microcytic anaemia encountered in Hong Kong clinical practice.
• In Hong Kong, the leading aetiologies are:
  • Menorrhagia in pre-menopausal women (very common — HK has high prevalence of uterine fibroids, a key cause of menorrhagia) ^[4].
  • Occult GI bleeding in older adults (peptic ulcer disease, colorectal carcinoma — CRC is the #1 most common cancer in HK) ^[5].
  • Dietary insufficiency is exceedingly rare in developed settings like HK as a sole cause but can be a contributing factor, particularly in vegetarians/vegans, the elderly, and infants exclusively breastfed beyond 6 months.

• Total body iron: approximately 3–5 g in adults (slightly more in males).

Think of iron like money in a household: most is "invested" (Hb, myoglobin, enzymes), some is "savings" (ferritin/haemosiderin stores), and a tiny amount is "cash in hand" (transferrin-bound plasma iron circulating at any given time).

Iron absorption takes place mainly through the duodenum ^[1][2][3].

Dietary iron exists in two forms:

1. Haem iron (from animal products — meat, fish): absorbed directly via the haem carrier protein 1 (HCP1) on the apical membrane of duodenal enterocytes. More efficiently absorbed (~20–30%).
2. Non-haem iron (from plant sources, fortified foods): exists as Fe³⁺ (ferric form); must be reduced to Fe²⁺ (ferrous form) by duodenal cytochrome b (Dcytb) before being transported across the apical membrane via DMT1 (divalent metal transporter 1).

Factors promoting reduction into ferrous (Fe²⁺) form ^[2][3]:

• ↑ Stomach acidity: gastric acid (HCl) converts Fe³⁺ → Fe²⁺. This is why:
  • Gastrectomy, prolonged PPI use, and autoimmune (A/I) gastritis all impair iron absorption.
• Reducing agents: e.g., vitamin C (ascorbic acid) — donates electrons to Fe³⁺ → Fe²⁺.

Inhibitors of iron absorption:

• Phytates (cereals, legumes), tannins (tea, coffee), calcium, oxalates — chelate non-haem iron.
• Achlorhydria (PPIs, H₂ blockers, atrophic gastritis).

Once inside the enterocyte, iron can:

1. Be stored as ferritin within the enterocyte (and lost when the cell is shed — a minor excretory mechanism).
2. Be exported across the basolateral membrane via ferroportin into the plasma, where it is oxidized back to Fe³⁺ by hephaestin and loaded onto transferrin for transport.

This is the single most important regulatory mechanism in iron metabolism.

• Hepcidin (from Greek hep- = liver + Latin -cidin = killing): a 25-amino-acid peptide hormone synthesised primarily by the liver.
• Hepcidin inhibits ferroportin ^[2][3] — it binds to ferroportin on cell surfaces, causing ferroportin to be internalised and degraded.
• Ferroportin is the only known iron exporter in mammalian cells, found on:
  1. Duodenal enterocytes (controls absorption)
  2. Reticuloendothelial macrophages (controls recycling)
  3. Hepatocytes (controls storage release)

Hepcidin acts at two key locations: duodenal mucosa and macrophages ^[3] — blocking ferroportin at both sites.

Internal cycling of iron: closed loop ^[2][3]:

1. Transferrin (Tf): iron is transported in plasma bound to transferrin. Each Tf binds 2× Fe³⁺ (diferric transferrin) ^[3].
2. Utilisation: transferrin delivers iron to erythroid precursors in the bone marrow via transferrin receptor 1 (TfR1) → receptor-mediated endocytosis → iron released in acidic endosome → incorporated into haem → haemoglobin synthesis.
3. RBC cycling: after ~120 days, senescent RBCs are phagocytosed by reticuloendothelial macrophages (mainly in spleen and liver). Iron is extracted from haem by haem oxygenase, then either stored as ferritin or exported via ferroportin back to plasma transferrin.

This internal recycling provides ~20–25 mg/day of iron — far more than the ~1–2 mg/day absorbed from diet. This is why the body is so carefully designed to recycle iron rather than rely on absorption.

Storage forms: ferritin and haemosiderin ^[2][3]:

• Ferritin: water-soluble, mobilisable iron store. Each ferritin molecule can hold up to ~4,500 Fe³⁺ atoms. A small amount is released into plasma (serum ferritin) and correlates with total body iron stores.
• Haemosiderin: water-insoluble, partially degraded ferritin aggregates; represents more long-term, less mobilisable storage. Seen on Prussian blue staining.

Site: reticuloendothelial system (RES) — macrophages of liver, bone marrow, and spleen ^[2][3]. Derived almost entirely from phagocytosis of senescent erythrocytes or defective developing red cells ^[3].

• The body has no active excretion mechanism for iron.
• Normal obligatory losses: ~1 mg/day in males through:
  • Desquamation of enterocytes (GI mucosal shedding)
  • Skin cell shedding
  • Urinary losses (minimal)
• Menstruation: additional ~0.5–1 mg/day averaged over a month.
• Pregnancy/lactation: significant additional demands.

The implication is clear: since the body cannot increase excretion, any condition causing chronic blood loss will inevitably deplete iron stores because absorption (max ~3–5 mg/day even when maximally upregulated) cannot keep pace.

Blood loss is the most common cause of IDA, because each mL of blood contains ~0.5 mg iron. Chronic loss of even small volumes overwhelms the body's limited ability to increase absorption.

↓ Intake/absorption: extremely uncommon in adults as a sole cause — normal iron stores can last ~8 years in an adult male before IDA develops → most commonly a contributing factor only ^[2].

• Urinary and pulmonary haemosiderosis: shedding of iron-laden cells with abnormal haemosiderin accumulation (e.g., Goodpasture syndrome → pulmonary haemorrhage → iron sequestered in lungs; paroxysmal nocturnal haemoglobinuria → haemosiderinuria).
• Iron-resistant IDA (IRIDA): TMPRSS6, SLC11A2 mutations ^[2] — genetic defects that cause inappropriately high hepcidin or impaired iron transport, leading to IDA that does not respond to oral iron therapy. Rare autosomal recessive conditions.

1. Iron stores depleted (Stage I) → serum ferritin falls, bone marrow stainable iron absent. No anaemia yet.

2. Iron supply inadequate for erythropoiesis (Stage II) → transferrin saturation < 16% (i.e., the "taxi" for iron is running empty). Erythroid precursors in BM receive insufficient iron. Soluble transferrin receptor (sTfR) rises as marrow upregulates receptors in a "hungry" attempt to capture more iron.

3. Impaired haemoglobin synthesis (Stage III) → iron is required at the final step of haem synthesis (insertion of Fe²⁺ into protoporphyrin IX by ferrochelatase). Without iron:

   • Less haem → less haemoglobin → hypochromic cells (pale centre > 1/3 cell diameter)
   • BM erythroblasts undergo extra cell divisions to try to reach a target Hb concentration, but never quite achieve it → microcytic cells (MCV < 80 fL)
   • Marked variation in RBC size → ↑ RDW (red cell distribution width) — a distinguishing feature from thalassaemia trait where RDW is typically normal

4. Reduced oxygen-carrying capacity → tissue hypoxia triggers:

   • ↑ EPO from renal peritubular interstitial cells
   • ↑ 2,3-DPG in RBCs → rightward shift of O₂-Hb dissociation curve (facilitates O₂ unloading)
   • Compensatory ↑ cardiac output → tachycardia, flow murmurs, high-output heart failure (in severe cases)

Iron is not only needed for Hb. It is a cofactor for many enzymes:

• Cytochrome oxidase (mitochondrial electron transport chain) → fatigue, exercise intolerance beyond what anaemia alone would explain
• Myoglobin → muscle weakness
• Epithelial enzymes → explains the characteristic epithelial changes:
  • Koilonychia (spoon nails) — abnormal nail matrix keratin synthesis
  • Angular stomatitis, glossitis — mucosal epithelial turnover impaired
  • Oesophageal webs (Plummer-Vinson / Paterson-Brown-Kelly syndrome)
  • Gastric atrophy
• Neurotransmitter synthesis (iron involved in dopamine production) → restless leg syndrome, pica (craving non-food substances like ice [pagophagia], clay, starch)
• Immune function → impaired T-cell function and neutrophil bactericidal activity

IDA falls under microcytic anaemia (MCV < 80 fL). The differential diagnosis of microcytic anaemia is classically remembered by the mnemonic TAILS:

• T — Thalassaemia
• A — Anaemia of chronic disease (some cases can be microcytic, though typically normocytic)
• I — Iron deficiency anaemia
• L — Lead poisoning (rare)
• S — Sideroblastic anaemia

Both conditions produce small (↓ MCV), pale (↓ MCH) red cells. Both cause target cells on PBS. Both are common in our population.

The GC lecture slide provides the definitive comparison table ^[9]:

Red cell indices can help differentiate between thalassaemia trait and iron deficiency, but cannot differentiate between severe thalassaemia and iron deficiency anaemia ^[11] — because in severe thalassaemia the Hb can also be very low and indices overlap significantly. You need iron studies and Hb electrophoresis.

The logic behind the RBC count distinction: In thalassaemia trait, the bone marrow is perfectly capable of producing red cells — it just can't fill them with enough haemoglobin (defective globin chain). So it compensates by making more small cells (↑ RBC count). In IDA, the bone marrow lacks the raw material (iron) to make haem, so it makes fewer cells that are also small (↓ RBC count).

The logic behind the RDW distinction: In thalassaemia trait, all cells are uniformly small (the genetic defect is the same in every cell) → normal RDW. In IDA, iron deficiency develops gradually — some cells were made when iron was available (normal size) and some when it wasn't (small) → variable sizes → ↑ RDW ^[8].

• Ring sideroblasts on BM Prussian blue stain (iron-laden mitochondria encircling > 1/3 of the nucleus)
• Can be hereditary (ALAS2 mutation, X-linked) or acquired (MDS — myelodysplastic syndrome, alcohol, drugs like isoniazid, lead)
• Paradox: iron overloaded (↑ ferritin, ↑ serum iron, ↑ Tf sat), yet anaemic — because iron can't be incorporated into haem
• PBS may show dimorphic picture (population of normal and hypochromic cells)

• Laboratory features: anaemia (mildly macrocytic usually) with reticulocytosis, ↑ unconjugated bilirubin, ↑ LDH, ↓ serum haptoglobin, ↑ methaemalbumin ^[12]
• PBS: polychromasia, spherocytes (hereditary spherocytosis, immune haemolytic anaemia), RBC fragmentation (microangiopathic haemolysis) ^[12]
• Although haemolytic anaemia is typically not microcytic, chronic intravascular haemolysis (e.g., PNH, mechanical heart valves) can cause secondary iron deficiency through urinary iron loss (haemosiderinuria/haemoglobinuria) — so a haemolytic patient may eventually develop microcytic IDA

• MCV may appear normal (averaged out) despite having two distinct populations — one microcytic, one macrocytic
• Causes: combined iron + B12/folate deficiency (e.g., post-gastrectomy — loss of acid impairs iron absorption AND loss of intrinsic factor impairs B12 absorption), or IDA being treated with iron (new normocytic cells emerging alongside old microcytic ones) ^[2]
• PBS shows distinct dual populations

• IDA causes reactive thrombocytosis (↑ EPO stimulates platelet precursors) ^[2][13]
• A patient with IDA may have platelets > 400 × 10⁹/L, which could raise concern for essential thrombocythaemia
• Key distinction: in reactive thrombocytosis from IDA, iron studies are abnormal, and platelets normalise after iron replacement. In essential thrombocythaemia, iron deficiency is actually a secondary cause to be excluded ^[14].

When investigating IDA and the patient reports black stool, exclude non-bleeding causes ^[5][16]:

• Iron tablets → characteristic green-black colour
• Bismuth → reddish-black
• Activated charcoal
• Certain foods (beetroot) → reddish-black

True melaena is black, tarry, loose, sticky, and malodorous — reflecting oxidation of haem by gut bacteria. It indicates at least ~50–100 mL of blood in the upper GI tract ^[16].

Occult GI bleeding is defined as GIB with blood not detected by naked eye — the only clue may be IDA +/- positive faecal occult blood test (FOBT/FIT) ^[16]. This is the classic presentation of right-sided colorectal carcinoma in an older patient.

Triad of dysphagia + IDA + oesophageal webs. Increases risk of oesophageal and hypopharyngeal cancer ^[6]. Rare in Asians. If a patient with IDA has dysphagia, this should be considered — but more commonly, dysphagia in an IDA patient should prompt exclusion of oesophageal/gastric malignancy.

If a patient with ITP (immune thrombocytopenic purpura) is anaemic, the most likely diagnosis is bleeding and iron-deficiency anaemia ^[17] — chronic mucocutaneous bleeding (menorrhagia, epistaxis, GI bleeding) from thrombocytopenia leads to iron loss.

Laboratory assessment of iron deficiency ^[10]:

• Histological: bone marrow biopsy for iron staining — the gold standard, but invasive and not routinely performed
• Haematological: CBC for HGB and MCV
• Biochemical: iron profile

The diagnosis is confirmed when you demonstrate the characteristic iron profile constellation:

Problems with ferritin: the reference range is only for reference ^[10]:

• Recruitment in daytime → does not take into account of diurnal rhythm
• May have other underlying diseases
• Not tailored for special patient groups

Clinical decision cutoffs for serum ferritin ^[10]:

• Adults: < 34 pmol/L (15 μg/L)
• Elderly hospitalised: < 100 pmol/L (45 μg/L)
• Elderly community-based: < 49 pmol/L (22 μg/L)
• Other specific groups: paediatric (age-specific), pregnancy (gestational week-specific), renal dialysis patients (disease-specific)

Why are elderly thresholds higher? Because elderly patients commonly have concomitant chronic diseases that elevate ferritin as an acute phase reactant. A "normal" ferritin of 30 μg/L in a hospitalised elderly patient with pneumonia may actually mask true iron deficiency — the inflammation is pushing ferritin up while iron stores are genuinely low. Hence the higher cutoff.

Response to therapeutic trial of iron ^[2][13] is sometimes used as a diagnostic confirmation:

• If Hb rises by ~1 g/dL per 7–10 days after starting oral iron ^[18], this strongly supports IDA
• Useful when iron studies are equivocal (e.g., mixed IDA + ACD picture)
• Not a substitute for investigating the underlying cause

In chronic kidney disease, different thresholds are used because of the interplay between renal anaemia (↓ EPO) and iron deficiency ^[19]:

• Iron saturation > 20%
• Serum ferritin at least 100 in pre-dialysis patients, 200 in haemodialysis patients ^[19]

35F, heavy periods. Hb 7.5, MCV 65, RBC 3.2 × 10¹², platelets 450, reticulocytes 0.5%. Iron: serum Fe 3 μmol/L (low), TIBC 85 μmol/L (high), Tf sat 4% (low), ferritin 4 μg/L (low).

Interpretation: Classic Stage III IDA. Low ferritin diagnostic. Reactive thrombocytosis from ↑ EPO. Cause almost certainly menorrhagia → pelvic USS for fibroids. CRP/ESR expected normal.

68M, rheumatoid arthritis on methotrexate. Hb 9.0, MCV 78, RBC 3.5 × 10¹². Iron: serum Fe 4 μmol/L (low), TIBC 40 μmol/L (low), Tf sat 10%, ferritin 120 μg/L (normal-high). CRP 45 mg/L (high), ESR 60.

Interpretation: Serum iron low in both IDA and ACD. But TIBC is LOW → negative APR + hepcidin effect → suggests ACD. However, ferritin of 120 in the setting of CRP 45 may be "falsely reassuring." If ferritin is normal-low (< 225), there may be concomitant iron deficiency ^[10]. Check sTfR — if elevated, there IS concurrent iron deficiency. This patient is on methotrexate (bone marrow suppressant) and RA (chronic inflammation) — may also have NSAID-related GI bleeding causing true iron loss superimposed on ACD.

28F, Southern Chinese, mild lifelong "anaemia." Now pregnant, Hb 8.5, MCV 68, RBC 4.8 × 10¹² (high). Ferritin 8 μg/L (low). Hb electrophoresis: HbA2 2.8% (borderline normal).

Interpretation: High RBC count with low MCV suggests thalassaemia trait, but ferritin is clearly low → co-existent IDA. Iron deficiency suppresses HbA2 back towards normal, masking β-thal trait ^[11]. Correct iron deficiency first → repeat Hb electrophoresis after iron stores replete. If HbA2 then rises > 3.5%, β-thal trait confirmed. Critical for prenatal counselling in pregnancy.

Indications: all patients with IDA, most patients with iron deficiency without anaemia ^[2][13].

The rationale for treating iron deficiency even without anaemia (Stage I–II): iron deficiency itself causes symptoms (fatigue, restless legs, impaired cognition, pica) through non-erythropoietic mechanisms (cytochrome oxidase, myoglobin, dopamine synthesis). Replenishing stores prevents progression to Stage III.

Transfusion if angina, heart failure, cerebral hypoxia, or Hb < 7 g/dL ^[2][13].

Important paradigm shift: In many cases, the anaemia is just due to iron deficiency → so use less red cells, use more iron supplements ^[22]. A young, haemodynamically stable woman with Hb 6–7 g/dL from chronic menorrhagia does NOT necessarily need transfusion — a single dose of IV iron and outpatient follow-up is often sufficient. Her bone marrow is healthy; it just needs iron to produce Hb. This is safer (avoids transfusion risks: TACO, TRALI, alloimmunisation) and more physiological.

Diet: iron-rich food (meat, egg, green vegetables), vitamin C (promote absorption) ^[18]:

Dietary iron alone is almost never sufficient to correct established IDA — remember, normal iron stores can last ~8 years in an adult male ^[2], meaning dietary insufficiency is rarely the sole cause, and once depleted, maximal dietary absorption (~3–5 mg/day) takes many months to replenish stores. Diet is adjunctive, not primary therapy.

Renal anaemia guideline: Hb target 10–11 g/dL (not > 12) ^[19]. Iron saturation > 20%, serum ferritin ≥ 100 (pre-dialysis), ≥ 200 (haemodialysis) ^[19].

• Increased iron demands (~1000 mg total over pregnancy)
• Oral iron is first-line in 1st trimester
• IV iron (ferric carboxymaltose or iron sucrose) is safe and increasingly preferred from the 2nd trimester onwards if oral iron is insufficient or not tolerated
• Avoid IV iron in the 1st trimester (limited safety data)
• Transfusion reserved for severe symptomatic anaemia or peri-partum haemorrhage

• Choice: Sytron (sodium iron edetate), Niferex (polysaccharide iron complex) ^[13] — liquid forms are easier to administer
• Dose: 3–6 mg/kg/day of elemental iron in divided doses
• Address dietary causes (excess cow's milk displacing iron-rich foods, prolonged exclusive breastfeeding)

• Part of Patient Blood Management (PBM) — optimise Hb pre-operatively to avoid transfusion
• Optimise red cell mass + Minimise blood loss & bleeding + Harness physiological reserve of anaemia ^[22]
• IV iron 2–4 weeks pre-op if time permits; consider ESA for selected patients (major surgery, Jehovah's Witness patients)

The heart's ability to compensate for anaemia is impressive — healthy young patients can tolerate very low haemoglobin (even 4–5 g/dL) if the decline is gradual. But once compensatory mechanisms are maximal, any further drop tips the balance into overt heart failure.

Complications of anaemia: cardiac ischaemia ^[24].

• Valvular heart disease: anaemia increases cardiac workload, worsening symptoms of aortic stenosis or mitral regurgitation
• Heart failure: anaemia is both a cause and an aggravating factor of HF (the "cardio-renal-anaemia syndrome" in CKD)
• Arrhythmias: tachycardia from anaemia can precipitate atrial fibrillation or other tachyarrhythmias in susceptible individuals

Iron deficiency → falsely high HbA1c ^[7].

Mechanism: ↓ erythropoiesis → ↓ RBC turnover → older RBCs accumulate → these older cells have had longer exposure to glucose for non-enzymatic glycosylation → HbA1c is artificially elevated.

Conversely, once iron supplements are given and new RBCs are produced rapidly, HbA1c can fall transiently ^[7] — the new cells haven't had time to be glycosylated.

Clinical implication: A diabetic patient with concurrent IDA may appear to have "poor glycaemic control" on HbA1c, leading to unnecessary escalation of anti-diabetic therapy. Always check iron status when HbA1c seems discordant with point-of-care glucose readings.

Reactive thrombocytosis due to ↑ stimulation of platelet precursors by ↑ EPO ^[2][13].

• Platelet count can exceed 400–600 × 10⁹/L in IDA
• This may trigger unnecessary haematology referral for suspected essential thrombocythaemia (ET)
• Key distinction: reactive thrombocytosis from IDA resolves completely with iron replacement; ET does not. Iron deficiency is actually one of the secondary causes that must be excluded before diagnosing ET ^[14].

When transfusion is used for severe symptomatic IDA, the standard transfusion complications apply: