iron deficiency

quick recognition

• fatigue, exercise intolerance, depression, insomnia disproportionate to haemoglobin
• pica (pagophagia = ice craving is classic) — highly specific
• restless leg syndrome — check ferritin in all new presentations
• new ↓ MCV — MCV is stable through life; a new drop is iron deficiency until proven otherwise (other causes: lead, sideroblastic — rare)
• glossitis, angular cheilitis, koilonychia (late signs)

diagnosis / investigations

iron studies — what each marker tells you

marker	what it reflects	strengths	pitfalls
ferritin	iron stores (liver, macrophages)	most sensitive/specific single test	acute-phase reactant — falsely ↑ in inflammation, liver disease, malignancy
TSAT	iron available for erythropoiesis — serum iron / TIBC x 100	less affected by inflammation than ferritin	diurnal variation; measure fasting AM; affected by recent meals, haemolysis
TIBC	transferrin capacity (surrogate)	↑ in absolute deficiency	↓ in inflammation (suppressed hepatic synthesis)
serum iron	circulating iron bound to transferrin	—	highly volatile; poor standalone marker
sTfR	tissue iron demand	not an acute-phase reactant	not universally available
MCV	red cell size	a new ↓ is very specific for iron deficiency	normal MCV does not exclude iron deficiency (normocytic IDA is common)

interpretation patterns

pattern	ferritin	TSAT	TIBC	interpretation
absolute iron deficiency	↓ (<30)	↓ (<20%)	↑	depleted stores; hepcidin suppressed
functional iron deficiency	normal/↑	↓ (<20%)	↓/normal	stores present but locked — inflammation-driven hepcidin blocks release
anaemia of chronic disease	normal/↑ (>100)	normal/↓	↓/normal	sequestration without true depletion
mixed (IDA + inflammation)	30–100	↓ (<20%)	normal/↑	most diagnostically challenging
iron overload	↑ (>300)	↑ (>45%)	↓	screen with TSAT >45% → HFE genotyping

context-specific diagnostic thresholds

clinical context	ferritin threshold (µg/L)	TSAT threshold	notes
healthy adults	<30–45	<20%	AGA recommends <45 for optimal sensitivity
chronic inflammation	<100	<20%	ferritin unreliable; TSAT preferred
CKD (non-dialysis)	<100	<20%	KDIGO: focus on TSAT
CKD (haemodialysis)	<200	<20%	higher threshold — chronic uraemic inflammation
heart failure	<100 (or 100–299 + TSAT <20%)	<20%	TSAT <20% is the primary predictor of IV iron benefit
pregnancy	<30	<20%	screen at booking and 24–28 weeks
acute inflammation	<70	<20%	ferritin unreliable

the grey zone — ferritin 30–100 µg/L

• if clinical suspicion persists → therapeutic trial of iron
• BSG recommendation: Hb rise ≥10 g/L within 2–4 weeks → confirms iron deficiency
• sTfR can help if available — elevated in true deficiency, normal in anaemia of chronic disease

gold standard

Bone marrow biopsy with Prussian blue stain — rarely performed in practice. The clinically relevant standard is response to iron repletion (symptoms + Hb + iron studies).

when to suspect — aetiological workup

mandatory investigations

• men and postmenopausal women → bidirectional endoscopy (GI malignancy found in ~11% — lower GI 8.9%, upper GI 2.0%)
• all patients → coeliac serology (tTG-IgA) and H. pylori testing — common treatable causes of malabsorption
• premenopausal women → evaluate for heavy menstrual bleeding first (see below); GI workup if refractory or GI symptoms present

premenopausal women — heavy menstrual bleeding

Iron deficiency prevalence in women: 11–20% (up to 40% in women ≤21 years). Significantly underdiagnosed.

history clues suggesting HMB:

• bleeding >7 days
• clots >2.5 cm (quarter-sized)
• gushing episodes
• overnight accidents
• changing products every 1–2 hours
• adaptive behaviours (double-padding, lifestyle changes)

workup for HMB:

• CBC, coagulation studies (PT, PTT, VWF panel, fibrinogen, platelet aggregation)
• iron studies, TSH, pregnancy test
• pelvic exam ± ultrasound (if structural cause suspected or age ≥40)

when to refer for endoscopy (premenopausal, no GI symptoms):

• iron deficiency persists despite treating HMB
• no identifiable cause of iron deficiency
• personal or family risk factors for GI malignancy
• age ≥40

management

step 1: treat the cause

• GI lesion → endoscopic/surgical management
• HMB → hormonal management + iron repletion concurrently
• coeliac / H. pylori → treat underlying condition
• if iron deficiency persists after HMB treatment → investigate for secondary GI cause

step 2: oral iron

first-line for stable patients who can tolerate oral iron, without malabsorption, active bleeding, or chronic inflammatory disease.

formulation	elemental iron per tablet
ferrous sulphate 325 mg	65 mg
ferrous fumarate 325 mg	106 mg
ferrous gluconate 325 mg	37.5 mg

• all formulations are equivalent in efficacy — choose affordable
• dosing: once daily or every other day — alternate-day dosing ↓ GI side effects and shows higher fractional absorption in isotope studies, but RCTs show no significant difference in Hb rise; consider alternate-day when daily dosing not tolerated
• take ≥30 min before meals, 1–2 h before other medications
• avoid concurrent milk, calcium, caffeine, antacids, tea, PPIs
• continue 6–12 months to replenish stores

step 3: IV iron

indications:

• oral iron failure (Hb rise <10 g/L in 2–4 weeks)
• malabsorption (IBD, coeliac, bariatric surgery)
• active bleeding or severe symptomatic anaemia
• chronic/inflammatory disease (CKD, HF, rheumatological)
• 2nd/3rd trimester pregnancy
• IBD (oral iron may be harmful — ↑ luminal inflammation)

formulation	infusions for 1 g	notes
iron derisomaltoside (Monoferric)	1	single-dose option
low-molecular-weight iron dextran	1	requires test dose at some centres
ferumoxytol (Feraheme)	1–2	rapid infusion option
ferric carboxymaltose (FCM)	2	hypophosphataemia risk — see below
iron sucrose / ferric gluconate	≥5	more infusion visits

• all formulations similar in efficacy
• dose: 1 g empirically or calculate with Ganzoni formula

heart failure — specific evidence

Heart Failure Diagnosis — check ferritin + TSAT in all HF patients.

FAIR-HF (2009), CONFIRM-HF (2015) — IV iron (FCM) in HFrEF with TSAT <20% → improved functional capacity and quality of life. AFFIRM-AHF (2020) — IV FCM at discharge after acute HF → ↓ total HF hospitalisations (RR 0.74), but primary composite endpoint (HF hospitalisations + CV death) not met (p=0.059).

what NOT to do

• do not use a “normal” ferritin to exclude iron deficiency in HF, CKD, or inflammatory disease — ferritin is an acute-phase reactant
• do not check iron studies earlier than 4–6 weeks post-IV iron — earlier values reflect the infusion, not true stores
• do not check iron studies post-transfusion — invalid for several weeks
• do not give IV iron during active bacteraemia — theoretical risk of promoting bacterial growth (iron is a bacterial growth factor)
• do not give epinephrine or antihistamines for Fishbane reactions — unnecessary and may cause adverse effects (see below)
• do not rely on serum iron alone — volatile, diurnal variation, poor discriminatory value
• do not prescribe iron BID/TID routinely — hepcidin surge after first dose blocks subsequent absorption; alternate-day dosing shows equivalent Hb outcomes with fewer side effects

safety and monitoring

oral iron

• GI side effects (nausea, constipation, dark stools) — manage by ↓ frequency or switching formulation
• post-treatment labs at 6 months: target ferritin >30–50 µg/L, TSAT >20%

IV iron — Fishbane reaction

• occurs in ~1% of infusions — not an allergic reaction (not IgE-mediated; no tryptase elevation)
• flushing, arthralgias, myalgias, back/chest pain; no urticaria, angioedema, or bronchospasm
• mechanism: likely related to labile (free) iron
• management: stop infusion → symptoms resolve spontaneously → restart at slower rate → symptoms do not recur

ferric carboxymaltose — 6H syndrome

• develops 1–2 weeks post-infusion: ↑ FGF-23 → renal phosphate wasting → hypophosphataemia, hypovitaminosis D, hypocalcaemia, secondary hyperparathyroidism
• incidence of hypophosphataemia: up to 74% with FCM
• complications: osteomalacia, fractures, muscle weakness, respiratory failure (with repeated dosing)
• monitor serum phosphate after FCM; consider iron derisomaltoside as alternative if recurrent dosing needed

IV iron and infection

• safe in patients with mild, resolving infections
• hold during active bacteraemia
• does not confer higher risk of nosocomial infection in hospitalised patients

special populations

pregnancy

• screen at booking and 24–28 weeks (ferritin <30 µg/L)
• oral iron first-line in 1st trimester; IV iron preferred in 2nd/3rd trimester if oral fails
• perinatal iron deficiency (even without anaemia) may contribute to neurodevelopmental delay — iron is shunted away from the developing brain to maintain haeme synthesis
• check iron parameters each trimester; repeat IV iron if still deficient

CKD

• diagnostic thresholds are higher (see table above) — sensitivity of standard cutoffs remains poor
• many iron-deficient CKD patients are missed
• ESRD on haemodialysis has a different approach (higher ferritin thresholds, routine IV iron protocols) — not covered here

key trials summary

trial	year	design	result
Stoffel, Lancet Haematol. 2017	2017	iron isotope study, iron-depleted premenopausal women	alternate-day dosing → higher fractional absorption (21.8% vs 16.3%) and lower hepcidin; subsequent clinical RCTs show no significant Hb difference
Li, JAMA Netw Open. 2020	2020	RCT, n=440, IDA	vitamin C co-administration → no difference in Hb rise at 2 weeks
FAIR-HF (2009)	2009	RCT, HFrEF + iron deficiency	IV FCM → improved self-reported patient global assessment and NYHA class
CONFIRM-HF (2015)	2015	RCT, HFrEF + iron deficiency	IV FCM → sustained improvement in 6MWT and ↓ HF hospitalisations over 52 weeks
AFFIRM-AHF (2020)	2020	RCT, acute HF + iron deficiency	IV FCM at discharge → primary composite (HF hospitalisations + CV death) not met (p=0.059); ↓ total HF hospitalisations alone (RR 0.74, p=0.013); no CV death difference