Iron Deficiency Anaemia

The World Health Organization (WHO) defines anaemia as a haemoglobin concentration lower than the following thresholds

• 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

• 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

• Testing for iron deficiency is indicated in:
  • 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

 Oral Iron Therapy

• 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)

• Used selectively in:
  • Chronic kidney disease (CKD).
  • Anaemia of chronic disease (ACD) unresponsive to underlying treatment.
  • Cancer-associated anaemia due to chemotherapy.
• Key considerations:
  • 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

 Chronic Kidney Disease (CKD)

• 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.

Cancer-Associated Anaemia

• 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.

Pregnancy

• 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.

Patients Requiring Urgent Correction

• 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 induces a compensatory increase in cardiac output due to reduced oxygen-carrying capacity.
• This increased workload may worsen pre-existing heart failure or provoke decompensation in individuals with marginal cardiac reserve.

Angina pectoris

• Increased myocardial oxygen demand in anaemia can:
  • Lower the threshold for exertional angina in patients with underlying coronary artery disease (CAD).
  • Reveal previously silent CAD due to impaired oxygen delivery.

Thrombotic risk with ESA therapy

• Erythropoiesis-stimulating agents (ESAs), especially when aiming for haemoglobin >120 g/L (>12 g/dL), are associated with increased risk of:
  • Venous thromboembolism
  • Arterial thrombotic events, including stroke and myocardial infarction
  • Vascular access thrombosis in haemodialysis patients

Neurological and Cognitive Effects

Depression

• Chronic anaemia-related fatigue and mental slowing may aggravate or precipitate depressive symptoms.

Neurocognitive impairment in children

• Iron deficiency anaemia (IDA) during infancy and early childhood is linked to:
  • Reduced IQ
  • Learning difficulties
  • Delayed psychomotor development
• These deficits may persist even after anaemia is corrected if it was longstanding or inadequately treated early.

Infectious Susceptibility

• Iron deficiency impairs several aspects of immune function, including T-cell and phagocytic activity.
• This may increase vulnerability to infections.

Pregnancy-Related Complications

• IDA is associated with adverse maternal and fetal outcomes, including:
  • Preterm delivery
  • Low birth weight
  • Increased maternal morbidity (e.g., fatigue, prolonged recovery postpartum)

Transfusion-Related Complications

Acute haemolytic transfusion reaction

• Usually due to ABO incompatibility.
• Presents with fever, hypotension, back pain, haemoglobinuria, and risk of acute renal failure or death.

Delayed haemolytic transfusion reaction

• Occurs 3–10 days post-transfusion.
• Caused by alloantibody-mediated red cell destruction.
• Often self-limited but may cause unexpected haemoglobin drop.

Transfusion-related acute lung injury (TRALI)

• Acute non-cardiogenic pulmonary oedema triggered by donor anti-leukocyte antibodies.
• May lead to respiratory failure and require ICU care.
• Can be fatal.

Iron overload

• Occurs with chronic transfusion therapy.
• Excess iron deposits in organs such as the liver, heart, and endocrine glands.
• May necessitate iron chelation therapy.

HLA sensitisation

• Alloimmunisation to donor lymphocytes may hinder future organ transplant compatibility.
• Risk reduced with leukoreduced blood components.

Transfusion-transmitted infections

• Rare in well-resourced settings due to advanced screening protocols.
• Potential pathogens include hepatitis B and C, HIV, HTLV, and bacterial contamination.

Complications from ESA Therapy

Hypertension

• Commonly observed in patients with renal impairment.
• Risk increases with rapid Hb rise or overtreatment.
• May require initiation or escalation of antihypertensive therapy.

Tumour progression

• Some studies link ESAs with enhanced tumour growth in oncology patients.
• Increased mortality noted when ESAs are used during curative-intent cancer treatment.

Pure red cell aplasia

• Rare immune-mediated complication resulting in selective suppression of erythropoiesis.
• Associated with certain ESA formulations; characterised by severe anaemia and reticulocytopenia.

Functional Impairments

Fatigue and muscular inefficiency

• Hallmark symptoms of moderate to severe IDA.
• Substantially impairs daily functioning, physical endurance, and occupational productivity.

Growth delay in children

• Chronic IDA may impair linear growth alongside neurodevelopmental deficits.

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