• Men (≥15 years): <130 g/L (13.0 g/dL)
• Non-pregnant women (≥15 years): <120 g/L (12.0 g/dL)
• Pregnant women: <110 g/L (11.0 g/dL)
  
  

Inadequate Iron Intake

• Diets low in iron-rich foods are a common contributor, particularly in populations with limited access to meat, which contains readily absorbable haem iron.
• Non-haem iron from plant sources is less bioavailable and more susceptible to inhibition by dietary constituents such as:
  • Phytates (found in legumes and whole grains)
  • Oxalates, phosphates, carbonates, and tannates (from tea and some vegetables)
• Vitamin C (ascorbic acid) enhances absorption of non-haem iron by reducing ferric to ferrous iron and forming soluble complexes, but does not affect haem iron uptake.
• Iron absorption is enhanced when meat is consumed concurrently with iron-rich plant foods, due to peptides from globin degradation improving solubility and uptake.
  
  

Impaired Iron Absorption

• Gastrointestinal causes:
  • Achlorhydria, including age-related or drug-induced hypochlorhydria (e.g., from proton pump inhibitors), reduces iron solubilisation in the stomach.
  • Post-gastrectomy or gastric bypass surgery, especially Roux-en-Y, bypasses the duodenum—the primary site of iron absorption—and decreases acid production, impairing iron reduction and uptake.
  • Coeliac disease and other enteropathies damage the duodenal mucosa, decreasing surface area and transport capacity.
• Other causes:
  • Pica (e.g., clay or starch eating) interferes with iron absorption.
  • Non-compliance with oral iron therapy may masquerade as malabsorption; absorption tests (e.g., oral iron challenge) can help clarify.
    
    

Increased Iron Loss

• Gastrointestinal bleeding is the most common source of chronic blood loss:
  • Causes include peptic ulcer disease, oesophagitis, gastritis, hiatal hernia, diverticulosis, haemorrhoids, colorectal cancer, inflammatory bowel disease, Meckel’s diverticulum, hookworm infestation, and salicylate ingestion.
• Menstrual blood loss (e.g., menorrhagia) remains a major contributor in premenopausal women.
• Haematuria and haemoglobinuria:
  • Seen in paroxysmal nocturnal haemoglobinuria, intravascular haemolysis, or mechanical valve haemolysis.
  • Hemosiderinuria results in renal loss of iron; intracellular iron in urinary sediment confirms the diagnosis.
• Pulmonary haemorrhage syndromes:
  • Chronic alveolar bleeding, as in idiopathic pulmonary haemosiderosis or Goodpasture’s syndrome, may cause insidious iron loss.
• Other contributors:
  • Frequent blood donation, haemodialysis, schistosomiasis, trichuriasis, angiodysplasia, and disorders of haemostasis.
    
    

Increased Iron Requirements

• Physiological states that demand increased iron include:
  • Infancy and early childhood (due to rapid growth)
  • Adolescence
  • Pregnancy and lactation
• These increased needs are often unmet in settings of marginal dietary iron, compounding the risk for deficiency.
  
  

Iron-Refractory Iron Deficiency Anaemia (IRIDA)

• A hereditary disorder caused by TMPRSS6 gene mutations resulting in unregulated hepcidin overproduction.
• High hepcidin levels inhibit iron absorption and release from stores.
• Typically presents as microcytic, hypochromic anaemia that is resistant to oral iron and only partially responsive to intravenous iron.
• Female predominance is observed; disease severity and response to therapy are highly variable.
• A rare variant is seen in postmenopausal women with androgen deficiency, responding only to androgen replacement due to impaired iron reutilisation.
  
  

Unknown or Multifactorial Causes

• In some patients, especially the elderly or those with complex comorbidities, no clear source of iron deficiency is identified.
• Multifactorial contributors such as dietary inadequacy, occult blood loss, and chronic inflammation may coexist.
  
  

Iron's Biological Role

• Iron is essential for the synthesis of haemoglobin, myoglobin, and haem enzymes (e.g., cytochromes).
• It also supports DNA replication and repair, electron transport, cell metabolism, and cell cycle regulation.
• Approximately 60% of body iron is in haemoglobin; the rest is stored in ferritin, haemosiderin, or incorporated into myoglobin and enzymes.
  
  

Iron Turnover and Requirements

• Total body iron in a 70-kg man is around 4 grams, with:
  • ~2.5 g in circulating haemoglobin,
  • ~1 g in storage (ferritin/haemosiderin),
  • ~0.3 g in myoglobin and enzymes.
• Daily requirement for iron is about 20–25 mg, mostly for haemoglobin synthesis and cellular turnover. This is largely recycled from senescent red blood cells.
• Absorption compensates for daily losses, which are:
  • ~1 mg in men and post-menopausal women,
  • ~2 mg in menstruating women,
  • Up to 580 mg lost during pregnancy, especially in the third trimester, due to fetal growth and expanded maternal blood volume.
    
    

Regulation of Iron Absorption

• Iron absorption occurs mainly in the duodenum and proximal jejunum and is the primary regulated point in iron homeostasis, as the body lacks a direct excretory mechanism.
• Iron is absorbed in two forms:
  • Haem iron (from animal sources): absorbed via vesicular transport, less affected by dietary inhibitors, released inside enterocytes by haem oxygenase.
  • Non-haem iron (from plant sources): absorbed in either ferrous (Fe²⁺) form via DMT-1 or ferric (Fe³⁺) form via the mobilferrin-integrin pathway after luminal reduction.
• Dietary enhancers and inhibitors:
  • Ascorbic acid enhances non-haem iron absorption by reducing Fe³⁺ to Fe²⁺.
  • Phytates, oxalates, phosphates, carbonates, and tannates inhibit non-haem iron absorption.
  • Globin degradation peptides aid both haem and non-haem absorption by preventing iron polymerisation and precipitation.
    
    

Role of Hepcidin in Iron Homeostasis

• Hepcidin, a peptide hormone produced by the liver, is the central regulator of systemic iron:
  • It inhibits intestinal iron absorption and release from macrophages by degrading ferroportin, the sole iron exporter.
  • Low hepcidin levels (as in iron deficiency or hypoxia) increase iron absorption.
  • High hepcidin levels (as in inflammation, infection, or chronic kidney disease) reduce iron availability, contributing to anaemia of chronic disease.
    
    
    

Enterocyte and Systemic Iron Transport

• Enterocytes respond to body iron levels:
  • In iron deficiency, enterocyte iron content is low, and absorption increases.
  • In iron overload (e.g., haemochromatosis), absorption decreases, but enterocyte iron remains paradoxically low.
• Iron exits enterocytes via ferroportin, assisted by hephaestin, and binds to transferrin in plasma.
• Nonintestinal cells acquire transferrin-bound iron via:
  • Transferrin receptor-mediated endocytosis (high affinity)
  • Receptor-independent pathways (low affinity, high capacity)
    
    
    

Mechanisms Leading to IDA

• When dietary iron is insufficient, absorption is impaired, or losses are excessive, iron stores are depleted.
• This leads to inadequate haemoglobin synthesis and results in microcytic, hypochromic red blood cells.
• In early IDA, blood indices may remain normal despite depleted iron stores. Progressive deficiency eventually leads to:
  • Low haemoglobin and haematocrit
  • Reduced mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH)
  • Increased red cell distribution width (RDW)
• Symptoms include fatigue, dyspnoea on exertion, pallor, and reduced exercise tolerance due to impaired oxygen transport.
  
  

Additional Influences on Absorption

• Endotoxins and pro-inflammatory cytokines diminish iron absorption independently of iron stores, primarily by increasing hepcidin.
• Erythropoietin downregulates hepcidin to promote iron availability during active erythropoiesis.
• Novel transport proteins (e.g., SFT, hephaestin) and cellular iron sensing mechanisms are under investigation for their roles in modulating absorption and cellular iron handling.
  
  

Global Prevalence and Trends

• Anaemia affects approximately 25–33% of the global population, with iron deficiency accounting for around 50% of these cases.
• A 2023 global burden of disease analysis (1990–2021) identified iron deficiency as the leading cause of anaemia and years lived with disability, affecting one in five females globally.
• The prevalence of iron deficiency without anaemia is consistently higher than that of iron deficiency anaemia (IDA) across all studied populations.
  
  

Regional and Socioeconomic Variation

• Lower-income regions (e.g. South Asia, sub-Saharan Africa, and the Caribbean) have the highest prevalence due to inadequate nutrition, high rates of infection, and poor healthcare access.
• Higher-income regions (e.g. North America and Western Europe) report significantly lower prevalence, though iron deficiency remains a concern in specific subgroups.
• In the United Kingdom, approximately 3% of men and 8% of women have IDA.
• In the United States, NHANES data from 1988–1994 and 1999–2010 showed:
  • 3–5% prevalence in non-pregnant women aged 16–49 years.
  • <1% prevalence in men aged 16–69 years.
  • 2.6% prevalence in pregnant women aged 12–49 years, increasing across trimesters to 27.5% in the third trimester.
    
    

Age and Gender Distribution

• Children: Prevalence is high due to growth-related iron demands and inadequate intake. In the U.S., ~9% of children aged 12–36 months are iron-deficient; a third develop IDA.
• Women of reproductive age: High risk due to menstrual losses and pregnancy demands. In Canadian data, 38% of reproductive-age women had iron deficiency (ferritin <30 ng/mL), with 75% of these non-anaemic.
• Pregnant women: Over 50% may be iron-deficient early in pregnancy, often pre-existing conception. Prevalence increases with gestation, with third-trimester rates as high as 27.5%.
• Postmenopausal women and men: Lower rates due to reduced physiological iron losses.
• Older adults: In individuals >65 years, ~12% of anaemia cases are due to iron deficiency.
  
  

Special Populations

• Athletes and military recruits: A 122-study meta-analysis of 17,519 participants found:
  • 31% had ferritin <30 ng/mL,
  • 54% had ferritin <50 ng/mL,
  • Females (31%) more affected than males (10%).
• Mechanisms include increased iron turnover, haemolysis, sweating, and gastrointestinal bleeding.
• Blood donors: Prevalence of subclinical iron deficiency ranges from 5% to 49%, particularly in premenopausal female donors.
• Non-anaemic iron deficiency (NAID): Common across populations and represents an early stage of deficiency, often progressing to IDA if uncorrected.
  
  

Ethnic and Racial Disparities

• In the U.S. HEIRS study of 60,000 women aged ≥25, the prevalence of iron deficiency (ferritin <15 ng/mL and TSAT <10%) was:
  • Hispanic Americans: 5.1%
  • Black Americans: 4.3%
  • Asian Americans: 2.1%
  • White Americans: 2.0%
• Native Americans and Pacific Islanders also had higher rates, though sample sizes were smaller.
• Disparities likely reflect differences in socioeconomic status, healthcare access, and systemic inequities.
  
  

General Symptoms Attributable to Iron Deficiency

• Fatigue and reduced exercise tolerance – Often insidious and underestimated until retrospectively recognised following treatment.
• Cognitive impairment – Subtle attention deficits or mental sluggishness, particularly in younger individuals or those with prolonged deficiency.
• Hair loss – Noted particularly in females; typically diffuse and reversible with iron repletion.
• Headache – Occurs with or without anaemia, possibly reflecting tissue hypoxia or neurotransmitter imbalance.
  
  

Iron Deficiency–Specific Features

• Pica – A craving for non-nutritive substances. May present even in the absence of anaemia:
  • Pagophagia (craving for ice) is strongly associated with iron deficiency.
  • Other forms include:
    • Geophagia (clay, dirt)
    • Amylophagia (laundry starch, raw rice, pasta)
    • Consumption of substances like chalk, coffee grounds, paint chips, or paper.
  • Intensity can be severe, and symptoms typically resolve rapidly after iron treatment.
  • Cultural practices should not be assumed to explain pica without excluding iron deficiency.
• Beeturia – Red urine after beet ingestion is significantly more frequent in iron-deficient individuals, due to impaired decolourisation of betalaine pigments in the absence of sufficient ferric iron.
  
  

Restless Legs Syndrome (RLS)

• RLS, or Willis-Ekbom disease, is a neurological disorder marked by an urge to move the legs during rest, relieved by motion.
• Iron deficiency is a common and potentially reversible cause:
  • Reduced brain iron concentrations are consistently noted in patients with RLS.
  • May occur with or without systemic iron deficiency.
• Prevalence is higher in White populations and disproportionately affects women.
• Case series have reported RLS in:
  • 40% of individuals with iron deficiency.
  • 24% of patients with iron deficiency anaemia—nearly 9-fold higher than the general population.
• RLS symptoms often improve following iron repletion, even in patients with near-normal haemoglobin.
  
  

Symptoms Attributable to Anaemia

• Exertional dyspnoea
• Tachycardia or palpitations
• Lightheadedness
• Pallor (reported by the patient or observed by others)
• Irritability or mood disturbances, especially in children and adolescents
• Syncope or pre-syncope in severe cases
  
  

Mood Changes and Neuropsychiatric Symptoms

• Iron deficiency has been associated with:
  • Depressed mood and irritability, especially in low-income women of reproductive age.
  • In one large survey, iron deficiency correlated with depressive symptoms, even after adjusting for socioeconomic status and other factors.
    
    

Hearing Loss

• Observational studies suggest an association between iron deficiency and sensorineural hearing loss, though causality remains unproven.
• In one retrospective study of >300,000 adults, iron deficiency was associated with a 2.4-fold increased odds of combined hearing loss.
• Routine hearing assessment is not indicated unless clinical suspicion arises.
  
  

Symptoms Pointing to the Underlying Cause of Iron Deficiency

• Gastrointestinal bleeding: Melaena, haematochezia, epigastric pain, or dark stools.
• Menstrual history: Menorrhagia, intermenstrual bleeding, postpartum haemorrhage.
• Dietary history: Poor intake of haem iron, vegetarian/vegan diet, or restrictive eating behaviours.
• Malabsorption indicators: Chronic diarrhoea, weight loss, or known conditions like coeliac disease.
• Donor history: Frequent blood donation.
• High physical activity: Endurance sports, especially in young women.
  
  

General Signs of Anaemia

• Pallor:
  • Most consistently observed finding.
  • May be evident in the conjunctivae, palmar creases, nail beds, and mucous membranes.
  • Sensitivity and specificity vary (sensitivity 19–70%; specificity 70–100%), depending on the site and observer.
• Cardiovascular manifestations:
  • In cases of moderate to severe anaemia:
    • Tachycardia may be present at rest or during exertion.
    • A flow murmur may be audible over the precordium.
    • In rare, profound anaemia, orthostatic hypotension or haemodynamic instability can occur.
      
      

Epithelial and Mucocutaneous Findings

• Glossitis:
  • Characterised by a smooth, erythematous tongue with loss of papillae.
  • May be associated with burning, discomfort, or a dry mouth sensation.
• Angular cheilitis (cheilosis):
  • Cracks or fissures at the corners of the mouth, sometimes with secondary infection.
  • Commonly observed in prolonged deficiency.
• Koilonychia (spoon-shaped nails):
  • Concave, brittle nails that may break or chip easily.
  • Classical but infrequent in modern clinical practice.
• Dry or rough skin:
  • Generalised xerosis may develop in chronic iron deficiency.
• Alopecia:
  • Rare, but diffuse hair thinning or hair loss may occur in severe, long-standing cases.
• Chlorosis:
  • Describes a faint greenish pallor of the skin historically associated with IDA in the early 20th century.
  • Now considered obsolete and extremely rare.
    
    

Gastrointestinal and Oropharyngeal Findings

• Atrophic changes of the upper gastrointestinal tract:
  • These include loss of tongue papillae and mucosal thinning.
  • May contribute to symptoms such as dysphagia or sensation of dryness.
• Oesophageal web:
  • Thin mucosal membrane in the upper oesophagus.
  • May present as dysphagia and is associated with Plummer-Vinson syndrome (also known as Patterson-Kelly syndrome).
  • More common in historical cohorts; now rare in high-income countries.
• Gastric atrophy:
  • Sometimes described with IDA, though causality is unclear.
  • May overlap with autoimmune gastritis or Helicobacter pylori infection, which themselves impair iron absorption.
    
    

Lymphoreticular Findings

• Splenomegaly:
  • May be observed in cases of chronic, untreated, or severe iron deficiency.
  • Rare in contemporary practice in developed countries.
• Lymphadenopathy and hepatosplenomegaly:
  • Should raise suspicion for other causes of anaemia such as infection, malignancy, or autoimmune disease.
    
    

Other Findings

• Signs of chronic disease: such as joint swelling (suggestive of autoimmune disease), rashes (vasculitis or connective tissue disorders), or fever (chronic infection).
• Signs of gastrointestinal bleeding: abdominal tenderness, palpable mass, or signs of liver disease (e.g., spider naevi, palmar erythema).
• Signs of malabsorption: dermatitis herpetiformis (in coeliac disease), glossitis, or weight loss.
  
  

Indications for Evaluation

• Patients with unexplained anaemia, particularly microcytic anaemia without reticulocytosis.
• Individuals with symptoms suggestive of iron deficiency (e.g., pagophagia, restless legs syndrome).
• Pregnant individuals.
• Patients with chronic kidney disease, especially if receiving erythropoiesis-stimulating agents or undergoing haemodialysis.
  
  

Initial Tests and Key Haematological Findings

• Complete Blood Count (CBC):
  • Low haemoglobin: <120 g/L in women; <130 g/L in men.
  • Low haematocrit, MCV, and MCHC.
  • Elevated red cell distribution width (RDW).
  • Peripheral smear: shows microcytic, hypochromic, and poikilocytotic red blood cells, including pencil-shaped cells and target cells.
  • Platelet count may be elevated due to erythropoietin-induced stimulation.
• Reticulocyte Count:
  • Usually low or inappropriately normal, reflecting reduced marrow response.
  • May be helpful in assessing marrow productivity.
    
    
    

Iron Studies

• Serum Ferritin:
  • Most specific test for iron deficiency when low.
  • Ferritin <30 ng/mL is considered diagnostic in most contexts.
  • Ferritin is an acute phase reactant and may be falsely normal or elevated in inflammation, liver disease, or malignancy.
• Serum Iron:
  • Low in both IDA and anaemia of chronic disease (ACD).
  • Influenced by dietary intake, diurnal variation, and recent iron supplementation.
• Total Iron-Binding Capacity (TIBC)/Transferrin:
  • Typically increased in IDA.
  • May be reduced or normal in ACD.
• Transferrin Saturation (TSAT):
  • Calculated as: (serum iron ÷ TIBC) × 100.
  • <20% is suggestive of iron deficiency; <10% is common in severe cases.
  • Fasting measurement is recommended due to postprandial fluctuation.
    
    

Advanced or Adjunctive Testing

• Soluble Transferrin Receptor (sTfR):
  • Elevated in IDA; normal in ACD.
  • Useful in distinguishing IDA from ACD, especially when ferritin is inconclusive.
• sTfR/log Ferritin Index:
  • 2 suggests iron deficiency or mixed IDA/ACD.
  • <1 suggests ACD alone.
• Reticulocyte Haemoglobin Content (CHr or Ret-He):
  • Low CHr (<28–29 pg) correlates with iron-restricted erythropoiesis.
  • Less affected by inflammation.
  • More commonly used in chronic kidney disease.
• RBC Zinc Protoporphyrin:
  • Elevated in IDA due to replacement of iron by zinc during haem synthesis.
  • Not specific; may be raised in inflammation, haemodialysis, or lead poisoning.

Bone Marrow Iron Staining (Rarely Required)

• Gold standard for assessing iron stores.
• Iron deficiency is confirmed by absence of stainable iron in erythroid precursors and macrophages.
• Rarely indicated due to availability of less invasive tests.

Test Interference and Timing Considerations

• Oral iron supplements can transiently raise serum iron and TSAT.
• Samples for iron studies should ideally be drawn after an overnight fast or 5–9 hours after iron ingestion.
• Intravenous iron and recent blood transfusion may temporarily alter test results; re-evaluation should be delayed until steady-state is re-established.
  
  

Diagnostic Sequence

• In most individuals, iron studies including ferritin, serum iron, TIBC, and TSAT are sufficient.
• In patients with comorbidities or inconclusive results, sTfR or a therapeutic trial of iron may be used.
• Ferritin <30 ng/mL or TSAT <20% in the right context confirms iron deficiency.
• Normal or borderline ferritin with low TSAT may still indicate IDA, especially in inflammation.
  
  

Therapeutic Trial of Iron

• In resource-limited settings or in typical clinical scenarios (e.g., anaemia in a multiparous female with menorrhagia), empirical iron therapy may be used diagnostically.
• A rise in haemoglobin by 10 g/L within 1–3 weeks supports the diagnosis.
• Lack of response should prompt re-evaluation for alternative diagnoses or malabsorption.
  
  

General Principles of Management

• Identify and treat the underlying cause: Investigations should be initiated concurrently with iron therapy to locate and manage sources of blood loss or malabsorption (e.g. gastrointestinal bleeding, menorrhagia, coeliac disease).
• Correct iron deficiency: Iron supplementation is essential, either orally or intravenously.
• Assess severity and risk: Consider the haemoglobin level, comorbidities, and presence of symptoms to guide therapy choice.
  
  
  

Iron Supplementation

• First-line treatment in most individuals with mild to moderate IDA and an intact gastrointestinal tract.
• Typical regimens include:
  • Ferrous sulphate 100–200 mg elemental iron daily, administered in divided doses.
  • Lower or alternate-day dosing may improve tolerance and enhance absorption via reduced hepcidin response.
• Adverse effects: Gastrointestinal symptoms (nausea, constipation, dark stools).
• Duration: Continue for 3–6 months after normalisation of haemoglobin to replenish iron stores.
  
  

Intravenous Iron Therapy

• Indications:
  • Poor absorption (e.g. after gastric bypass, active coeliac disease).
  • Intolerance to oral iron.
  • Rapid repletion required (e.g. in late pregnancy, severe anaemia).
  • Functional iron deficiency in chronic diseases (e.g. cancer, CKD).
• Preferred formulations:
  • Ferric carboxymaltose or iron isomaltoside for single-dose large infusions.
  • Iron sucrose for fractionated dosing.
• Benefits:
  • Faster correction of anaemia.
  • Decreased need for erythropoiesis-stimulating agents (ESAs).
• Risks:
  • Infusion reactions are rare with modern formulations.

Erythropoiesis-Stimulating Agents (ESAs)

• Chronic kidney disease (CKD).
• Anaemia of chronic disease (ACD) unresponsive to underlying treatment.
• Cancer-associated anaemia due to chemotherapy.
  
  

• ESAs (e.g. epoetin alfa, darbepoetin alfa) increase Hb and reduce transfusion need.
• Used only after ruling out iron deficiency, and typically combined with iron (often intravenous) to overcome functional iron deficiency.
• Risks:
  • Thromboembolic events, hypertension.
  • Possible increased tumour progression in cancer.
  • Pure red cell aplasia (rare, antibody-mediated).
• Target Hb:
  • In CKD: avoid exceeding 10–11 g/dL.
  • In cancer: initiate when Hb <10 g/dL and only in palliative settings.
• Monitoring: Hb levels weekly during initiation, then monthly.
  
  
  

Red Blood Cell (RBC) Transfusion

• Reserved for severe or life-threatening anaemia, or when rapid correction is necessary (e.g. acute bleeding, cardiovascular compromise).
• Should be used with caution:
  • Risks: volume overload, transfusion reactions, alloimmunisation, iron overload.
  • Restrictive thresholds recommended (Hb <7–8 g/dL in stable patients).
• May be necessary in:
  • Patients who cannot tolerate anaemia.
  • Those awaiting response to iron or ESA therapy.
  • Patients refusing ESAs or with contraindications (e.g. cancer patients receiving curative therapy).
    
    

Special Populations and Contexts

• ESAs are central to anaemia management in advanced CKD (Hb <10 g/dL).
• Iron supplementation (often IV) is usually required due to functional deficiency.
• Hb targets should avoid exceeding 11 g/dL due to cardiovascular risk.
  
  

• ESAs may be considered in patients with chemotherapy-induced anaemia and Hb <10 g/dL.
• Avoid ESAs in curative-intent settings due to concerns of tumour progression and decreased survival.
• IV iron may be used regardless of ferritin/TSAT to support ESA efficacy.
  
  

• Increased iron requirements make oral supplementation standard during gestation.
• Intravenous iron is preferred in second or third trimester if anaemia is severe or oral therapy fails.

• Jehovah’s Witnesses or patients with rare blood types/allosensitisation may benefit from early ESA + IV iron as a pre-emptive strategy to avoid transfusion.
  
  

Monitoring and Follow-Up

• Hb and iron studies (ferritin, TSAT) should be monitored periodically to:
  • Assess response to treatment.
  • Guide iron repletion duration.
  • Prevent iron overload with IV iron or ESA use.
• Ferritin and TSAT thresholds vary by clinical context:
  • Functional deficiency: Ferritin 30–500 ng/mL with TSAT <20–50%.
  • True deficiency: Ferritin <30 ng/mL.
    
    

General Prognosis

• Excellent short-term outcomes are typical for otherwise healthy individuals with uncomplicated IDA who receive effective iron therapy.
• Resolution of symptoms such as fatigue, exercise intolerance, and pica usually follows within weeks of initiating treatment.
• Long-term outcome is dependent on the identification and correction of the underlying aetiology (e.g. chronic blood loss, malabsorption, dietary insufficiency).
  
  

Consequences of Untreated or Recurrent IDA

• Poor prognosis if the cause of iron deficiency is undiagnosed or uncorrected, especially in cases linked to:
  • Gastrointestinal malignancy
  • Chronic inflammatory disorders
  • Renal or gynaecological bleeding
• Persistent or recurrent IDA may:
  • Lead to chronic hypoxic stress, exacerbating underlying cardiopulmonary conditions (e.g. heart failure, chronic lung disease).
  • Result in reduced exercise capacity and impaired quality of life.
    
    

Impact of Comorbid Conditions

• Patients with cardiovascular disease (e.g. coronary artery disease) or pulmonary disease are particularly vulnerable, as even moderate anaemia may precipitate decompensation.
• In rare cases, death from hypoxia has been reported in severe anaemia, especially among patients who decline transfusion therapy (e.g. for religious reasons).
• Muscle fatigue and reduced work performance can affect occupational and daily activities in working-age adults.
  
  

Paediatric Implications

• In infants and young children, untreated iron deficiency anaemia can have long-lasting developmental effects:
  • Delayed growth
  • Lower intelligence quotient (IQ)
  • Reduced cognitive and psychomotor development
  • Diminished learning capacity
• Early intervention is crucial to prevent irreversible neurodevelopmental deficits.
  
  

Cardiovascular Complications

• Heart failure exacerbation: Anaemia increases cardiac output to compensate for reduced oxygen delivery, potentially decompensating pre-existing heart failure or precipitating new-onset heart failure in those with marginal reserve.
• Angina pectoris: Myocardial oxygen demand increases in anaemia, which may:
  • Trigger angina at lower levels of exertion in patients with coronary artery disease (CAD).
  • Unmask previously asymptomatic CAD.
• Thrombotic risk with ESA therapy: Use of ESAs, particularly when targeting Hb >120 g/L (>12 g/dL), is associated with:
  • Venous and arterial thromboembolic events: including stroke, myocardial infarction, and vascular access thrombosis in haemodialysis patients.
    
    

Neurological and Cognitive Effects

• Depression: Fatigue and mental sluggishness due to chronic anaemia may contribute to or worsen depressive symptoms.
• Neurocognitive impairment in children:
  • IDA during infancy and early childhood is associated with lower IQ, learning difficulties, and delayed psychomotor development.
  • These effects may persist even after correction of anaemia if not addressed early.
    
    

Infectious Susceptibility

• Iron plays a role in immune function; iron deficiency may impair host defences, potentially increasing susceptibility to infections.
  
  

Pregnancy-Related Complications

• Adverse outcomes in pregnancy include:
  • Preterm delivery
  • Low birth weight
  • Increased maternal morbidity
• Untreated IDA may also exacerbate maternal fatigue and postpartum recovery.
  
  

Transfusion-Related Complications

• Acute haemolytic transfusion reaction:
  • Often due to ABO mismatch.
  • Presents with fever, hypotension, and risk of acute renal failure or death.
• Delayed haemolytic reaction:
  • Occurs 3–10 days post-transfusion due to alloantibody formation.
  • Self-limiting, but causes unexpected drop in haemoglobin.
• Transfusion-related acute lung injury (TRALI):
  • A form of non-cardiogenic pulmonary oedema caused by donor anti-leukocyte antibodies.
  • May require intensive care; can be fatal.
• Iron overload:
  • With repeated transfusions, iron accumulates in the liver, heart, and endocrine glands.
  • May require iron chelation therapy.
• HLA sensitisation:
  • Alloimmunisation from donor lymphocytes may complicate future transplant compatibility.
  • Risk reduced with leukoreduction of blood products.
• Transfusion-transmitted infections:
  • Rare in high-resource settings due to rigorous screening.
  • Risks include hepatitis B and C, HIV, HTLV, and bacterial sepsis.
    
    

Complications from ESA Therapy

• Hypertension:
  • Common in patients with renal impairment, especially if Hb rises rapidly or overshoots target range.
  • May necessitate antihypertensive therapy.
• Tumour progression:
  • Some evidence suggests ESAs may stimulate tumour growth in cancer patients.
  • Increased mortality reported in those receiving ESAs during curative-intent therapy.
• Pure red cell aplasia:
  • Rare, antibody-mediated suppression of erythropoiesis, sometimes linked to certain ESA formulations.
    
    

Functional Impairments

• Fatigue and muscular inefficiency:
  • Most common symptom of moderate to severe IDA.
  • Reduces quality of life and work capacity.
• Growth delay in children:
  • Chronic IDA impairs physical growth alongside neurodevelopmental deficits.

1. Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015;372(19):1832–1843
2. Goddard AF, James MW, McIntyre AS, Scott BB. Guidelines for the management of iron deficiency anaemia. Gut. 2011;60(10):1309–1316.
3. Miller JL. Iron deficiency anemia: a common and curable disease. Cold Spring Harb Perspect Med. 2013;3(7):a011866.
4. DeLoughery TG. Iron deficiency anemia. Med Clin North Am. 2017;101(2):319–332.
5. Cook JD. Diagnosis and management of iron-deficiency anaemia. Best Pract Res Clin Haematol. 2005;18(2):319–332.
6. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL. Prevalence of iron deficiency in the United States. JAMA. 1997;277(12):973–976.
7. Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician. 2007;75(5):671–678.
8. Auerbach M, Adamson JW. How we diagnose and treat iron deficiency anemia. Am J Hematol. 2016;91(1):31–38.
9. Locatelli F, Bárány P, Covic A, et al. KDIGO guidelines on anaemia management in chronic kidney disease. Kidney Int Suppl. 2012;2(4):311–316.
10. Avni T, Bieber A, Grossman A, et al. The safety of intravenous iron preparations: a systematic review. Mayo Clin Proc. 2015;90(1):12–23.
11. Qunibi WY. The safety of intravenous iron dextran: facts and fiction. Am J Kidney Dis. 2002;40(5):993–997.
12. Bennett CL, Silver SM, Djulbegovic B, et al. VTE and mortality with erythropoietin and darbepoetin. JAMA. 2008;299(8):914–924.
13. Guralnik JM, Eisenstaedt RS, Ferrucci L, et al. Prevalence of anaemia in older Americans. Blood. 2004;104(8):2263–2268.
14. Safiri S, Kolahi AA, Noori M, et al. Global burden of anemia and its causes, 1990–2021. Lancet Haematol. 2023;10(6):e409–e420.
15. McLean E, Cogswell M, Egli I, et al. Worldwide prevalence of anaemia, 1993–2005. Public Health Nutr. 2009;12(4):444–454.
16. WHO. Haemoglobin concentrations for the diagnosis of anaemia. World Health Organization; 2011.
17. Beard JL. Iron biology in immune, muscle, and neural function. J Nutr. 2001;131(2S-2):568S–580S.
18. Thomas C, Thomas L. Biochemical markers in functional iron deficiency. Clin Chem. 2002;48(7):1066–1076.
19. Beguin Y. Soluble transferrin receptor in iron status evaluation. Clin Chim Acta. 2003;329(1-2):9–22.
20. Punnonen K, Irjala K, Rajamäki A. Transferrin receptor/ferritin ratio in iron deficiency. Blood. 1997;89(3):1052–1057.
21. Mast AE, Blinder MA, Gronowski AM, et al. Reticulocyte haemoglobin content in iron deficiency. Blood. 2002;99(4):1489–1491.
22. Milman N. Serum ferritin across lifespan and in pregnancy. Int J Hematol. 1996;63(2):103–135.
23. Fleming RE, Ponka P. Iron overload in disease. N Engl J Med. 2012;366(4):348–359.
24. Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012;1823(9):1434–1443.
25. Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpet for iron metabolism. Cell. 2017;168(3):344–361.
26. Hallberg L, Brune M, Rossander L. Vitamin C’s role in iron absorption. Int J Vitam Nutr Res Suppl. 1989;30:103–108.
27. Cook JD, Monsen ER. Food iron absorption in man. J Clin Invest. 1976;57(2):418–425.
28. Beard JL, Hendricks MK, Perez EM, et al. Maternal IDA affects postpartum cognition. J Nutr. 2005;135(2):267–272.
29. Balarajan Y, Ramakrishnan U, Özaltin E, et al. Anaemia in low- and middle-income countries. Lancet. 2011;378(9809):2123–2135.