Beta-Thalassaemia

Genetic and Phenotypic Spectrum

The genetic basis includes both homozygous and heterozygous mutations

• Homozygous or compound heterozygous mutations result in the most severe form, termed beta-thalassaemia major (Cooley anaemia), which is typically transfusion-dependent from infancy.
• Heterozygous mutations (beta-thalassaemia trait or minor) usually cause a mild microcytic anaemia, which is often asymptomatic.
• Compound heterozygosity with other haemoglobin variants, such as haemoglobin E, can result in a clinical syndrome resembling beta-thalassaemia major or intermedia, frequently more severe than either defect alone.

Overall

• Beta-thalassaemia arises from a diverse range of genetic mutations affecting the beta-globin gene, located within a gene cluster on chromosome 11.
• The expression of the beta-globin gene is regulated by an upstream locus control region (LCR).
• Mutations can impact either the gene itself or its regulatory regions, disrupting normal beta-globin synthesis.
• The main mechanisms of disruption include abnormal initiation or termination of transcription, defective RNA splicing or cleavage, nucleotide substitutions, and frameshift mutations.
• These molecular abnormalities lead to significantly reduced or completely absent beta-globin chain production.
• The resulting imbalance in globin chain synthesis causes ineffective erythropoiesis and the clinical spectrum of beta-thalassaemia syndromes.

Types of Mutations and Their Impact

• Beta-zero (β⁰) mutations result in complete absence of beta-globin production, commonly due to nonsense mutations, frameshift mutations, or severe splicing defects.
• Beta-plus (β⁺) mutations allow partial beta-globin production, often caused by mutations in promoter regions or less severe splicing defects.
• Specific mutations and their prevalence are often linked to particular ethnic or geographic groups, reflecting historical founder effects and population migrations.

Inheritance Patterns

• Beta-thalassaemia is most often inherited in an autosomal recessive pattern.
• Heterozygous individuals carry one normal and one mutated allele, typically manifesting as the beta-thalassaemia trait (minor) with mild or asymptomatic microcytic anaemia.
• Homozygous or compound heterozygous individuals (possessing two pathogenic variants) display beta-thalassaemia major or intermedia, which are associated with more severe clinical features.
• Rare dominantly inherited mutations can also result in an intermedia phenotype.

Silent Carriers and Modifying Factors

• Some mutations may cause a silent carrier state, with normal haematological indices and haemoglobin analysis, only detectable by molecular testing.
• Co-inheritance of alpha-globin gene mutations (such as alpha-thalassaemia) or persistence of fetal haemoglobin (HbF) can lessen disease severity by restoring globin chain balance.

Genetic and Phenotypic Diversity

• More than 350 distinct mutations of the beta-globin gene have been identified globally, but a small number account for the majority of cases due to geographic clustering.
• The clinical phenotype is shaped by the combination of beta-globin gene mutations and additional genetic modifiers, resulting in a spectrum ranging from asymptomatic carriers to those with severe, transfusion-dependent anaemia.

Modifying Genetic and Environmental Factors

• Expression of the disease is influenced by factors such as levels of fetal haemoglobin (HbF), co-inheritance of alpha-thalassaemia, and other haemoglobinopathies (e.g., sickle cell trait).
• Higher HbF levels generally correlate with milder disease. Co-inheritance of alpha-thalassaemia can also reduce the imbalance of globin chain synthesis and improve clinical outcomes.
• When sickle cell trait coexists with beta-thalassaemia, the resulting clinical features reflect both disorders.

Ineffective Erythropoiesis and Haemoglobin Switching

• The primary defect in beta-thalassaemia is ineffective erythropoiesis, which emerges as a consequence of reduced or absent synthesis of beta-globin chains.
• Clinically, the disorder becomes apparent only after the normal physiological transition from fetal haemoglobin (HbF, which consists of two alpha and two gamma chains) to adult haemoglobin (HbA, comprising two alpha and two beta chains) that occurs within the first six months after birth.
• The insufficient production of beta-globin chains leads to decreased assembly of functional HbA, resulting in anaemia and tissue hypoxia.
• Ineffective erythropoiesis is defined by increased proliferation but premature death (apoptosis) of erythroid precursors within the bone marrow, which are unable to mature into functional red blood cells.

Alpha/Beta Globin Chain Imbalance and Red Cell Destruction

• A hallmark of beta-thalassaemia is the persistent synthesis of alpha-globin chains despite the deficiency or absence of beta-globin.
• The resulting imbalance causes excess unpaired alpha chains to aggregate and precipitate within erythroid precursors and maturing red cells.
• These alpha chain aggregates are highly toxic, causing oxidative damage and instability of the red cell membrane.
• The damaged erythroid cells undergo intramedullary destruction (ineffective erythropoiesis) and, to a lesser extent, destruction in the peripheral circulation, contributing to profound anaemia.
• The imbalance between alpha and beta chains, and thus the severity of ineffective erythropoiesis, varies according to the specific beta-globin mutations present.

Bone Marrow Response and Extramedullary Haematopoiesis

• Chronic anaemia stimulates the bone marrow to increase erythroid production in an attempt to compensate, leading to marked erythroid hyperplasia.
• Marrow expansion is especially pronounced in the skull, facial bones, long bones, and vertebrae. Radiological changes include widening of the diploë and the classic “hair-on-end” appearance of the skull.
• The overactive marrow may fail to meet the body’s demand for red cells, and extramedullary haematopoiesis develops, particularly in the liver and spleen. This causes hepatosplenomegaly and further alters the normal architecture of these organs.
• Persistent erythroid hyperplasia contributes to characteristic skeletal deformities, dental malocclusion, and increased fracture risk.

Spectrum of Clinical Severity

• Beta-thalassaemia major (homozygous or compound heterozygous states) is characterised by near-total or complete absence of beta-globin synthesis, resulting in severe, transfusion-dependent anaemia from early infancy.
• Beta-thalassaemia intermedia arises when there is partial reduction in beta-globin synthesis, leading to variable degrees of anaemia and a clinical course that may not require regular transfusions.
• Individuals with heterozygous mutations (beta-thalassaemia trait) maintain one functional beta-globin gene and usually have only mild, often subclinical, anaemia.
• Additional mutations affecting other globin genes (such as alpha, delta, or gamma) or genetic modifiers can alter the phenotype, mitigating or exacerbating the severity of chain imbalance and the resultant clinical features.

Iron Regulation and Overload

• Ineffective erythropoiesis and chronic anaemia result in suppression of hepcidin, a liver-derived hormone that regulates iron absorption.
• Downregulation of hepcidin leads to increased intestinal absorption of dietary iron, even in the presence of systemic iron overload.
• In transfusion-dependent patients, repeated red cell transfusions contribute significantly to iron burden.
• Initially, excess iron is stored within the monocyte-macrophage (reticuloendothelial) system, but as stores are saturated, iron is increasingly deposited in parenchymal organs—particularly the liver, heart, pancreas, and various endocrine glands.
• Chronic iron overload leads to hepatic fibrosis and cirrhosis, diabetes mellitus, hypogonadism, hypothyroidism, and—most commonly—cardiac failure, which remains the leading cause of mortality without appropriate chelation therapy.

Oxidative Stress and Additional Pathogenic Mechanisms

• Oxidative stress is a critical component of beta-thalassaemia pathophysiology, as the accumulation of unpaired alpha chains generates excess reactive oxygen species (ROS).
• Normally, antioxidant defences—such as reduced glutathione—neutralise ROS, but in beta-thalassaemia, the balance is overwhelmed, resulting in oxidative damage to red cells, white blood cells, and platelets.
• This increases the risk of haemolysis, recurrent infections (due to impaired leukocyte function), hypercoagulability, and progressive organ dysfunction.
• The combination of ineffective erythropoiesis, iron overload, and oxidative stress causes cumulative tissue damage, which underlies many of the multisystem complications associated with beta-thalassaemia.

Global Distribution and Prevalence

• Beta-thalassaemia is found worldwide, but its highest prevalence is in the Mediterranean, the Middle East, South and Southeast Asia, and southern China.
• Approximately 1.5% of the global population—estimated at 80 to 90 million individuals—are carriers (heterozygotes) for beta-thalassaemia mutations.
• Each year, around 68,000 children are born with beta-thalassaemia major worldwide.
• The disorder is less common in northern Europe and North America; however, migration and population movement have led to increasing prevalence in these regions.
• In the United States, prevalence rates have risen notably in states with high immigrant populations, such as California. Although precise national figures are not available, thalassaemia is increasingly diagnosed due to changing demographics and improved detection.

Regional Patterns and Country-Specific Data

• The highest prevalence rates—up to 10%—are recorded in regions adjacent to the Persian Gulf and Caspian Sea in Iran, with about 20,000 individuals homozygous for the condition and an estimated 3.75 million carriers.
• In India, approximately 10,000 to 20,000 children are born annually with beta-thalassaemia. Premarital screening programmes have significantly reduced the incidence of affected newborns in some regions.
• In Bangladesh, 60,000 to 70,000 individuals are affected by thalassaemia of varying severity, with around 2,500 new cases of thalassaemia major reported annually.
• Compound heterozygosity with haemoglobin E is common in Thailand, Laos, Cambodia, and southern China, resulting in a phenotype similar to beta-thalassaemia major or intermedia. The frequency of the haemoglobin E gene is particularly high in these populations.
• Over 90% of children born with clinically significant beta-thalassaemia syndromes are from Asia, India, and the Middle East, many involving haemoglobin E mutations.

Genetic Factors and Adaptive Advantage

• Mutations in the beta-globin gene cluster are especially frequent in the Mediterranean, Middle East, northern Africa, India, and most of Southeast Asia.
• These mutations likely arose spontaneously but have been retained at high frequencies because heterozygous carrier states confer some protection against severe malaria, particularly Plasmodium falciparum infection.
• Elevated levels of fetal haemoglobin (HbF) in individuals with beta-thalassaemia and related haemoglobinopathies are thought to inhibit the development of the malarial parasite, though the precise mechanisms are not fully understood.
• Genetic drift and population history also contribute to the distribution and persistence of thalassaemia mutations.

Population Demographics and Age Factors

• Beta-thalassaemia trait and disease occur in all ethnicities, but they are especially common among populations of Mediterranean, African, and Southeast Asian descent.
• Mediterranean populations most frequently possess mutations that cause abnormal splicing or premature translation termination; Southeast Asian populations often have concurrent haemoglobin E or alpha-thalassaemia mutations.
• Africans with thalassaemia are more likely to have genetic defects associated with alpha-thalassaemia rather than classic beta-thalassaemia.
• The clinical manifestations of beta-thalassaemia typically do not appear until the physiological transition from fetal haemoglobin to adult haemoglobin is completed, usually by six months of age.

Epidemiological and Genetic Risk Factors

Country of origin or ancestry

• High prevalence in individuals from the Mediterranean, Middle East, South Asia, Southeast Asia, northern Africa, and southern China.

Family history

• Enquire about relatives with beta-thalassaemia major or trait, need for regular blood transfusions, anaemia unresponsive to iron therapy, or known carrier status.
• Family history of similar clinical features may be present due to the autosomal recessive inheritance pattern.

Consanguinity

• Increased risk if parents are related.

Age of Onset and Initial Symptoms

Timing

• Symptoms of beta-thalassaemia major typically begin after 6 months of age, following the physiological transition from fetal haemoglobin (HbF) to adult haemoglobin (HbA).

Presentation in minor/trait

• Often asymptomatic or may present with mild anaemia, discovered incidentally.

Thalassaemia intermedia

• Onset and severity of symptoms can be variable; not transfusion dependent but may exhibit mild to moderate anaemia.

Symptoms Related to Anaemia and Ineffective Erythropoiesis

Pallor

• Persistent and pronounced, affecting conjunctivae, nail beds, and mucous membranes.
• More severe in beta-thalassaemia major and intermedia; milder or absent in trait.

Lethargy and fatigue

• Resulting from moderate to severe anaemia.

Shortness of breath and irritability

• Common in infants and young children with significant anaemia.

Failure to thrive (FTT)

• Poor growth, failure to gain weight, and low height/weight percentiles, especially in untreated or inadequately transfused children.

Progressive abdominal distension

• Due to hepatosplenomegaly, described as increasing over time by caregivers.

Skeletal and Growth Abnormalities

History of bone pain or deformity

• Bony changes due to marrow expansion, especially in the skull, face, and long bones.

Craniofacial abnormalities

• Frontal bossing, prominent cheekbones, depressed nasal bridge, maxillary hypertrophy (chipmunk facies), and dental malocclusion.

Spinal abnormalities

• Back pain, spinal changes, or a history of vertebral deformity.

Large head

• Frontal and parietal bossing may be noted, especially in severe cases.

Other Systemic Manifestations

Jaundice

• Chronic or intermittent, more pronounced in severe cases or with concurrent haemoglobin E heterozygosity.

Dark urine

• May be reported due to haemolysis.

Gallstone formation

• History of gallstones, often due to chronic haemolysis.

Skin changes

• Brown discolouration or leg ulcers in poorly managed cases.

Infection risk

• Frequent fevers or history of recurrent infections, particularly after splenectomy.

Cardiac, Hepatic, and Endocrine Complications

History of cardiac symptoms

• Palpitations, exertional dyspnoea, or documented arrhythmias, possibly linked to chronic anaemia or iron overload.

Abdominal symptoms

• Right upper quadrant pain or history suggestive of hepatomegaly, gallbladder disease, or splenomegaly.

Delayed puberty or growth failure

• Endocrine dysfunction secondary to iron overload, particularly in adolescents.

Transfusion and Iron Overload History

Blood transfusions

• Age of initiation, frequency, and adequacy of transfusion support.

Iron chelation

• History of iron chelation therapy, compliance, and complications.

Symptoms suggestive of iron overload

• Cardiac issues, diabetes, or hypothyroidism.

Risk Factors for Disease Severity

Positive family history

• If both parents are carriers, the risk for an affected child is 25% per pregnancy.

Ethnic background

• Some mutations are more severe or more common in certain populations.

History of consanguinity

• Increased likelihood of homozygous mutations and severe disease.

General Appearance

• Patients with beta-thalassaemia trait (minor) usually have no abnormal findings on examination.
• In beta-thalassaemia major and some cases of intermedia, physical findings reflect the consequences of chronic anaemia, ineffective erythropoiesis, extramedullary haematopoiesis, and iron overload.

Skin and Mucous Membranes

 Pallor of the skin, conjunctivae, nail beds, and mucous membranes

• Due to anaemia.

Jaundice (icterus), particularly scleral icterus

• Result of ongoing haemolysis and hyperbilirubinaemia.

Brown discolouration of the skin

• Seen in chronic, poorly transfused cases.

Skin ulceration on the extremities

• May be seen in severe or poorly managed disease.

Facial and Craniofacial Features

 Frontal bossing and parietal bossing

• Gives a prominent forehead.

Maxillary hypertrophy and prominent cheekbones (chipmunk facies)

• Caused by marrow expansion in the facial bones.

Depressed nasal bridge and malocclusion

• Misaligned or widely spaced teeth due to maxillary enlargement.

Large head appearance

• Consequence of cranial marrow expansion.

Dental abnormalities and increased rate of dental caries

• Potentially related to decreased salivary flow and protection.

Skeletal System

 Long bone abnormalities and deformities

• Result from chronic marrow expansion.

Spinal changes

• Includes osteopenia, vertebral deformity, and in severe cases, extrusion of haematopoietic tissue from vertebral bodies.

Increased risk of fractures

• Due to bone fragility.

Knock knees (genu valgum)

• May be seen in chronically untreated individuals.

Abdominal Examination

 Hepatosplenomegaly

• Enlargement of the liver and spleen is typical, reflecting extramedullary haematopoiesis and increased red cell destruction.

Abdominal distension

• Palpable spleen and liver, more pronounced with increasing severity of anaemia.

Gallbladder

• May be palpable or tender if gallstones (cholelithiasis) are present due to chronic haemolysis.

Signs of chronic liver disease

• May be seen in those with iron overload or transfusion-acquired hepatitis.

Cardiac Findings

 Tachycardia and possible signs of heart failure

• Gallop rhythm, displaced apex beat, peripheral oedema may be observed due to chronic anaemia or iron overload.

Arrhythmias

• Such as atrial fibrillation, particularly in those with cardiac iron deposition.

Endocrine and Other Systemic Manifestations

 Delayed puberty, underdeveloped secondary sexual characteristics, or growth failure

• Apparent in children or adolescents with iron overload.

Testicular or thyroid atrophy and signs of diabetes mellitus

• Observed in advanced iron overload.

Gallbladder and Other Findings

 Jaundice and history of gallstones

• Evident especially in those with chronic haemolysis.

Portal hypertension or cirrhosis

• May be detected in advanced liver involvement.

Initial Approach and Clinical Considerations

• Diagnosis of beta-thalassaemia major is often suspected in infants who develop severe anaemia a few months after birth, as levels of fetal haemoglobin (HbF) fall and adult haemoglobin (HbA) fails to rise.
• The clinical context, including age, ethnic background, and family history, is crucial for early suspicion. In some instances, increased erythroblasts in peripheral blood may be mistaken for leukaemia or myelodysplasia.

Laboratory Investigations

Full Blood Count (FBC) and Reticulocyte Count

• Reveals microcytic, hypochromic anaemia; the degree is usually more severe in beta-thalassaemia major.
• White blood cell and platelet counts may be mildly elevated due to generalised marrow hyperactivity but decrease with significant splenomegaly.
• Reticulocyte count is typically elevated, reflecting increased (but ineffective) erythropoietic activity.

Peripheral Blood Film

• Shows microcytosis, hypochromia, anisopoikilocytosis, target cells, teardrop cells, nucleated red blood cells, and basophilic stippling.
• In severe cases, Heinz bodies (denatured haemoglobin inclusions) may be visible.
• Beta-thalassaemia minor shows mild microcytosis, target cells, and often a normal red cell count; major shows marked abnormalities.

Haemoglobin Analysis (Electrophoresis or HPLC)

• Beta-thalassaemia trait: Mostly HbA with elevated HbA2 (4–6%) and mild elevation of HbF.
• Beta-thalassaemia major: Minimal or absent HbA, markedly elevated HbF (often >90%), and elevated HbA2 (5–8%).
• Beta-thalassaemia intermedia: Variable reduction of HbA with elevated HbF and HbA2.
• Newborn screening using haemoglobin analysis is standard in many developed countries.
• In compound heterozygotes (e.g., HbE/beta-thalassaemia), patterns of both HbE and HbF are seen.

Iron Studies

• Serum iron, transferrin, and ferritin levels help exclude iron deficiency as a cause of microcytic anaemia.
• Iron overload may be evident, especially in transfusion-dependent individuals.

Markers of Haemolysis

• Indirect hyperbilirubinaemia, elevated lactate dehydrogenase (LDH), and low haptoglobin indicate ongoing haemolysis.
• Liver function tests (LFTs) may show mild to moderate unconjugated hyperbilirubinaemia.

Free Erythrocyte Porphyrin (FEP)

• FEP is normal in beta-thalassaemia but increased in iron deficiency or lead poisoning; useful for distinguishing causes of microcytosis.

Radiological and Imaging Investigations

Plain Radiographs

• Skull: “Hair-on-end” appearance from expanded marrow spaces in the cranial vault.
• Maxillofacial bones: Classic “chicken wire” or lattice pattern due to marrow hyperplasia; non-pneumatisation of maxillary sinuses.
• Long bones and vertebrae: Osteopenia, cortical thinning, and widening of medullary spaces; increased risk of pathological fractures.
• Vertebral bodies: May show a ground-glass appearance.

Abdominal Ultrasound

• Hepatosplenomegaly of varying degree, depending on the severity and duration of anaemia.
• Detection of gallstones or gallbladder sludge, especially in older patients with chronic haemolysis.

Magnetic Resonance Imaging (MRI)

• MRI of the liver, heart, and brain to assess tissue iron deposition in those with suspected iron overload.
• Cardiac MRI with T2* mapping is the standard for quantifying myocardial iron; a T2* value <10 ms is strongly predictive of heart failure.

Additional Diagnostic Tests

Genetic Testing

• Molecular diagnosis confirms the specific beta-globin mutations and is useful for carrier detection, family counselling, and prenatal diagnosis.

Prenatal Diagnosis

• Performed via chorionic villus sampling (8–10 weeks) or amniocentesis (14–20 weeks) for at-risk pregnancies.
• DNA is analysed using polymerase chain reaction (PCR) and oligonucleotide probe panels.
• Fetal blood sampling for globin chain synthesis (18–22 weeks) may be performed but is less reliable than DNA analysis.

Bone Marrow Examination

• May be required to exclude other causes of microcytic anaemia (e.g., sideroblastic anaemia, leukaemia).

HLA Typing

• Performed if haematopoietic stem cell transplantation is being considered.

Alpha-Thalassaemia

• Alpha-thalassaemia major presents as hydrops fetalis and is typically identified at birth or prenatally, often in individuals of Chinese ancestry.
• Haemoglobin H disease can mimic beta-thalassaemia intermedia with chronic, moderate-to-severe microcytic anaemia, jaundice, and gallstones.
• Haemoglobin analysis reveals haemoglobin H (β₄ tetramers) and, in most cases, some haemoglobin A, distinguishing it from beta-thalassaemia.

Iron Deficiency Anaemia

• The clinical presentation of mild iron deficiency anaemia overlaps with beta-thalassaemia trait (mild anaemia, pallor).
• Laboratory distinction: Serum iron and transferrin saturation are low in iron deficiency but typically normal in beta-thalassaemia trait.
• Red cell distribution width (RDW) is usually elevated in iron deficiency but normal in thalassaemia.
• The Mentzer index (>13 suggests iron deficiency; <13 supports thalassaemia trait).
• Haemoglobin electrophoresis or HPLC confirms diagnosis by demonstrating elevated HbA2 and/or HbF in beta-thalassaemia trait.

Sideroblastic Anaemia

• Distinguished by the presence of ring sideroblasts in the bone marrow and increased erythrocyte protoporphyrin.
• Anaemia is often microcytic or dimorphic.
• Iron studies may show increased serum iron and ferritin.

Anaemia of Chronic Disease (ACD) and Renal Failure

• Typically presents as normocytic or mildly microcytic anaemia.
• Associated with chronic inflammatory conditions, infections, autoimmune disorders, or chronic kidney disease.
• Serum iron is low, total iron-binding capacity is low or normal, and ferritin is normal or increased.
• Haemoglobin analysis is normal in ACD; in beta-thalassaemia, there is an abnormal haemoglobin pattern.

Congenital Dyserythropoietic Anaemia (CDA)

• Presents with anaemia, but usually macrocytic rather than microcytic.
• May be suspected in the absence of family history or typical ethnic background.
• Haemoglobin analysis usually reveals normal or elevated HbF but most haemoglobin is HbA.

Pyruvate Kinase (PK) Deficiency

• Presents in the neonatal period with severe, prolonged jaundice and profound anaemia.
• The peripheral blood smear shows many nucleated red cells; fewer are seen in beta-thalassaemia.
• Haemoglobin analysis shows a predominance of HbA, not the pattern seen in beta-thalassaemia.

Haemolytic Anaemia (Other Causes)

• Can be caused by autoantibodies, drugs, or malignancy
• Anaemia is normocytic with elevated MCHC, whereas beta-thalassaemia is microcytic with low MCHC.
• Direct antiglobulin test (Coombs’ test) distinguishes immune-mediated haemolysis.

Other Haemoglobinopathies

• Haemoglobin E trait and compound heterozygous states (e.g., HbE/β-thalassaemia) can have overlapping clinical features.
• Haemoglobin electrophoresis and family studies are crucial for accurate diagnosis.

Distinguishing Features in Laboratory and Clinical Assessment

• Family history and ethnicity help raise suspicion for thalassaemia syndromes.
• Peripheral blood film and haemoglobin analysis are fundamental for differentiating microcytic anaemias.
• Iron studies (serum ferritin, transferrin saturation) are essential to rule out iron deficiency.
• Bone marrow examination may be necessary if there is diagnostic uncertainty or suspicion for sideroblastic anaemia or CDA.
• Direct antiglobulin test (Coombs’) helps differentiate immune from non-immune causes of haemolysis.

General Principles and Genetic Counselling

• All patients—regardless of phenotype—should receive genetic counselling, including information about inheritance, risk to offspring, and reproductive options.

Beta-Thalassaemia Trait (Minor)

• Generally asymptomatic; do not require regular transfusions or ongoing medical management.
• Iron supplementation should only be given if iron deficiency is confirmed, as inappropriate supplementation may lead to iron overload.
• Carrier status should be documented, and reproductive advice provided.

Beta-Thalassaemia Intermedia

• Most patients do not need regular transfusions and are classified as having non-transfusion-dependent thalassaemia (NTDT).
• Anaemia may worsen during stress, infection, or surgery, at which times temporary transfusion support may be needed.
• Splenomegaly is common; splenectomy may be indicated for symptomatic hypersplenism or excessive transfusion requirements.
• A subgroup may become transfusion-dependent due to worsening ineffective erythropoiesis, impaired growth, skeletal deformities, or increasing anaemia. These individuals are managed as for beta-thalassaemia major, with regular transfusions and iron chelation.

Beta-Thalassaemia Major

• Lifelong regular packed red cell transfusions, typically started in infancy, aim to maintain haemoglobin above 95–100 g/L (9.5–10 g/dL) to prevent anaemia-related complications, facilitate normal growth, and suppress ineffective erythropoiesis.
• Transfusion intervals are commonly every 3–4 weeks in childhood, increasing in frequency as weight and clinical needs dictate. Adults often receive 2 units every 2–3 weeks.
• Leuko-reduced, phenotype-matched packed red cells are preferred to reduce alloimmunisation and transfusion reactions.
• All transfusion-dependent patients require close monitoring for iron overload and appropriate iron chelation therapy.

Iron Overload: Assessment and Chelation

Monitoring iron burden

• Liver iron concentration (LIC) by MRI is the standard for assessing total body iron. LIC >7 mg Fe/g dry weight increases risk of organ complications; the ideal range is 3–7 mg Fe/g.
• Cardiac iron burden should be evaluated by cardiac MRI (T2*), as liver and cardiac iron do not correlate well; T2* <10 ms indicates high risk of cardiac dysfunction.
• Serum ferritin is monitored but is less reliable as a sole marker.

Chelation therapy

• Initiated in patients with LIC >5 mg Fe/g dry weight or after 6–8 transfusions of 15 mL/kg.
• Three main chelators:
  • Desferrioxamine: Parenteral, short half-life, first choice in many settings; requires regular monitoring for ototoxicity and visual disturbances.
  • Deferasirox: Oral, long half-life, effective for both transfusion-dependent and NTDT patients; potential hepatic and renal toxicity.
  • Deferiprone: Oral, short half-life, effective for myocardial iron removal; risk of agranulocytosis and arthropathy, so requires frequent blood count monitoring.
• Chelator choice and intensity are guided by iron burden, patient age, organ function, adherence, and side effect profile. Combination therapy may be indicated for severe or refractory iron overload.
• Intensive chelation may be needed for those with high LIC or cardiac iron (T2* <10 ms), using intravenous desferrioxamine and/or combined oral agents.

Other Disease-Modifying Interventions

Allogeneic Haematopoietic Stem Cell Transplantation

• The only curative therapy for beta-thalassaemia.
• Best outcomes are in children with well-matched sibling donors, performed before significant iron overload or organ damage develops.
• Prognosis is stratified by iron burden, liver size, and presence of fibrosis (Pesaro classification).

Splenectomy

• Considered for massive splenomegaly, hypersplenism causing increased transfusion requirements, or symptomatic cytopenias.
• Reduces transfusion volume by 20–30%.
• Increases infection and thromboembolic risks; lifelong prophylactic antibiotics and vaccinations (against pneumococcus, meningococcus, and Haemophilus influenzae) are essential.

Supportive Measures

• Monitor and address endocrine, cardiac, and hepatic complications of iron overload.
• Provide psychosocial support and regular follow-up with a multidisciplinary team.

Special Considerations

• Avoid unnecessary iron supplementation in non-deficient individuals.
• Genetic screening and counselling for at-risk family members, especially in regions with high prevalence.
• Early identification and management of iron overload, endocrine complications, and psychosocial issues are key to optimising outcomes.

Beta-Thalassaemia Trait (Minor)

• Individuals with beta-thalassaemia trait typically have a normal life expectancy.
• Most remain asymptomatic, presenting only with mild microcytic anaemia that does not result in significant morbidity or mortality.
• No transfusion support or regular medical intervention is required, provided that iron supplementation is avoided unless true iron deficiency is documented.

Beta-Thalassaemia Intermedia

• Prognosis is variable and largely depends on the degree of anaemia, complications of iron overload, and the management of secondary issues.
• Some individuals develop significant cosmetic changes (e.g., craniofacial and skeletal deformities) that can affect quality of life.
• Morbidity may arise from iron overload, which can occur even in the absence of transfusions due to increased gastrointestinal absorption; complications include hepatic, endocrine, and cardiac dysfunction.
• Co-inherited genetic modifiers (e.g., hereditary haemochromatosis, Gilbert’s syndrome, or thrombophilic mutations) can influence disease severity and risk for complications.
• Those who require transfusions face the same long-term risks as beta-thalassaemia major, including complications related to iron overload.

Beta-Thalassaemia Major

• If untreated, beta-thalassaemia major is fatal in early childhood, with death typically resulting from heart failure due to severe anaemia.
• With regular transfusions and effective iron chelation therapy, life expectancy and quality of life have improved dramatically over recent decades.
• Median survival has risen from 12–17 years in the 1960s–70s to near-normal lifespan in well-managed patients born in the past 20 years.
• The leading cause of death in treated patients is cardiac failure secondary to iron-induced cardiomyopathy, particularly when chelation therapy is inadequate.
• Additional morbidity arises from complications such as infections (especially post-splenectomy), endocrinopathies (e.g., diabetes, hypogonadism), liver dysfunction, and increased risk of thromboembolic events.

Morbidity and Mortality: Key Determinants

• The primary determinants of prognosis in beta-thalassaemia major are adherence to hypertransfusion protocols and lifelong iron chelation.
• Improved blood product screening, interprofessional management, and heightened awareness have further enhanced survival.
• Curative treatment is possible through allogeneic stem cell transplantation, ideally performed early before organ damage ensues.
• Neurological complications, though usually subclinical, may include cognitive impairment, abnormal evoked potentials, cerebrovascular disease, and peripheral neuropathy.

Global Trends and Improvements

• Advances in management have led to significant improvements in median and overall survival globally, with countries implementing multidisciplinary care, enhanced patient education, and broader access to effective therapies.
• For example, in Palestine, the average lifespan for affected patients increased from 7–8 years in 1996 to 19–20 years in 2015. In the UK, the mortality rate for thalassaemia fell sharply with modern therapy and coordinated care.
• Overall, the outlook for children born today with beta-thalassaemia major is increasingly optimistic, provided they have access to comprehensive care.

Transfusion-Related Complications

Acute Reactions

• These may include severe allergic reactions, septic shock, and acute haemolysis.
• Prompt recognition and management are critical.

Chronic Complications

• Iron Overload: This is the most significant long-term complication in transfusion-dependent patients.
  • Iron progressively accumulates, as the body cannot actively excrete the iron from transfused red cells.
  • The excess iron deposits primarily in the heart, liver, pancreas, and endocrine glands.
  • Cardiac iron overload leads to cardiomyopathy, arrhythmias, and is the leading cause of mortality if not addressed.
  • Liver iron overload results in fibrosis, cirrhosis, and risk of hepatocellular carcinoma.
  • Endocrine complications include diabetes, hypogonadism, hypothyroidism, and hypoparathyroidism.
  • Skin pigmentation (bronze skin) and growth/developmental delays may also occur.
  • Prevention: Iron chelation therapy is essential to prevent and manage these effects.
• Alloimmunisation:
  • Chronic transfusion can result in the development of antibodies against transfused red blood cell antigens (such as ABO, Rh, Kell).
  • This makes future transfusions challenging.
  • The use of phenotype-matched, screened blood products can help reduce this risk.
• Transfusion-Transmitted Infections
  • Despite improved screening, patients remain at risk for viral (HBV, HCV, HIV), bacterial, and parasitic infections.
  • This is especially true in regions with limited resources.
  • Adherence to guidelines on donor screening and selection reduces this risk.

Haematological and Coagulation Complications

Thrombotic/Hypercoagulable State

• Patients with beta-thalassaemia, especially those who are splenectomised or undertreated, have an increased risk of thrombosis.
• These include deep vein thrombosis, pulmonary embolism, and cerebrovascular events.

Aplastic Crisis

• Usually triggered by parvovirus B19 infection.
• Occurs in patients with high red cell turnover and limited marrow reserve.
• Results in a sudden drop in haemoglobin.

Musculoskeletal and Dental Complications

Skeletal Abnormalities

• Chronic marrow expansion leads to osteopenia, osteoporosis, bone pain, deformities, and increased fracture risk.
• Craniofacial changes can lead to dental malocclusion and misaligned teeth.

Arthropathy

• Iron deposition in joints can cause arthropathy, although this is less common than other complications.

Dental Problems

• Maxillary hypertrophy, dental crowding, and increased risk of tooth decay may occur.
• Caused by facial bone expansion and reduced salivary protection.

Endocrine and Metabolic Complications

Delayed Growth and Puberty

• Iron deposition in the anterior pituitary results in growth failure, delayed or arrested puberty, and infertility.

Diabetes Mellitus

• Pancreatic iron deposition impairs insulin secretion and glucose tolerance.

Thyroid and Parathyroid Dysfunction

• Hypothyroidism and hypoparathyroidism may arise.
• These contribute to further metabolic complications and risk of osteoporosis.

Other Chronic Complications

Gallstones (Cholelithiasis)

• Chronic haemolysis and elevated bilirubin increase the risk of gallstone formation.
• Particularly common in beta-thalassaemia intermedia.

Skin Complications

• Hyperpigmentation and bronzing are caused by iron deposition in the skin.

Leg Ulcers

• Chronic hypoxia, anaemia, and vascular changes may result in chronic, slow-healing ulcers.
• Especially affect the lower limbs.

Cord Compression

• Extramedullary haematopoietic masses, particularly in the spine, may cause compressive symptoms.

Gout

• The risk of secondary gout and pseudoxanthoma elasticum is higher, particularly in intermedia.

Infection Risk after Splenectomy

• Splenectomised patients are more susceptible to encapsulated bacterial infections.
• May develop pulmonary hypertension and thromboembolic events due to thrombocytosis.
• Lifelong prophylactic antibiotics and appropriate vaccinations are crucial.

Cardiovascular Complications

Arrhythmias and Heart Failure

• Iron-induced cardiac dysfunction can present as asymptomatic arrhythmias.
• May progress to overt heart failure.
• Regular cardiac assessment and MRI for iron overload are recommended for early intervention.

Liver and Hepatobiliary Complications

Hepatomegaly, Dysfunction, and Cirrhosis

• With mild iron overload, the liver remains normal in size and function.
• Progressive iron loading leads to hepatomegaly, abnormal liver function, fibrosis, cirrhosis, and risk of hepatocellular carcinoma.

Transfusion-acquired Hepatitis

• Patients exposed to unscreened blood products may develop hepatitis B or C.
• Requires specialist follow-up and treatment.

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